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1
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Ferreira YAM, Santamarina AB, Mennitti LV, de Souza EA, Prado CM, Pisani LP. Unsaturated fatty acids enhance mitochondrial function and PGC1-α expression in brown adipose tissue of obese mice on a low-carbohydrate diet. J Nutr Biochem 2025; 140:109873. [PMID: 39986635 DOI: 10.1016/j.jnutbio.2025.109873] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2024] [Revised: 12/06/2024] [Accepted: 02/15/2025] [Indexed: 02/24/2025]
Abstract
Brown adipose tissue (BAT) exhibits greater resilience against inflammation compared to white adipose tissue. However, chronic consumption of a high-fat diet can render brown adipocytes vulnerable to proinflammatory conditions, leading to a decline in their thermogenic capacity and subsequent dysfunction. The analysis of the effects of type fatty acids intake must be important in the context of the dietary pattern and obesity. This study aims to investigate the impact of a low-carbohydrate/high-fat diet, enriched with different types of fatty acids, on mitochondrial activity on brown adipose tissue in obese mice. Male mice were allocated into different dietary groups: a control diet (CTL), and a high-fat diet (HFD) for a duration of 10 weeks to induce obesity. Subsequently, the HFD group was subdivided into the following categories for an additional 6 weeks: HFD with a low carbohydrate content enriched with saturated fatty acids; HFD with a low carbohydrate content enriched with fish oil; HFD with a low carbohydrate content enriched with soybean oil; and HFD with a low carbohydrate content enriched with olive oil. The findings indicated that in comparison to a low-carbohydrate diet rich in saturated fats, diets rich in unsaturated fatty acids-particularly omega-6 (n-6) and omega-9 (n-9)-resulted in elevated expression of UCP1, a marker of BAT activity. Moreover, there was an increase in the expression of PGC1-α, a protein involved in mitochondrial biogenesis, and enhanced functionality of the oxidative phosphorylation system within BAT mitochondria. These results suggest that n-6 and n-9 fatty acids may confer greater benefits to BAT functionality than saturated fats within the context of a low-carbohydrate diet. Therefore, this study revealed some molecular components that mediate BAT mitochondria function influenced by different fatty acids in a low carbohydrate diet, making it an important therapeutic target in obesity.
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Affiliation(s)
- Yasmin Alaby Martins Ferreira
- Department of Biosciences, Institute of Health and Science, Federal University of São Paulo (UNIFESP), Santos, São Paulo, Brazil
| | - Aline Boveto Santamarina
- Department of Biosciences, Institute of Health and Science, Federal University of São Paulo (UNIFESP), Santos, São Paulo, Brazil
| | - Laís Vales Mennitti
- Metabolic Research Laboratories and MRC Metabolic Diseases Unit, University of Cambridge, Cambridge, United Kingdom
| | - Esther Alves de Souza
- Department of Biosciences, Institute of Health and Science, Federal University of São Paulo (UNIFESP), Santos, São Paulo, Brazil
| | - Carla Maximo Prado
- Department of Biosciences, Institute of Health and Science, Federal University of São Paulo (UNIFESP), Santos, São Paulo, Brazil
| | - Luciana Pellegrini Pisani
- Department of Biosciences, Institute of Health and Science, Federal University of São Paulo (UNIFESP), Santos, São Paulo, Brazil.
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2
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Asimakidou E, Saipuljumri EN, Lo CH, Zeng J. Role of metabolic dysfunction and inflammation along the liver-brain axis in animal models with obesity-induced neurodegeneration. Neural Regen Res 2025; 20:1069-1076. [PMID: 38989938 PMCID: PMC11438328 DOI: 10.4103/nrr.nrr-d-23-01770] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2023] [Accepted: 04/26/2024] [Indexed: 07/12/2024] Open
Abstract
The interaction between metabolic dysfunction and inflammation is central to the development of neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. Obesity-related conditions like type 2 diabetes and non-alcoholic fatty liver disease exacerbate this relationship. Peripheral lipid accumulation, particularly in the liver, initiates a cascade of inflammatory processes that extend to the brain, influencing critical metabolic regulatory regions. Ceramide and palmitate, key lipid components, along with lipid transporters lipocalin-2 and apolipoprotein E, contribute to neuroinflammation by disrupting blood-brain barrier integrity and promoting gliosis. Peripheral insulin resistance further exacerbates brain insulin resistance and neuroinflammation. Preclinical interventions targeting peripheral lipid metabolism and insulin signaling pathways have shown promise in reducing neuroinflammation in animal models. However, translating these findings to clinical practice requires further investigation into human subjects. In conclusion, metabolic dysfunction, peripheral inflammation, and insulin resistance are integral to neuroinflammation and neurodegeneration. Understanding these complex mechanisms holds potential for identifying novel therapeutic targets and improving outcomes for neurodegenerative diseases.
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Affiliation(s)
- Evridiki Asimakidou
- Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK
| | - Eka Norfaishanty Saipuljumri
- School of Applied Science, Republic Polytechnic, Singapore, Singapore
- Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore
| | - Chih Hung Lo
- Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore
| | - Jialiu Zeng
- Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore
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3
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Sasaki T, Sugiyama M, Kuno M, Miyata T, Kobayashi T, Yasuda Y, Onoue T, Takagi H, Hagiwara D, Iwama S, Suga H, Banno R, Arima H. Voluntary exercise suppresses inflammation and improves insulin resistance in the arcuate nucleus and ventral tegmental area in mice on a high-fat diet. Physiol Behav 2024; 287:114703. [PMID: 39342979 DOI: 10.1016/j.physbeh.2024.114703] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2024] [Revised: 09/10/2024] [Accepted: 09/20/2024] [Indexed: 10/01/2024]
Abstract
A high-fat diet (HFD) causes inflammation with an increase in microglial activity in the hypothalamic arcuate nucleus (ARC) and ventral tegmental area (VTA), resulting in insulin resistance in both regions. This leads to a deterioration in glucose and energy metabolism. The effect of voluntary exercise on HFD-induced inflammation in the central nervous system (CNS) remains unclear. To clarify the effects of voluntary exercise on the CNS, 8-week-old male C57BL6 mice were fed a chow diet (CHD) or HFD for 4 weeks; each group was further divided into running exercise (EX+) on a wheel and no exercise (EX-) groups. The expression of the inflammatory cytokine, tumor necrosis factor alpha (TNFα), in the ARC and VTA was significantly increased in the HFD/EX- group, with an increase of microglial activity noted, compared to the CHD/EX- group. The expression of TNFα was significantly suppressed, with a decrease of microglial activity, in the HFD/EX+ compared to HFD/EX- group. Insulin resistance in the ARC and VTA was improved with the suppression of TNFα expression. The HFD/EX- group showed significant weight gain and impaired glucose metabolism compared to the CHD/EX- group. The HFD/EX+ group showed an improvement in glucose and energy metabolism compared to the HFD/EX- group. In addition, voluntary wheel running suppressed HFD-induced inflammation in the ARC, with a decrease in microglial activity observed independently of weight changes. Our data suggest that voluntary exercise prevents obesity and improves glucose metabolism by suppressing inflammation in the ARC and VTA under HFD conditions.
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Affiliation(s)
- Tomoyuki Sasaki
- Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan
| | - Mariko Sugiyama
- Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.
| | - Mitsuhiro Kuno
- Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan
| | - Takashi Miyata
- Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan
| | - Tomoko Kobayashi
- Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan
| | - Yoshinori Yasuda
- Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan
| | - Takeshi Onoue
- Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan
| | - Hiroshi Takagi
- Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan; Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Nagoya 467-8602, Japan
| | - Daisuke Hagiwara
- Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan
| | - Shintaro Iwama
- Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan
| | - Hidetaka Suga
- Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan
| | - Ryoichi Banno
- Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan; Research Center of Health, Physical Fitness and Sports, Nagoya University, Nagoya 464-8601, Japan
| | - Hiroshi Arima
- Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan
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4
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Zhang Y, Wang R, Liu T, Wang R. Exercise as a Therapeutic Strategy for Obesity: Central and Peripheral Mechanisms. Metabolites 2024; 14:589. [PMID: 39590824 PMCID: PMC11596326 DOI: 10.3390/metabo14110589] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2024] [Revised: 10/25/2024] [Accepted: 10/28/2024] [Indexed: 11/28/2024] Open
Abstract
Obesity is a complex, multifactorial condition involving excessive fat accumulation due to an imbalance between energy intake and expenditure, with its global prevalence steadily rising. This condition significantly increases the risk of chronic diseases, including sarcopenia, type 2 diabetes, and cardiovascular diseases, highlighting the need for effective interventions. Exercise has emerged as a potent non-pharmacological approach to combat obesity, targeting both central and peripheral mechanisms that regulate metabolism, energy expenditure, and neurological functions. In the central nervous system, exercise influences appetite, mood, and cognitive functions by modulating the reward system and regulating appetite-controlling hormones to manage energy intake. Concurrently, exercise promotes thermogenesis in adipose tissue and regulates endocrine path-ways and key metabolic organs, such as skeletal muscle and the liver, to enhance fat oxidation and support energy balance. Despite advances in understanding exercise's role in obesity, the precise interaction between the neurobiological and peripheral metabolic pathways remains underexplored, particularly in public health strategies. A better understanding of these interactions could inform more comprehensive obesity management approaches by addressing both central nervous system influences on behavior and peripheral metabolic regulation. This review synthesizes recent insights into these roles, highlighting potential therapeutic strategies targeting both systems for more effective obesity interventions.
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Affiliation(s)
- Yiyin Zhang
- School of Exercise and Health, Shanghai University of Sport, Shanghai 200438, China; (Y.Z.); (R.W.)
| | - Ruwen Wang
- School of Exercise and Health, Shanghai University of Sport, Shanghai 200438, China; (Y.Z.); (R.W.)
| | - Tiemin Liu
- State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai 200433, China
| | - Ru Wang
- School of Exercise and Health, Shanghai University of Sport, Shanghai 200438, China; (Y.Z.); (R.W.)
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5
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Beddows CA, Shi F, Horton AL, Dalal S, Zhang P, Ling CC, Yong VW, Loh K, Cho E, Karagiannis C, Rose AJ, Montgomery MK, Gregorevic P, Watt MJ, Packer NH, Parker BL, Brown RM, Moh ESX, Dodd GT. Pathogenic hypothalamic extracellular matrix promotes metabolic disease. Nature 2024; 633:914-922. [PMID: 39294371 PMCID: PMC11424483 DOI: 10.1038/s41586-024-07922-y] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2022] [Accepted: 08/07/2024] [Indexed: 09/20/2024]
Abstract
Metabolic diseases such as obesity and type 2 diabetes are marked by insulin resistance1,2. Cells within the arcuate nucleus of the hypothalamus (ARC), which are crucial for regulating metabolism, become insulin resistant during the progression of metabolic disease3-8, but these mechanisms are not fully understood. Here we investigated the role of a specialized chondroitin sulfate proteoglycan extracellular matrix, termed a perineuronal net, which surrounds ARC neurons. In metabolic disease, the perineuronal net of the ARC becomes augmented and remodelled, driving insulin resistance and metabolic dysfunction. Disruption of the perineuronal net in obese mice, either enzymatically or with small molecules, improves insulin access to the brain, reversing neuronal insulin resistance and enhancing metabolic health. Our findings identify ARC extracellular matrix remodelling as a fundamental mechanism driving metabolic diseases.
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Affiliation(s)
- Cait A Beddows
- Department of Anatomy and Physiology, The University of Melbourne, Melbourne, Victoria, Australia
| | - Feiyue Shi
- Department of Anatomy and Physiology, The University of Melbourne, Melbourne, Victoria, Australia
| | - Anna L Horton
- Department of Biochemistry and Pharmacology, The University of Melbourne, Melbourne, Victoria, Australia
- Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Melbourne, Victoria, Australia
| | - Sagar Dalal
- ARC Centre of Excellence in Synthetic Biology, School of Natural Sciences, Macquarie University, Sydney, New South Wales, Australia
| | - Ping Zhang
- Department of Chemistry, University of Calgary, Calgary, Alberta, Canada
| | - Chang-Chun Ling
- Department of Chemistry, University of Calgary, Calgary, Alberta, Canada
| | - V Wee Yong
- Department of Clinical Neurosciences and the Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Kim Loh
- St Vincent's Institute of Medical Research, Melbourne, Victoria, Australia
| | - Ellie Cho
- Biological Optical Microscopy Platform, The University of Melbourne, Melbourne, Victoria, Australia
| | - Chris Karagiannis
- Centre for Muscle Research, The University of Melbourne, Melbourne, Victoria, Australia
| | - Adam J Rose
- Department of Biochemistry and Molecular Biology, Monash Biomedicine Discovery Institute, Monash University, Melbourne, Victoria, Australia
| | - Magdalene K Montgomery
- Department of Anatomy and Physiology, The University of Melbourne, Melbourne, Victoria, Australia
| | - Paul Gregorevic
- Centre for Muscle Research, The University of Melbourne, Melbourne, Victoria, Australia
- Department of Neurology, The University of Washington School of Medicine, Seattle, Washington, USA
| | - Matthew J Watt
- Department of Anatomy and Physiology, The University of Melbourne, Melbourne, Victoria, Australia
| | - Nicolle H Packer
- ARC Centre of Excellence in Synthetic Biology, School of Natural Sciences, Macquarie University, Sydney, New South Wales, Australia
| | - Benjamin L Parker
- Department of Anatomy and Physiology, The University of Melbourne, Melbourne, Victoria, Australia
| | - Robyn M Brown
- Department of Biochemistry and Pharmacology, The University of Melbourne, Melbourne, Victoria, Australia
- Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Melbourne, Victoria, Australia
| | - Edward S X Moh
- ARC Centre of Excellence in Synthetic Biology, School of Natural Sciences, Macquarie University, Sydney, New South Wales, Australia
| | - Garron T Dodd
- Department of Anatomy and Physiology, The University of Melbourne, Melbourne, Victoria, Australia.
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6
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Frago LM, Gómez-Romero A, Collado-Pérez R, Argente J, Chowen JA. Synergism Between Hypothalamic Astrocytes and Neurons in Metabolic Control. Physiology (Bethesda) 2024; 39:0. [PMID: 38530221 DOI: 10.1152/physiol.00009.2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2024] [Revised: 03/05/2024] [Accepted: 03/22/2024] [Indexed: 03/27/2024] Open
Abstract
Astrocytes are no longer considered as passive support cells. In the hypothalamus, these glial cells actively participate in the control of appetite, energy expenditure, and the processes leading to obesity and its secondary complications. Here we briefly review studies supporting this conclusion and the advances made in understanding the underlying mechanisms.
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Affiliation(s)
- Laura M Frago
- Department of Endocrinology, Hospital Infantil Universitario Niño Jesús, Instituto de Investigación La Princesa, Madrid, Spain
- Department of Pediatrics, Faculty of Medicine, Universidad Autónoma de Madrid, Madrid, Spain
- Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, Madrid, Spain
| | - Alfonso Gómez-Romero
- Department of Endocrinology, Hospital Infantil Universitario Niño Jesús, Instituto de Investigación La Princesa, Madrid, Spain
- Department of Pediatrics, Faculty of Medicine, Universidad Autónoma de Madrid, Madrid, Spain
| | - Roberto Collado-Pérez
- Department of Endocrinology, Hospital Infantil Universitario Niño Jesús, Instituto de Investigación La Princesa, Madrid, Spain
- Department of Pediatrics, Faculty of Medicine, Universidad Autónoma de Madrid, Madrid, Spain
| | - Jesús Argente
- Department of Endocrinology, Hospital Infantil Universitario Niño Jesús, Instituto de Investigación La Princesa, Madrid, Spain
- Department of Pediatrics, Faculty of Medicine, Universidad Autónoma de Madrid, Madrid, Spain
- Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, Madrid, Spain
- IMDEA Food Institute, Campus of International Excellence, Universidad Autónoma de Madrid, Consejo Superior de Investigaciones Científicas, Madrid, Spain
| | - Julie A Chowen
- Department of Endocrinology, Hospital Infantil Universitario Niño Jesús, Instituto de Investigación La Princesa, Madrid, Spain
- Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, Madrid, Spain
- IMDEA Food Institute, Campus of International Excellence, Universidad Autónoma de Madrid, Consejo Superior de Investigaciones Científicas, Madrid, Spain
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7
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Netam RK. Short-term feeding of high-fat diet induces neuroinflammation and oxidative stress in arcuate nucleus in rats. INDIAN JOURNAL OF PHYSIOLOGY AND PHARMACOLOGY 2024; 68:126-134. [DOI: 10.25259/ijpp_627_2023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
Abstract
Objectives:
This study aimed to compare the effects of high-fat diet-induced neuroinflammation and oxidative stress in the arcuate nucleus (ARC) of obese-prone and obese-resistant rats.
Materials and Methods:
Rats were divided into obese-prone and obese-resistant groups based on their initial body weight. They were then fed either a 5% or 60% fat-containing diet. In the ARC, the expression of inflammatory markers [Interleukin (IL-6); Nuclear Factor Kappa-B Inhibitor Alpha (NFKBIA); Cluster of Differentiation (CD)-66; and mucin-like hormone receptor-like 1 (EMR-1)], as well as levels of reactive oxygen species (ROS) and antioxidant enzymes (glutathione and glutathione peroxidase and superoxide dismutase), was assessed along with body weight, blood glucose, Homeostatic Model Assessment for Insulin Resistance, plasma insulin and plasma leptin levels after ten days of intervention.
Results:
The results showed a significantly higher expression of inflammatory markers in the ARC of high-fat diet-induced obese rats after ten days. Body weight, plasma insulin, plasma leptin and hydrogen peroxide production were also significantly higher in obese-prone rats fed a high-fat diet.
Conclusion:
In conclusion, this study demonstrates that short-term consumption of a high-fat diet can lead to hypothalamic inflammation and ROS production in the ARC of rats. Obese-prone rats exhibited hyperinsulinaemia and hyperleptinaemia after short-term high-fat diet consumption.
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Affiliation(s)
- Ritesh Kumar Netam
- Department of Physiology, All India Institute of Medical Sciences, New Delhi, Delhi, India,
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8
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Devi S, Gedda DUK, Chawla S, Doucette J, Yadav N, Mirshahi S, de Moura LP, Velloso LA, Mekary RA. The effect of weight loss on hypothalamus structure and function in obese individuals: a systematic review and meta-analysis. Int J Neurosci 2024; 134:75-87. [PMID: 35659180 DOI: 10.1080/00207454.2022.2086127] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2022] [Accepted: 05/30/2022] [Indexed: 10/18/2022]
Abstract
INTRODUCTION Obesity presents with structural and functional hypothalamic dysfunction. However, it is unclear whether weight loss can lead to hypothalamic changes. We therefore aimed to conduct a systematic review and meta-analysis to determine the effect of body mass reduction in obese individuals on hypothalamic structure and function. METHODS PubMed, Embase and Cochrane databases were searched for studies that reported the change in hypothalamic structure and function after weight loss. Qualitative and quantitative analyses were performed on magnetic resonance imaging techniques, medio-basal hypothalamus T2-relaxation time, blood oxygen level dependent (BOLD) contrast, voxel-based morphometry (VBM) and biomarkers including glucose, insulin, leptin, ghrelin and inflammatory markers of interleukins. Mean differences between pre- and post-weight loss and 95% confidence intervals (CIs) were pooled using random-effects models. RESULTS Thirteen pre-post studies were included, of which six accounted for the meta-analysis. Studies showed a favorable decrease in T2-relaxation time (n = 1), favorable change in hypothalamic activity after weight loss on BOLD contrast (n = 4), with higher peak activities after surgical weight loss (n = 2). No differences were found in the gray matter density of the hypothalamus on VBM (n = 1). Pooled mean differences between pre- and post-surgical weight loss revealed a decrease of 8.53 mg/dl (95% CI: 5.17, 11.9) in glucose, 7.73 pmol/l (95% CI: 5.07, 10.4) in insulin, 15.5 ng/ml (95% CI: 9.40, 21.6) in leptin, 142.9 pg/ml (95% CI: 79.0, 206.8) in ghrelin and 9.43 pg/ml (95% CI: -6.89, 25.7) in IL-6 level. CONCLUSIONS Our study showed weight reduction in obesity led to limited structural change and significant functional changes in the hypothalamus.
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Affiliation(s)
- Sharmila Devi
- Faculty of Life Sciences and Medicine, King's College of London (KCL), London, UK
- Department of Neurosurgery, Computational Neurosurgical Outcomes Center, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Durga Udaya Keerthi Gedda
- School of Pharmacy, Massachusetts College of Pharmacy and Health Sciences (MCPHS) University, Boston, MA, USA
| | - Shreya Chawla
- Faculty of Life Sciences and Medicine, King's College of London (KCL), London, UK
- Department of Neurosurgery, Computational Neurosurgical Outcomes Center, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Joanne Doucette
- School of Pharmacy, Massachusetts College of Pharmacy and Health Sciences (MCPHS) University, Boston, MA, USA
| | - Nishi Yadav
- School of Pharmacy, Massachusetts College of Pharmacy and Health Sciences (MCPHS) University, Boston, MA, USA
| | - Shervin Mirshahi
- Department of Neurosurgery, Computational Neurosurgical Outcomes Center, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
- Department of Radiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Leandro P de Moura
- Laboratory of Molecular Biology of Exercise (LaBMEx), School of Applied Sciences, University of Campinas (UNICAMP), Limeira, Brazil
- CEPECE - Center of Research in Sport Sciences, School of Applied Sciences, University of Campinas, Limeira, Brazil
| | - Lício A Velloso
- Department of Internal Medicine, Laboratory of Cell Signaling, University of Campinas, Campinas, Brazil
| | - Rania A Mekary
- Department of Neurosurgery, Computational Neurosurgical Outcomes Center, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
- School of Pharmacy, Massachusetts College of Pharmacy and Health Sciences (MCPHS) University, Boston, MA, USA
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9
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Abi-Ghanem C, Salinero AE, Smith RM, Kelly RD, Belanger KM, Richard RN, Paul AS, Herzog AA, Thrasher CA, Rybka KA, Riccio D, Gannon OJ, Kordit D, Kyaw NR, Mansour FM, Groom E, Brooks HL, Robison LS, Pumiglia K, Zuloaga DG, Zuloaga KL. Effects of Menopause and High Fat Diet on Metabolic Outcomes in a Mouse Model of Alzheimer's Disease. J Alzheimers Dis 2024; 101:1177-1194. [PMID: 39302361 DOI: 10.3233/jad-231332] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/22/2024]
Abstract
Background About two-thirds of those with Alzheimer's disease (AD) are women, most of whom are post-menopausal. Menopause accelerates dementia risk by increasing the risk for metabolic, cardiovascular, and cerebrovascular diseases. Mid-life metabolic disease (obesity, diabetes/prediabetes) is a well-known risk factor for dementia. A high fat diet can lead to poor metabolic health in both humans and rodents. Objective Our goal was to determine the effects of a high fat diet on metabolic outcomes in the AppNL-F knock-in mouse model of AD and assess the effects of menopause. Methods First, 3-month-old AppNL-F and WT female mice were placed on either a control or a high fat diet until 10 months of age then assessed for metabolic outcomes. Next, we did a more extensive assessment in AppNL-F mice that were administered VCD (4-vinylcyclohexene diepoxide) or vehicle (oil) and placed on a control or high fat diet for 7 months. VCD was used to model menopause by causing accelerated ovarian failure. Results Compared to WT controls, AD female mice had worse glucose intolerance. Menopause led to metabolic impairment (weight gain and glucose intolerance) and further exacerbated obesity in response to a high fat diet. There were interactions between diet and menopause on some metabolic health serum biomarkers and the expression of hypothalamic markers related to energy balance. Conclusions This work highlights the need to model endocrine aging in animal models of dementia and will contribute to further understanding the interaction between menopause and metabolic health in the context of AD.
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Affiliation(s)
- Charly Abi-Ghanem
- Department of Neuroscience & Experimental Therapeutics, Albany Medical College, Albany, NY, USA
| | - Abigail E Salinero
- Department of Neuroscience & Experimental Therapeutics, Albany Medical College, Albany, NY, USA
| | - Rachel M Smith
- Department of Neuroscience & Experimental Therapeutics, Albany Medical College, Albany, NY, USA
| | - Richard D Kelly
- Department of Neuroscience & Experimental Therapeutics, Albany Medical College, Albany, NY, USA
| | - Kasey M Belanger
- Department of Neuroscience & Experimental Therapeutics, Albany Medical College, Albany, NY, USA
| | - Riane N Richard
- Department of Neuroscience & Experimental Therapeutics, Albany Medical College, Albany, NY, USA
| | - Aaron S Paul
- Department of Neuroscience & Experimental Therapeutics, Albany Medical College, Albany, NY, USA
| | - Ava A Herzog
- Department of Neuroscience & Experimental Therapeutics, Albany Medical College, Albany, NY, USA
| | - Christina A Thrasher
- Department of Neuroscience & Experimental Therapeutics, Albany Medical College, Albany, NY, USA
| | - Krystyna A Rybka
- Department of Psychology and Center for Neuroscience Research, State University of New York at Albany, Albany, NY, USA
| | - David Riccio
- Department of Neuroscience & Experimental Therapeutics, Albany Medical College, Albany, NY, USA
| | - Olivia J Gannon
- Department of Neuroscience & Experimental Therapeutics, Albany Medical College, Albany, NY, USA
| | - David Kordit
- Department of Neuroscience & Experimental Therapeutics, Albany Medical College, Albany, NY, USA
| | - Nyi-Rein Kyaw
- Department of Neuroscience & Experimental Therapeutics, Albany Medical College, Albany, NY, USA
| | - Febronia M Mansour
- Department of Neuroscience & Experimental Therapeutics, Albany Medical College, Albany, NY, USA
| | - Emily Groom
- Department of Neuroscience & Experimental Therapeutics, Albany Medical College, Albany, NY, USA
| | - Heddwen L Brooks
- Department of Physiology, Tulane University School of Medicine, New Orleans, LA, USA
| | - Lisa S Robison
- Department of Psychology and Neuroscience, Nova Southeastern University, Fort Lauderdale, FL, USA
| | - Kevin Pumiglia
- Department of Regenerative and Cancer Cell Biology, Albany Medical College, Albany, NY, USA
| | - Damian G Zuloaga
- Department of Psychology and Center for Neuroscience Research, State University of New York at Albany, Albany, NY, USA
| | - Kristen L Zuloaga
- Department of Neuroscience & Experimental Therapeutics, Albany Medical College, Albany, NY, USA
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10
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Kwon J, Aoki Y, Takahashi H, Nakata R, Kawarasaki S, Ni Z, Yu R, Inoue H, Inoue K, Kawada T, Goto T. Inflammation-induced nitric oxide suppresses PPARα expression and function via downregulation of Sp1 transcriptional activity in adipocytes. BIOCHIMICA ET BIOPHYSICA ACTA. GENE REGULATORY MECHANISMS 2023; 1866:194987. [PMID: 37739218 DOI: 10.1016/j.bbagrm.2023.194987] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/14/2023] [Revised: 09/05/2023] [Accepted: 09/15/2023] [Indexed: 09/24/2023]
Abstract
The activation of peroxisome proliferator-activated receptor alpha (PPARα), a ligand-dependent transcription factor that regulates lipid oxidation-related genes, has been employed to treat hyperlipidemia. Emerging evidence indicates that Ppara gene expression decreases in adipose tissue under obese conditions; however, the underlying molecular mechanisms remain elusive. Here, we demonstrate that nitric oxide (NO) suppresses Ppara expression by regulating its promoter activity via suppression of specificity protein 1 (Sp1) transcriptional activity in adipocytes. NO derived from lipopolysaccharide (LPS) -activated macrophages or a NO donor (NOR5) treatment, suppressed Ppara mRNA expression in 10T1/2 adipocytes. In addition, Ppara transcript levels were reduced in the white adipose tissue (WAT) in both acute and chronic inflammation mouse models; however, such suppressive effects were attenuated via a nitric oxide synthase 2 (NOS2) inhibitor. Endoplasmic reticulum (ER) stress inhibitors attenuated the NO-induced repressive effects on Ppara gene expression in 10T1/2 adipocytes. Promoter mutagenesis and chromatin immunoprecipitation assays revealed that NO decreased the Sp1 occupancy in the proximal promoter regions of the Ppara gene, which might partially result from the reduced Sp1 expression levels by NO. This study delineated the molecular mechanism that modulates Ppara gene transcription upon NO stimulation in white adipocytes, suggesting a possible mechanism for the transcriptional downregulation of Ppara in WAT under obese conditions.
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Affiliation(s)
- Jungin Kwon
- Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Uji 611-0011, Japan
| | - Yumeko Aoki
- Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Uji 611-0011, Japan
| | - Haruya Takahashi
- Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Uji 611-0011, Japan
| | - Rieko Nakata
- Department of Food Science and Nutrition, Nara Women's University, Nara 630-8506, Japan
| | - Satoko Kawarasaki
- Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Uji 611-0011, Japan
| | - Zheng Ni
- Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Uji 611-0011, Japan
| | - Rina Yu
- Department of Food Science and Nutrition, University of Ulsan, Ulsan 44610, Republic of Korea
| | - Hiroyasu Inoue
- Department of Food Science and Nutrition, Nara Women's University, Nara 630-8506, Japan
| | - Kazuo Inoue
- Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Uji 611-0011, Japan; Research Unit for Physiological Chemistry, The Center for the Promotion of Interdisciplinary Education and Research, Kyoto University, Kyoto 606-8501, Japan
| | - Teruo Kawada
- Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Uji 611-0011, Japan; Research Unit for Physiological Chemistry, The Center for the Promotion of Interdisciplinary Education and Research, Kyoto University, Kyoto 606-8501, Japan
| | - Tsuyoshi Goto
- Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Uji 611-0011, Japan; Research Unit for Physiological Chemistry, The Center for the Promotion of Interdisciplinary Education and Research, Kyoto University, Kyoto 606-8501, Japan.
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11
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Oliveira LDC, Morais GP, de Oliveira FP, Mata MM, Vera ASC, da Rocha AL, Elias LLK, Teixeira GR, de Moraes C, Cintra DE, Ropelle ER, de Moura LP, Pauli JR, de Freitas EC, Rorato R, da Silva ASR. Intermittent fasting combined with exercise training reduces body mass and alleviates hypothalamic disorders induced by high-fat diet intake. J Nutr Biochem 2023:109372. [PMID: 37169229 DOI: 10.1016/j.jnutbio.2023.109372] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2022] [Revised: 04/20/2023] [Accepted: 05/06/2023] [Indexed: 05/13/2023]
Abstract
High-fat diet consumption causes hypothalamic inflammation, dysregulating the leptin pathway, which, in turn, compromises the modulation of hypothalamic neuronal activities and predisposes obesity development. Intermittent fasting (IF) and exercise training (ET) have been demonstrated as efficient interventions to modulate hypothalamic inflammation and neuronal activity. However, no studies have evaluated whether combining these interventions could induce better results in reestablishing hypothalamic homeostasis disrupted by high-fat diet intake. The 8-week-old male C57BL/6 mice were randomly assigned into two groups: sedentary mice fed a standard diet (CT), and sedentary mice fed a high-fat diet (HF). After 8 weeks of an HF diet, part of the HF group (now 16 weeks old) was randomly subjected to different interventions for 6 weeks: HF-IF = HF diet mice submitted to IF; HF-T = HF diet mice submitted to ET; HF-IFT = HF diet mice submitted to IF and ET. All interventions decreased the body weight gain induced by high-fat diet intake, associated with reduced calorie consumption in week 14. Only the HF-IFT group presented improved serum insulin, leptin, resistin, and Tnf-alpha levels concomitantly with decreased hypothalamic inflammation. The HF-IFT group also demonstrated increased Pomc mRNA expression associated with enhanced pSTAT3 expression in the hypothalamic arcuate and ventromedial hypothalamic nuclei. Our data indicate that the beneficial effects of the combination of IF and ET on energy homeostasis are associated with increased leptin sensitivity in the hypothalamic arcuate nucleus and ventromedial hypothalamic nucleus, which is likely due to an improvement in hypothalamic inflammatory pathways in these nuclei.
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Affiliation(s)
- Luciana da Costa Oliveira
- Postgraduate Program in Rehabilitation and Functional Performance, Ribeirão Preto Medical School, University of São Paulo (USP), Ribeirão Preto, São Paulo, Brazil
| | - Gustavo Paroschi Morais
- Postgraduate Program in Rehabilitation and Functional Performance, Ribeirão Preto Medical School, University of São Paulo (USP), Ribeirão Preto, São Paulo, Brazil
| | - Franciane Pereira de Oliveira
- Laboratory of Stress Neuroendocrinology, Department of Biophysics, Paulista Medical School, Federal University of Sao Paulo, Sao Paulo, SP, Brazil
| | - Milene Montavoni Mata
- Departament of Physiology, Ribeirão Preto Medical School, University of São Paulo, Brazil
| | - Allice Santos Cruz Vera
- Multicenter Graduate Program in Physiological Sciences, São Paulo State University (UNESP), Presidente Prudente, SP, Brazil
| | - Alisson Luiz da Rocha
- School of Physical Education and Sport of Ribeirão Preto, University of São Paulo (USP), Ribeirão Preto, São Paulo, Brazil
| | | | - Giovana Rampazzo Teixeira
- Multicenter Graduate Program in Physiological Sciences, São Paulo State University (UNESP), Presidente Prudente, SP, Brazil
| | - Camila de Moraes
- Laboratory of Molecular Biology of Exercise (LaBMEx), School of Applied Sciences, University of Campinas (UNICAMP), Limeira, São Paulo, Brazil
| | - Dennys E Cintra
- School of Physical Education and Sport of Ribeirão Preto, University of São Paulo (USP), Ribeirão Preto, São Paulo, Brazil
| | - Eduardo R Ropelle
- School of Physical Education and Sport of Ribeirão Preto, University of São Paulo (USP), Ribeirão Preto, São Paulo, Brazil
| | - Leandro P de Moura
- School of Physical Education and Sport of Ribeirão Preto, University of São Paulo (USP), Ribeirão Preto, São Paulo, Brazil
| | - José R Pauli
- School of Physical Education and Sport of Ribeirão Preto, University of São Paulo (USP), Ribeirão Preto, São Paulo, Brazil
| | - Ellen C de Freitas
- Laboratory of Molecular Biology of Exercise (LaBMEx), School of Applied Sciences, University of Campinas (UNICAMP), Limeira, São Paulo, Brazil
| | - Rodrigo Rorato
- Laboratory of Stress Neuroendocrinology, Department of Biophysics, Paulista Medical School, Federal University of Sao Paulo, Sao Paulo, SP, Brazil
| | - Adelino Sanchez R da Silva
- Postgraduate Program in Rehabilitation and Functional Performance, Ribeirão Preto Medical School, University of São Paulo (USP), Ribeirão Preto, São Paulo, Brazil.; Laboratory of Molecular Biology of Exercise (LaBMEx), School of Applied Sciences, University of Campinas (UNICAMP), Limeira, São Paulo, Brazil..
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12
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Zhang J, Li S, Luo X, Zhang C. Emerging role of hypothalamus in the metabolic regulation in the offspring of maternal obesity. Front Nutr 2023; 10:1094616. [PMID: 36819678 PMCID: PMC9928869 DOI: 10.3389/fnut.2023.1094616] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2022] [Accepted: 01/17/2023] [Indexed: 02/04/2023] Open
Abstract
Maternal obesity has a significant impact on the metabolism of offspring both in childhood and adulthood. The metabolic regulation of offspring is influenced by the intrauterine metabolic programming induced by maternal obesity. Nevertheless, the precise mechanisms remain unclear. The hypothalamus is the primary target of metabolic programming and the principal regulatory center of energy metabolism. Accumulating evidence has indicated the crucial role of hypothalamic regulation in the metabolism of offspring exposed to maternal obesity. This article reviews the development of hypothalamus, the role of the hypothalamic regulations in energy homeostasis, possible mechanisms underlying the developmental programming of energy metabolism in offspring, and the potential therapeutic approaches for preventing metabolic diseases later in life. Lastly, we discuss the challenges and future directions of hypothalamic regulation in the metabolism of children born to obese mothers.
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13
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Calcaterra V, Magenes VC, Hruby C, Siccardo F, Mari A, Cordaro E, Fabiano V, Zuccotti G. Links between Childhood Obesity, High-Fat Diet, and Central Precocious Puberty. CHILDREN (BASEL, SWITZERLAND) 2023; 10:children10020241. [PMID: 36832370 PMCID: PMC9954755 DOI: 10.3390/children10020241] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 12/22/2022] [Revised: 01/24/2023] [Accepted: 01/28/2023] [Indexed: 01/31/2023]
Abstract
In recent years, the existing relationship between excess overweight and central precocious puberty (CPP) has been reported, especially in girls. Different nutritional choices have been associated with different patterns of puberty. In particular, the involvement of altered biochemical and neuroendocrine pathways and a proinflammatory status has been described in connection with a high-fat diet (HFD). In this narrative review, we present an overview on the relationship between obesity and precocious pubertal development, focusing on the role of HFDs as a contributor to activating the hypothalamus-pituitary-gonadal axis. Although evidence is scarce and studies limited, especially in the paediatric field, the harm of HFDs on PP is a relevant problem that cannot be ignored. Increased knowledge about HFD effects will be useful in developing strategies preventing precocious puberty in children with obesity. Promoting HFD-avoiding behavior may be useful in preserving children's physiological development and protecting reproductive health. Controlling HFDs may represent a target for policy action to improve global health.
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Affiliation(s)
- Valeria Calcaterra
- Department of Internal Medicine, University of Pavia, 27100 Pavia, Italy
- Pediatric Department, Buzzi Children’s Hospital, 20154 Milano, Italy
- Correspondence:
| | | | - Chiara Hruby
- Pediatric Department, Buzzi Children’s Hospital, 20154 Milano, Italy
| | | | - Alessandra Mari
- Pediatric Department, Buzzi Children’s Hospital, 20154 Milano, Italy
| | - Erika Cordaro
- Pediatric Department, Buzzi Children’s Hospital, 20154 Milano, Italy
| | - Valentina Fabiano
- Pediatric Department, Buzzi Children’s Hospital, 20154 Milano, Italy
- Department of Biomedical and Clinical Science “L. Sacco”, University of Milano, 20157 Milano, Italy
| | - Gianvincenzo Zuccotti
- Pediatric Department, Buzzi Children’s Hospital, 20154 Milano, Italy
- Department of Biomedical and Clinical Science “L. Sacco”, University of Milano, 20157 Milano, Italy
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14
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Littig JPB, Moellmer R, Agrawal DK, Rai V. Future applications of exosomes delivering resolvins and cytokines in facilitating diabetic foot ulcer healing. World J Diabetes 2023; 14:35-47. [PMID: 36684384 PMCID: PMC9850797 DOI: 10.4239/wjd.v14.i1.35] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/10/2022] [Revised: 11/22/2022] [Accepted: 12/21/2022] [Indexed: 01/10/2023] Open
Abstract
Type 2 diabetes mellitus (T2DM) increases the risk of many lethal and debilitating conditions. Among them, foot ulceration due to neuropathy, vascular disease, or trauma affects the quality of life of millions in the United States and around the world. Physiological wound healing is stalled in the inflammatory phase by the chronicity of inflammation without proceeding to the resolution phase. Despite advanced treatment, diabetic foot ulcers (DFUs) are associated with a risk of amputation. Thus, there is a need for novel therapies to address chronic inflammation, decreased angiogenesis, and impaired granulation tissue formation contributing to the non-healing of DFUs. Studies have shown promising results with resolvins (Rv) and anti-inflammatory therapies that resolve inflammation and enhance tissue healing. But many of these studies have encountered difficulty in the delivery of Rv in terms of efficiency, tissue targetability, and immunogenicity. This review summarized the perspective of optimizing the therapeutic application of Rv and cytokines by pairing them with exosomes as a novel strategy for targeted tissue delivery to treat non-healing chronic DFUs. The articles discussing the T2DM disease state, current research on Rv for treating inflammation, the role of Rv in enhancing wound healing, and exosomes as a delivery vehicle were critically reviewed to find support for the proposition of using Rv and exosomes in combination for DFUs therapy. The literature reviewed suggests the beneficial role of Rv and exosomes and exosomes loaded with anti-inflammatory agents as promising therapeutic agents in ulcer healing.
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Affiliation(s)
- Joshua P B Littig
- Translational Research, Western University of Health Sciences, Pomona, CA 91766, United States
| | - Rebecca Moellmer
- College of Podiatry, Western University of Health Sciences, Pomona, CA 91766, United States
| | - Devendra K Agrawal
- Translational Research, Western University of Health Sciences, Pomona, CA 91766, United States
| | - Vikrant Rai
- Translational Research, Western University of Health Sciences, Pomona, CA 91766, United States
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15
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Bakker W, Imbernon M, Salinas CG, Moro Chao DH, Hassouna R, Morel C, Martin C, Leger C, Denis RG, Castel J, Peter A, Heni M, Maetzler W, Nielsen HS, Duquenne M, Schwaninger M, Lundh S, Johan Hogendorf WF, Gangarossa G, Secher A, Hecksher-Sørensen J, Pedersen TÅ, Prevot V, Luquet S. Acute changes in systemic glycemia gate access and action of GLP-1R agonist on brain structures controlling energy homeostasis. Cell Rep 2022; 41:111698. [PMID: 36417883 PMCID: PMC9715912 DOI: 10.1016/j.celrep.2022.111698] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2020] [Revised: 08/19/2022] [Accepted: 10/20/2022] [Indexed: 11/23/2022] Open
Abstract
Therapies based on glucagon-like peptide-1 (GLP-1) long-acting analogs and insulin are often used in the treatment of metabolic diseases. Both insulin and GLP-1 receptors are expressed in metabolically relevant brain regions, suggesting a cooperative action. However, the mechanisms underlying the synergistic actions of insulin and GLP-1R agonists remain elusive. In this study, we show that insulin-induced hypoglycemia enhances GLP-1R agonists entry in hypothalamic and area, leading to enhanced whole-body fat oxidation. Mechanistically, this phenomenon relies on the release of tanycyctic vascular endothelial growth factor A, which is selectively impaired after calorie-rich diet exposure. In humans, low blood glucose also correlates with enhanced blood-to-brain passage of insulin, suggesting that blood glucose gates the passage other energy-related signals in the brain. This study implies that the preventing hyperglycemia is important to harnessing the full benefit of GLP-1R agonist entry in the brain and action onto lipid mobilization and body weight loss.
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Affiliation(s)
- Wineke Bakker
- Université Paris Cité, CNRS, Unité de Biologie Fonctionnelle et Adaptative, 75013 Paris, France,Global Drug Discovery, Novo Nordisk A/S, Måløv, Denmark,Corresponding author
| | - Monica Imbernon
- University Lille, Inserm, CHU Lille, Laboratory of Development and Plasticity of the Neuroendocrine Brain, Lille Neuroscience & Cognition, EGID, UMR-S 1172, 59000 Lille, France
| | - Casper Gravesen Salinas
- Global Drug Discovery, Novo Nordisk A/S, Måløv, Denmark,Image Analysis & Computer Graphics, Department of Applied Mathematics and Computer Science, Technical University of Denmark, Kgs. Lyngby, Denmark,Gubra ApS, Hørsholm Kongevej 11B, 2970 Hørsholm, Denmark
| | | | - Rim Hassouna
- Université Paris Cité, CNRS, Unité de Biologie Fonctionnelle et Adaptative, 75013 Paris, France
| | - Chloe Morel
- Université Paris Cité, CNRS, Unité de Biologie Fonctionnelle et Adaptative, 75013 Paris, France
| | - Claire Martin
- Université Paris Cité, CNRS, Unité de Biologie Fonctionnelle et Adaptative, 75013 Paris, France
| | - Caroline Leger
- Université Paris Cité, CNRS, Unité de Biologie Fonctionnelle et Adaptative, 75013 Paris, France
| | - Raphael G.P. Denis
- Université Paris Cité, CNRS, Unité de Biologie Fonctionnelle et Adaptative, 75013 Paris, France,Institut Cochin, Université Paris Cité, INSERM U1016, CNRS UMR 8104, 75014 Paris, France
| | - Julien Castel
- Université Paris Cité, CNRS, Unité de Biologie Fonctionnelle et Adaptative, 75013 Paris, France
| | - Andreas Peter
- Institute of Diabetes Research and Metabolic Diseases (IDM) of the Helmholtz Center Munich at the University of Tübingen, Tübingen, Germany,German Center for Diabetes Research (DZD), Tübingen, Germany,Institute for Clinical Chemistry and Pathobiochemistry, Department for Diagnostic Laboratory Medicine, University Hospital of Tübingen, Tübingen, Germany
| | - Martin Heni
- Department of Internal Medicine IV, Division of Endocrinology, Diabetology and Nephrology, University of Tübingen, Tübingen, Germany,Institute of Diabetes Research and Metabolic Diseases (IDM) of the Helmholtz Center Munich at the University of Tübingen, Tübingen, Germany,German Center for Diabetes Research (DZD), Tübingen, Germany
| | - Walter Maetzler
- Department of Neurodegenerative Diseases, Center of Neurology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany,German Center for Neurodegenerative Diseases, Tübingen, Germany,Department of Neurology, University of Kiel, Kiel, Germany
| | | | - Manon Duquenne
- University Lille, Inserm, CHU Lille, Laboratory of Development and Plasticity of the Neuroendocrine Brain, Lille Neuroscience & Cognition, EGID, UMR-S 1172, 59000 Lille, France
| | - Markus Schwaninger
- Institute for Experimental and Clinical Pharmacology and Toxicology, University of Lübeck, Lübeck, Germany
| | - Sofia Lundh
- Global Drug Discovery, Novo Nordisk A/S, Måløv, Denmark
| | | | - Giuseppe Gangarossa
- Université Paris Cité, CNRS, Unité de Biologie Fonctionnelle et Adaptative, 75013 Paris, France
| | - Anna Secher
- Global Drug Discovery, Novo Nordisk A/S, Måløv, Denmark
| | - Jacob Hecksher-Sørensen
- Global Drug Discovery, Novo Nordisk A/S, Måløv, Denmark,Gubra ApS, Hørsholm Kongevej 11B, 2970 Hørsholm, Denmark
| | | | - Vincent Prevot
- University Lille, Inserm, CHU Lille, Laboratory of Development and Plasticity of the Neuroendocrine Brain, Lille Neuroscience & Cognition, EGID, UMR-S 1172, 59000 Lille, France
| | - Serge Luquet
- Université Paris Cité, CNRS, Unité de Biologie Fonctionnelle et Adaptative, 75013 Paris, France,Corresponding author
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16
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Park S, Oh S, Kim EK. Glucagon-like peptide-1 analog liraglutide leads to multiple metabolic alterations in diet-induced obese mice. J Biol Chem 2022; 298:102682. [PMID: 36356900 PMCID: PMC9730228 DOI: 10.1016/j.jbc.2022.102682] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2022] [Revised: 10/27/2022] [Accepted: 10/31/2022] [Indexed: 11/09/2022] Open
Abstract
Liraglutide, a glucagon-like peptide-1 analog, has beneficial metabolic effects in patients with type 2 diabetes and obesity. Although the high efficacy of liraglutide as an anti-diabetic and anti-obesity drug is well known, liraglutide-induced metabolic alterations in diverse tissues remain largely unexplored. Here, we report the changes in metabolic profiles induced by a 2-week subcutaneous injection of liraglutide in diet-induced obese mice fed a high-fat diet for 8 weeks. Our comprehensive metabolomic analyses of the hypothalamus, plasma, liver, and skeletal muscle showed that liraglutide intervention led to various metabolic alterations in comparison with diet-induced obese or nonobese mice. We found that liraglutide remarkably coordinated not only fatty acid metabolism in the hypothalamus and skeletal muscle but also amino acid and carbohydrate metabolism in plasma and liver. Comparative analyses of metabolite dynamics revealed that liraglutide rewired intertissue metabolic correlations. Our study points to a previously unappreciated metabolic alteration by liraglutide in several tissues, which may underlie its therapeutic effects within and across the tissues.
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Affiliation(s)
- Seokjae Park
- Department of Brain Sciences, Daegu Gyeongbuk Institute of Science and Technology, Daegu, Republic of Korea,Neurometabolomics Research Center, Daegu Gyeongbuk Institute of Science and Technology, Daegu, Republic of Korea
| | - Sungjoon Oh
- Department of Brain Sciences, Daegu Gyeongbuk Institute of Science and Technology, Daegu, Republic of Korea,Neurometabolomics Research Center, Daegu Gyeongbuk Institute of Science and Technology, Daegu, Republic of Korea
| | - Eun-Kyoung Kim
- Department of Brain Sciences, Daegu Gyeongbuk Institute of Science and Technology, Daegu, Republic of Korea,Neurometabolomics Research Center, Daegu Gyeongbuk Institute of Science and Technology, Daegu, Republic of Korea,For correspondence: Eun-Kyoung Kim
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17
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Trends in Gliosis in Obesity, and the Role of Antioxidants as a Therapeutic Alternative. Antioxidants (Basel) 2022; 11:antiox11101972. [PMID: 36290695 PMCID: PMC9598641 DOI: 10.3390/antiox11101972] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2022] [Revised: 09/23/2022] [Accepted: 09/29/2022] [Indexed: 11/16/2022] Open
Abstract
Obesity remains a global health problem. Chronic low-grade inflammation in this pathology has been related to comorbidities such as cognitive alterations that, in the long term, can lead to neurodegenerative diseases. Neuroinflammation or gliosis in patients with obesity and type 2 diabetes mellitus has been related to the effect of adipokines, high lipid levels and glucose, which increase the production of free radicals. Cerebral gliosis can be a risk factor for developing neurodegenerative diseases, and antioxidants could be an alternative for the prevention and treatment of neural comorbidities in obese patients. AIM Identify the immunological and oxidative stress mechanisms that produce gliosis in patients with obesity and propose antioxidants as an alternative to reducing neuroinflammation. METHOD Advanced searches were performed in scientific databases: PubMed, ProQuest, EBSCO, and the Science Citation index for research on the physiopathology of gliosis in obese patients and for the possible role of antioxidants in its management. CONCLUSION Patients with obesity can develop neuroinflammation, conditioned by various adipokines, excess lipids and glucose, which results in an increase in free radicals that must be neutralized with antioxidants to reduce gliosis and the risk of long-term neurodegeneration.
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18
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da Silva RKB, de Vasconcelos DAA, da Silva AVE, da Silva RPB, de Oliveira Neto OB, Galindo LCM. Effects of maternal high-fat diet on the hypothalamic components related to food intake and energy expenditure in mice offspring. Life Sci 2022; 307:120880. [PMID: 35963301 DOI: 10.1016/j.lfs.2022.120880] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2022] [Revised: 08/02/2022] [Accepted: 08/08/2022] [Indexed: 11/25/2022]
Abstract
Maternal exposure to a high-fat diet (HFD) during pregnancy and lactation has been related to changes in the hypothalamic circuits involved in the regulation of food intake. Furthermore, maternal HFD during the critical period of development can alter the offspring's metabolic programming with long-term repercussions. This study systematically reviewed the effects of HFD consumption during pre-pregnancy, pregnancy and/or lactation. The main outcomes evaluated were food intake; body weight; cellular or molecular aspects of peptides and hypothalamic receptors involved in the regulation of energy balance in mice. Two independent authors performed a search in the electronic databases Medline/PubMed, LILACS, Web of Science, EMBASE, SCOPUS and Sigle via Open Gray. Included were experimental studies of mice exposed to HFD during pregnancy and/or lactation that evaluated body composition, food intake, energy expenditure and hypothalamic components related to energy balance. Internal validity was assessed using the SYRCLE risk of bias. The Kappa index was measured to analyze the agreement between reviewers. The PRISMA statement was used to report this systematic review. Most studies demonstrated that there was a higher body weight, body fat deposits and food intake, as well as alterations in the expression of hypothalamic neuropeptides in offspring that consumed HFD. Therefore, the maternal diet can affect the phenotype and metabolism of the offspring, in addition to harming the hypothalamic circuits and favoring the orexigenic pathways.
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Affiliation(s)
- Regina Katiuska Bezerra da Silva
- Post-Graduate Program in Nutrition, Physical Activity and Phenotypic Plasticity, Federal University of Pernambuco, 55608-680 Vitória de Santo Antão, PE, Brazil
| | - Diogo Antonio Alves de Vasconcelos
- Post-Graduate Program in Nutrition, Physical Activity and Phenotypic Plasticity, Federal University of Pernambuco, 55608-680 Vitória de Santo Antão, PE, Brazil; Department of Nutrition, Federal University of Pernambuco, 50670-901 Recife, PE, Brazil; Nutrition and Phenotypic Plasticity Study Unit, Department of Nutrition, Federal University of Pernambuco, 50670-901 Recife, PE, Brazil
| | | | - Roxana Patrícia Bezerra da Silva
- Post-Graduate Program in Nutrition, Physical Activity and Phenotypic Plasticity, Federal University of Pernambuco, 55608-680 Vitória de Santo Antão, PE, Brazil
| | | | - Lígia Cristina Monteiro Galindo
- Post-Graduate Program in Nutrition, Physical Activity and Phenotypic Plasticity, Federal University of Pernambuco, 55608-680 Vitória de Santo Antão, PE, Brazil; Department of Anatomy, Federal University of Pernambuco, 50670-901 Recife, PE, Brazil; Nutrition and Phenotypic Plasticity Study Unit, Department of Nutrition, Federal University of Pernambuco, 50670-901 Recife, PE, Brazil.
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19
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López-Gambero AJ, Pacheco-Sánchez B, Rosell-Valle C, Medina-Vera D, Navarro JA, Fernández-Arjona MDM, de Ceglia M, Sanjuan C, Simon V, Cota D, Rivera P, Rodríguez de Fonseca F, Suárez J. Dietary administration of D-chiro-inositol attenuates sex-specific metabolic imbalances in the 5xFAD mouse model of Alzheimer's disease. Biomed Pharmacother 2022; 150:112994. [PMID: 35483188 DOI: 10.1016/j.biopha.2022.112994] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2022] [Revised: 04/13/2022] [Accepted: 04/17/2022] [Indexed: 11/02/2022] Open
Abstract
Increasing evidence shows that hypothalamic dysfunction, insulin resistance, and weight loss precede and progress along with the cognitive decline in sporadic Alzheimer's Disease (AD) with sex differences. This study aimed to determine the effect of oral dietary administration of D-Chiro-inositol (DCI), an inositol used against insulin resistance associated with polycystic ovary, on the occurrence of metabolic disorders in the transgenic 5xFAD mouse model of AD (FAD: Family Alzheimer's Disease). DCI was administered from 6 to 10 months of age to male and female 5xFAD mice and control (non-Tg) littermates. Energy balance and multiple metabolic and inflammatory parameters in the hypothalamus, liver and plasma were evaluated to assess the central and peripheral effects of DCI. Results indicated that weight loss and reduced food intake in 5xFAD mice were associated with decreased neuropeptides controlling food intake and the appearance of a pro-inflammatory state in the hypothalamus. Oral administration of DCI partially restored energy balance and hypothalamic parameters, highlighting an increased expression of Npy and Agrp and female-specific downregulation of Gfap and Igf1. DCI also partially normalized impaired insulin signaling and circulating insulin, GLP-1, and GIP deficiencies in 5xFAD mice. Principal component analysis of metabolic parameters indicated the presence of a female-specific fatty liver in 5xFAD mice: DCI administration reversed hepatic fat accumulation, β-oxidation, inflammation and increased GOT and GPT levels. Our study depicts that metabolic impairment along with the cognitive decline in a mouse model of AD, which is exacerbated in females, can be ameliorated by oral supplementation with insulin-sensitizing DCI.
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Affiliation(s)
- Antonio J López-Gambero
- Instituto de investigación Biomédica de Málaga-IBIMA, 29010 Málaga, Spain; UGC Salud Mental, Hospital Regional Universitario de Málaga, 29010 Málaga, Spain; Universidad de Málaga, Andalucia Tech, Departamento de Biología Celular, Genética y Fisiología, Campus de Teatinos s/n, 29071 Málaga, Spain.
| | | | | | - Dina Medina-Vera
- Instituto de investigación Biomédica de Málaga-IBIMA, 29010 Málaga, Spain; Universidad de Málaga, Andalucia Tech, Departamento de Biología Celular, Genética y Fisiología, Campus de Teatinos s/n, 29071 Málaga, Spain; Universidad de Málaga, Andalucia Tech, Facultad de Medicina, Campus de Teatinos s/n, 29071 Málaga, Spain; UGC Corazón, Hospital Universitario Virgen de la Victoria, 29010 Málaga, Spain.
| | - Juan Antonio Navarro
- Instituto de investigación Biomédica de Málaga-IBIMA, 29010 Málaga, Spain; UGC Salud Mental, Hospital Regional Universitario de Málaga, 29010 Málaga, Spain; Universidad de Málaga, Andalucia Tech, Facultad de Medicina, Campus de Teatinos s/n, 29071 Málaga, Spain.
| | - María Del Mar Fernández-Arjona
- Instituto de investigación Biomédica de Málaga-IBIMA, 29010 Málaga, Spain; UGC Salud Mental, Hospital Regional Universitario de Málaga, 29010 Málaga, Spain.
| | - Marialuisa de Ceglia
- Instituto de investigación Biomédica de Málaga-IBIMA, 29010 Málaga, Spain; UGC Salud Mental, Hospital Regional Universitario de Málaga, 29010 Málaga, Spain.
| | - Carlos Sanjuan
- EURONUTRA S.L, Parque Tecnológico de Andalucía, Campanillas, 29590, Spain.
| | - Vincent Simon
- University of Bordeaux, INSERM, Neurocentre Magendie, U1215, 33000 Bordeaux, France.
| | - Daniela Cota
- University of Bordeaux, INSERM, Neurocentre Magendie, U1215, 33000 Bordeaux, France.
| | - Patricia Rivera
- Instituto de investigación Biomédica de Málaga-IBIMA, 29010 Málaga, Spain; UGC Salud Mental, Hospital Regional Universitario de Málaga, 29010 Málaga, Spain.
| | - Fernando Rodríguez de Fonseca
- Instituto de investigación Biomédica de Málaga-IBIMA, 29010 Málaga, Spain; UGC Salud Mental, Hospital Regional Universitario de Málaga, 29010 Málaga, Spain.
| | - Juan Suárez
- Instituto de investigación Biomédica de Málaga-IBIMA, 29010 Málaga, Spain; Universidad de Málaga, Andalucia Tech, Facultad de Medicina, Campus de Teatinos s/n, 29071 Málaga, Spain; Departamento de Anatomía Humana, Medicina Legal e Historia de la Ciencia, Universidad de Málaga, 29071 Málaga, Spain.
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20
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Gao D, Jiao J, Wang Z, Huang X, Ni X, Fang S, Zhou Q, Zhu X, Sun L, Yang Z, Yuan H. The roles of cell-cell and organ-organ crosstalk in the type 2 diabetes mellitus associated inflammatory microenvironment. Cytokine Growth Factor Rev 2022; 66:15-25. [PMID: 35459618 DOI: 10.1016/j.cytogfr.2022.04.002] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2022] [Revised: 04/08/2022] [Accepted: 04/11/2022] [Indexed: 11/30/2022]
Abstract
Type 2 diabetes mellitus (T2DM) is a classic metaflammatory disease, and the inflammatory states of the pancreatic islet and insulin target organs have been well confirmed. However, abundant evidence demonstrates that there are countless connections between these organs in the presence of a low degree of inflammation. In this review, we focus on cell-cell crosstalk among local cells in the islet and organ-organ crosstalk among insulin-related organs. In contrast to that in acute inflammation, macrophages are the dominant immune cells causing inflammation in the islets and insulin target organs in T2DM. In the inflammatory microenvironment (IME) of the islet, cell-cell crosstalk involving local macrophage polarization and proinflammatory cytokine production impair insulin secretion by β-cells. Furthermore, organ-organ crosstalk, including the gut-brain-pancreas axis and interactions among insulin-related organs during inflammation, reduces insulin sensitivity and induces endocrine dysfunction. Therefore, this crosstalk ultimately results in a cascade leading to β-cell dysfunction. These findings could have broad implications for therapies aimed at treating T2DM.
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Affiliation(s)
- Danni Gao
- The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology of National Health Commission, Beijing 100730, PR China; Peking University Fifth School of Clinical Medicine, Beijing 100730, PR China
| | - Juan Jiao
- Department of Clinical Laboratory, the Seventh Medical Centre of Chinese PLA General Hospital, Beijing 100700, PR China
| | - Zhaoping Wang
- The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology of National Health Commission, Beijing 100730, PR China
| | - Xiuqing Huang
- The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology of National Health Commission, Beijing 100730, PR China
| | - Xiaolin Ni
- The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology of National Health Commission, Beijing 100730, PR China
| | - Sihang Fang
- The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology of National Health Commission, Beijing 100730, PR China
| | - Qi Zhou
- The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology of National Health Commission, Beijing 100730, PR China
| | - Xiaoquan Zhu
- The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology of National Health Commission, Beijing 100730, PR China
| | - Liang Sun
- The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology of National Health Commission, Beijing 100730, PR China
| | - Ze Yang
- The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology of National Health Commission, Beijing 100730, PR China
| | - Huiping Yuan
- The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology of National Health Commission, Beijing 100730, PR China; Peking University Fifth School of Clinical Medicine, Beijing 100730, PR China.
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21
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Oliveira LDC, Morais GP, Ropelle ER, de Moura LP, Cintra DE, Pauli JR, de Freitas EC, Rorato R, da Silva ASR. Using Intermittent Fasting as a Non-pharmacological Strategy to Alleviate Obesity-Induced Hypothalamic Molecular Pathway Disruption. Front Nutr 2022; 9:858320. [PMID: 35445066 PMCID: PMC9014844 DOI: 10.3389/fnut.2022.858320] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2022] [Accepted: 02/25/2022] [Indexed: 12/18/2022] Open
Abstract
Intermittent fasting (IF) is a popular intervention used to fight overweight/obesity. This condition is accompanied by hypothalamic inflammation, limiting the proper signaling of molecular pathways, with consequent dysregulation of food intake and energy homeostasis. This mini-review explored the therapeutic modulation potential of IF regarding the disruption of these molecular pathways. IF seems to modulate inflammatory pathways in the brain, which may also be correlated with the brain-microbiota axis, improving hypothalamic signaling of leptin and insulin, and inducing the autophagic pathway in hypothalamic neurons, contributing to weight loss in obesity. Evidence also suggests that when an IF protocol is performed without respecting the circadian cycle, it can lead to dysregulation in the expression of circadian cycle regulatory genes, with potential health damage. In conclusion, IF may have the potential to be an adjuvant treatment to improve the reestablishment of hypothalamic responses in obesity.
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Affiliation(s)
- Luciana da Costa Oliveira
- Postgraduate Program in Rehabilitation and Functional Performance, Ribeirão Preto Medical School, University of São Paulo, São Paulo, Brazil
| | - Gustavo Paroschi Morais
- Postgraduate Program in Rehabilitation and Functional Performance, Ribeirão Preto Medical School, University of São Paulo, São Paulo, Brazil
| | - Eduardo R. Ropelle
- Laboratory of Molecular Biology of Exercise, School of Applied Sciences, University of Campinas, São Paulo, Brazil
| | - Leandro P. de Moura
- Laboratory of Molecular Biology of Exercise, School of Applied Sciences, University of Campinas, São Paulo, Brazil
| | - Dennys E. Cintra
- Laboratory of Molecular Biology of Exercise, School of Applied Sciences, University of Campinas, São Paulo, Brazil
| | - José R. Pauli
- Laboratory of Molecular Biology of Exercise, School of Applied Sciences, University of Campinas, São Paulo, Brazil
| | - Ellen C. de Freitas
- School of Physical Education and Sport of Ribeirão Preto, University of São Paulo, São Paulo, Brazil
| | - Rodrigo Rorato
- Postgraduate Program in Molecular Biology, Laboratory of Stress Neuroendocrinology, Department of Biophysics, Paulista Medical School, Federal University of São Paulo, São Paulo, Brazil
- Rodrigo Rorato,
| | - Adelino Sanchez R. da Silva
- Postgraduate Program in Rehabilitation and Functional Performance, Ribeirão Preto Medical School, University of São Paulo, São Paulo, Brazil
- School of Physical Education and Sport of Ribeirão Preto, University of São Paulo, São Paulo, Brazil
- *Correspondence: Adelino Sanchez R. da Silva,
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22
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Sa M, Park MG, Lee CJ. Role of Hypothalamic Reactive Astrocytes in Diet-Induced Obesity. Mol Cells 2022; 45:65-75. [PMID: 35236781 PMCID: PMC8907000 DOI: 10.14348/molcells.2022.2044] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2021] [Revised: 01/07/2022] [Accepted: 01/12/2022] [Indexed: 11/30/2022] Open
Abstract
Hypothalamus is a brain region that controls food intake and energy expenditure while sensing signals that convey information about energy status. Within the hypothalamus, molecularly and functionally distinct neurons work in concert under physiological conditions. However, under pathological conditions such as in diet-induced obesity (DIO) model, these neurons show dysfunctional firing patterns and distorted regulation by neurotransmitters and neurohormones. Concurrently, resident glial cells including astrocytes dramatically transform into reactive states. In particular, it has been reported that reactive astrogliosis is observed in the hypothalamus, along with various neuroinflammatory signals. However, how the reactive astrocytes control and modulate DIO by influencing neighboring neurons is not well understood. Recently, new lines of evidence have emerged indicating that these reactive astrocytes directly contribute to the pathology of obesity by synthesizing and tonically releasing the major inhibitory transmitter GABA. The released GABA strongly inhibits the neighboring neurons that control energy expenditure. These surprising findings shed light on the interplay between reactive astrocytes and neighboring neurons in the hypothalamus. This review summarizes recent discoveries related to the functions of hypothalamic reactive astrocytes in obesity and raises new potential therapeutic targets against obesity.
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Affiliation(s)
- Moonsun Sa
- KU-KIST Graduate School of Converging Science and Technology, Korea University, Seoul 02841, Korea
- Center for Cognition and Sociality, Institute for Basic Science (IBS), Daejeon 34126, Korea
| | - Mingu Gordon Park
- KU-KIST Graduate School of Converging Science and Technology, Korea University, Seoul 02841, Korea
- Center for Cognition and Sociality, Institute for Basic Science (IBS), Daejeon 34126, Korea
| | - C. Justin Lee
- KU-KIST Graduate School of Converging Science and Technology, Korea University, Seoul 02841, Korea
- Center for Cognition and Sociality, Institute for Basic Science (IBS), Daejeon 34126, Korea
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23
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Obara-Michlewska M. The contribution of astrocytes to obesity-associated metabolic disturbances. J Biomed Res 2022; 36:299-311. [PMID: 36131679 PMCID: PMC9548436 DOI: 10.7555/jbr.36.20200020] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Affiliation(s)
- Marta Obara-Michlewska
- Department of Neurotoxicology, Mossakowski Medical Research Institute, Polish Academy of Sciences, Warsaw 02-106, Poland
- Marta Obara-Michlewska, Department of Neurotoxicology, Mossakowski Medical Research Institute, Polish Academy of Sciences, 5 A. Pawinskiego Street, Warsaw 02-106, Poland. Tel/Fax: +48-22-6046416, E-mail:
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24
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Bhusal A, Rahman MH, Suk K. Hypothalamic inflammation in metabolic disorders and aging. Cell Mol Life Sci 2021; 79:32. [PMID: 34910246 PMCID: PMC11071926 DOI: 10.1007/s00018-021-04019-x] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2021] [Revised: 09/01/2021] [Accepted: 10/29/2021] [Indexed: 12/15/2022]
Abstract
The hypothalamus is a critical brain region for the regulation of energy homeostasis. Over the years, studies on energy metabolism primarily focused on the neuronal component of the hypothalamus. Studies have recently uncovered the vital role of glial cells as an additional player in energy balance regulation. However, their inflammatory activation under metabolic stress condition contributes to various metabolic diseases. The recruitment of monocytes and macrophages in the hypothalamus helps sustain such inflammation and worsens the disease state. Neurons were found to actively participate in hypothalamic inflammatory response by transmitting signals to the surrounding non-neuronal cells. This activation of different cell types in the hypothalamus leads to chronic, low-grade inflammation, impairing energy balance and contributing to defective feeding habits, thermogenesis, and insulin and leptin signaling, eventually leading to metabolic disorders (i.e., diabetes, obesity, and hypertension). The hypothalamus is also responsible for the causation of systemic aging under metabolic stress. A better understanding of the multiple factors contributing to hypothalamic inflammation, the role of the different hypothalamic cells, and their crosstalks may help identify new therapeutic targets. In this review, we focus on the role of glial cells in establishing a cause-effect relationship between hypothalamic inflammation and the development of metabolic diseases. We also cover the role of other cell types and discuss the possibilities and challenges of targeting hypothalamic inflammation as a valid therapeutic approach.
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Affiliation(s)
- Anup Bhusal
- Department of Pharmacology, School of Medicine, Kyungpook National University, Daegu, 41944, Republic of Korea
- BK21 Plus KNU Biomedical Convergence Program, Department of Biomedical Science, School of Medicine, Kyungpook National University, Daegu, 41944, Republic of Korea
| | - Md Habibur Rahman
- Department of Pharmacology, School of Medicine, Kyungpook National University, Daegu, 41944, Republic of Korea
- Division of Endocrinology, Department of Medicine, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, 08901, USA
| | - Kyoungho Suk
- Department of Pharmacology, School of Medicine, Kyungpook National University, Daegu, 41944, Republic of Korea.
- BK21 Plus KNU Biomedical Convergence Program, Department of Biomedical Science, School of Medicine, Kyungpook National University, Daegu, 41944, Republic of Korea.
- Brain Science and Engineering Institute, Kyungpook National University, Daegu, 41944, Republic of Korea.
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25
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Meneyrol K, Estévez-Salguero Á, González-García I, Guitton J, Taouis M, Benomar Y, Magnan C, López M, Le Stunff H. Ovarian insufficiency impairs glucose-stimulated insulin secretion through activation of hypothalamic de novo ceramide synthesis. Metabolism 2021; 123:154846. [PMID: 34371064 DOI: 10.1016/j.metabol.2021.154846] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/22/2021] [Revised: 07/25/2021] [Accepted: 08/02/2021] [Indexed: 12/20/2022]
Abstract
Oestrogens regulate body weight through their action on hypothalamus to modulate food intake and energy expenditure. Hypothalamic de novo ceramide synthesis plays a central role on obesity induced by oestrogen deficiency. Depletion in oestrogens is also known to be associated with glucose intolerance, which favours type 2 diabetes (T2D). However, the implication of hypothalamic ceramide in the regulation of glucose homeostasis by oestrogen is unknown. Here, we studied glucose homeostasis and insulin secretion in ovariectomized (OVX) female rats. OVX induces body weight gain associated with a hypothalamic inflammation and impaired glucose homeostasis. Genetic blockade of ceramide synthesis in the ventromedial nucleus of the hypothalamus (VMH) reverses hypothalamic inflammation and partly restored glucose tolerance induced by OVX. Furthermore, glucose-stimulated insulin secretion (GSIS) is increased in OVX rats due to a raise of insulin secretion second phase, a characteristic of early stage of T2D. In contrast, GSIS from isolated islets of OVX rats is totally blunted. Inhibition of ceramide synthesis in the VMH restores GSIS from isolated OVX islets and represses the second phase of insulin secretion. Stimulation of oestrogen receptor α (ERα) by oestradiol (E2) down-regulates ceramide synthesis in hypothalamic neuronal GT1-7 cells but no in microglial SIM-A9 cells. In contrast, genetic inactivation of ERα in VMH upregulates ceramide synthesis. These results indicate that hypothalamic neuronal de novo ceramide synthesis triggers the OVX-dependent impairment of glucose homeostasis which is partly mediated by a dysregulation of GSIS.
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Affiliation(s)
- Kelly Meneyrol
- Unité de Biologie Fonctionnelle et Adaptative, CNRS UMR 8251, Université de Paris, Paris, France
| | - Ánxela Estévez-Salguero
- NeurObesity Group, Department of Physiology, CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela 15782, Spain; CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), 15706, Spain
| | - Ismael González-García
- NeurObesity Group, Department of Physiology, CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela 15782, Spain; CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), 15706, Spain
| | - Jeanne Guitton
- Institut des Neurosciences Paris-Saclay, CNRS UMR 9197, Université Paris Saclay, Orsay, France
| | - Mohammed Taouis
- Institut des Neurosciences Paris-Saclay, CNRS UMR 9197, Université Paris Saclay, Orsay, France
| | - Yacir Benomar
- Institut des Neurosciences Paris-Saclay, CNRS UMR 9197, Université Paris Saclay, Orsay, France
| | - Christophe Magnan
- Unité de Biologie Fonctionnelle et Adaptative, CNRS UMR 8251, Université de Paris, Paris, France
| | - Miguel López
- NeurObesity Group, Department of Physiology, CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela 15782, Spain; CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), 15706, Spain.
| | - Hervé Le Stunff
- Unité de Biologie Fonctionnelle et Adaptative, CNRS UMR 8251, Université de Paris, Paris, France; Institut des Neurosciences Paris-Saclay, CNRS UMR 9197, Université Paris Saclay, Orsay, France.
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26
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Zhou B, Yuan Y, Shi L, Hu S, Wang D, Yang Y, Pan Y, Kong D, Shikov AN, Duez P, Jin M, Li X, Hu X. Creation of an Anti-Inflammatory, Leptin-Dependent Anti-Obesity Celastrol Mimic with Better Druggability. Front Pharmacol 2021; 12:705252. [PMID: 34526895 PMCID: PMC8435713 DOI: 10.3389/fphar.2021.705252] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2021] [Accepted: 08/04/2021] [Indexed: 12/25/2022] Open
Abstract
Obesity is characterized by an excessive body mass, but is also closely associated with metabolic syndrome. And, so far, only limited pharmacological treatments are available for obesity management. Celastrol, a pentacyclic triterpenoid from a traditional Chinese medicine (Tripterygium wilfordii Hook.f.), has shown remarkable potency against obesity, inflammation and cancer, but its high toxicity, low natural abundance and tedious chemical synthesis hindered its translation into clinics. In the present work, a triterpenoid library was screened for compounds with both high natural abundance and structural similarity to celastrol; from this library, glycyrrhetinic acid (GA), a compound present in extremely high yields in Glycyrrhiza uralensis Fisch. ex DC., was selected as a possible scaffold for a celastrol mimic active against obesity. A simple chemical modification of GA resulted in GA-02, a derivative that suppressed 68% of food intake in diet-induced obesity mice and led to 26.4% weight loss in 2 weeks. GA-02 plays a role in obesity treatment by re-activating leptin signaling and reducing systemic and, more importantly, hypothalamic inflammation. GA-02 was readily bioavailable with unnoticeable in vitro and in vivo toxicities. The strategy of scaffold search and modification on the basis of bio-content and structural similarity has proved to be a green, economic, efficient and practical way of widening the medicinal applications of “imperfect” bioactive natural compounds.
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Affiliation(s)
- Bo Zhou
- Laboratory of Natural Medicine and Molecular Engineering, College of Plant Science and Technology, Huazhong Agricultural University, Wuhan, China
| | - Yaxia Yuan
- Department of Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville, FL, United States
| | - Le Shi
- Laboratory of Natural Medicine and Molecular Engineering, College of Plant Science and Technology, Huazhong Agricultural University, Wuhan, China
| | - Sheng Hu
- Hubei Cancer Hospital, Wuhan, China
| | - Dong Wang
- Agricultural Bioinformatics Key Laboratory of Hubei Province, College of Informatics, Huazhong Agricultural University, Wuhan, China
| | - Yang Yang
- Laboratory of Natural Medicine and Molecular Engineering, College of Plant Science and Technology, Huazhong Agricultural University, Wuhan, China
| | - Yuanhu Pan
- National Reference Laboratory of Veterinary Drug Residues and MAO Key Laboratory for Detection of Veterinary Drug Residues, Huazhong Agricultural University, Wuhan, China
| | - Dexin Kong
- Agricultural Bioinformatics Key Laboratory of Hubei Province, College of Informatics, Huazhong Agricultural University, Wuhan, China
| | - Alexander N Shikov
- Department of Pharmaceutical Formulations, St. Petersburg State Chemical Pharmaceutical University, St. Petersburg, Russia
| | - Pierre Duez
- Unit of Therapeutic Chemistry and Pharmacognosy, University of Mons, Mons, Belgium
| | - Moonsoo Jin
- Department of Radiology, Weill Cornell Medical College, New York, NY, United States
| | - Xiaohua Li
- Laboratory of Natural Medicine and Molecular Engineering, College of Plant Science and Technology, Huazhong Agricultural University, Wuhan, China
| | - Xuebo Hu
- Laboratory of Natural Medicine and Molecular Engineering, College of Plant Science and Technology, Huazhong Agricultural University, Wuhan, China
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Hsu YH, Wu CH, Chiu CJ, Chen WT, Chang YC, Wabitsch M, Chang MS. IL-20 is involved in obesity by modulation of adipogenesis and macrophage dysregulation. Immunology 2021; 164:817-833. [PMID: 34403503 DOI: 10.1111/imm.13403] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2021] [Revised: 08/06/2021] [Accepted: 08/07/2021] [Indexed: 12/20/2022] Open
Abstract
IL-20 is a proinflammatory cytokine of the IL-10 family and involved in several diseases. However, the regulatory role of IL-20 in obesity is not well understood. We explored the function of IL-20 in the pathogenesis of obesity-induced insulin resistance by ELISA, Western blotting and flow cytometry. The therapeutic potential of IL-20 monoclonal antibody 7E for ameliorating diet-induced obesity was analysed in murine models. Higher serum IL-20 levels were detected in obese patients. It was upregulated in leptin-deficient (ob/ob), leptin-resistant (db/db) and high-fat diet (HFD)-induced murine obesity models. In vitro, IL-20 regulated the adipocyte differentiation and the polarization of bone marrow-derived macrophages into proinflammatory M1 type. It also caused inflammation and macrophage retention in adipose tissues by upregulating TNF-α, monocyte chemotactic protein 1 (MCP-1), netrin 1 and unc5b (netrin receptor) expression in macrophages and netrin 1, leptin and MCP-1 in adipocytes. IL-20 promoted insulin resistance by inhibiting glucose uptake in mature adipocytes through the SOCS-3 pathway. In HFD-induced obesity in mice, 7E treatment reduced body weight and improved glucose tolerance and insulin sensitivity; it also reduced local inflammation and the number of M1-like macrophages in adipose tissues. We have identified a critical role of IL-20 in obesity-induced inflammation and insulin resistance, and we conclude that IL-20 may be a novel target for treating obesity and insulin resistance in patients with metabolic disorders.
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Affiliation(s)
- Yu-Hsiang Hsu
- Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan.,Research Center of Clinical Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Chih-Hsing Wu
- Department of Family Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Chiao-Juno Chiu
- Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Wei-Ting Chen
- Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Yi-Chieh Chang
- Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Martin Wabitsch
- Division of Pediatric Endocrinology and Diabetes, Department of Pediatrics and Adolescent Medicine, Ulm University Medical Center, Ulm, Germany
| | - Ming-Shi Chang
- Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan
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Ullah R, Rauf N, Nabi G, Yi S, Yu-Dong Z, Fu J. Mechanistic insight into high-fat diet-induced metabolic inflammation in the arcuate nucleus of the hypothalamus. Biomed Pharmacother 2021; 142:112012. [PMID: 34388531 DOI: 10.1016/j.biopha.2021.112012] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2021] [Revised: 07/31/2021] [Accepted: 08/03/2021] [Indexed: 12/16/2022] Open
Abstract
A high-fat diet (HFD) is linked with cytokines production by non-neuronal cells within the hypothalamus, which mediates metabolic inflammation. These cytokines then activate different inflammatory mediators in the arcuate nucleus of the hypothalamus (ARC), a primary hypothalamic area accommodating proopiomelanocortin (POMC) and agouti-related peptide (AGRP) neurons, first-order neurons that sense and integrate peripheral metabolic signals and then respond accordingly. These mediators, such as inhibitor of κB kinase-β (IKKβ), suppression of cytokine signaling 3 (SOCS3), c-Jun N-terminal kinases (JNKs), protein kinase C (PKC), etc., cause insulin and leptin resistance in POMC and AGRP neurons and support obesity and related metabolic complications. On the other hand, inhibition of these mediators has been shown to counteract the impaired metabolism. Therefore, it is important to discuss the contribution of neuronal and non-neuronal cells in HFD-induced hypothalamic inflammation. Furthermore, understanding few other questions, such as the diets causing hypothalamic inflammation, the gender disparity in response to HFD feeding, and how hypothalamic inflammation affects ARC neurons to cause impaired metabolism, will be helpful for the development of therapeutic approaches to prevent or treat HFD-induced obesity.
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Affiliation(s)
- Rahim Ullah
- Department of Endocrinology, Children's Hospital, Zhejiang University School of Medicine, Hangzhou 310052, China; Center for Brain Research and Brain-Machine Integration, School of Brain Science and Brain Medicine, Zhejiang University, Hangzhou, China
| | - Naveed Rauf
- Department of Endocrinology, Children's Hospital, Zhejiang University School of Medicine, Hangzhou 310052, China
| | - Ghulam Nabi
- Laboratory of Animal Physiology, Biochemistry and Molecular Biology of Hebei Province, College of Life Sciences, Hebei Normal University, Shijiazhuang 050024, Hebei Province, China; Department of Life Sciences, School of Science, University of Management and Technology (UMT), Lahore, Pakistan
| | - Shen Yi
- Center for Brain Research and Brain-Machine Integration, School of Brain Science and Brain Medicine, Zhejiang University, Hangzhou, China.
| | - Zhou Yu-Dong
- Center for Brain Research and Brain-Machine Integration, School of Brain Science and Brain Medicine, Zhejiang University, Hangzhou, China.
| | - Junfen Fu
- Department of Endocrinology, Children's Hospital, Zhejiang University School of Medicine, Hangzhou 310052, China; National Clinical Research Center for Child Health, Hangzhou 310052, China; National Children's Regional Medical Center, Hangzhou 310052, China.
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Bramorska A, Zarzycka W, Podolecka W, Kuc K, Brzezicka A. Age-Related Cognitive Decline May Be Moderated by Frequency of Specific Food Products Consumption. Nutrients 2021; 13:2504. [PMID: 34444664 PMCID: PMC8399560 DOI: 10.3390/nu13082504] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2021] [Revised: 07/18/2021] [Accepted: 07/18/2021] [Indexed: 02/06/2023] Open
Abstract
Our study aimed to evaluate whether the type of food products and the frequency of their consumption are associated with cognitive functioning in younger and older adults. The impact of diets that are high in added sugars and saturated fat on cognitive functioning, especially on memory, was at the center of our interest. Participants in the study were 204 healthy adults (aged 20-55) who performed a multitasking cognitive test and completed dietary and psychological questionnaires. Stepwise regression analysis with age and food consumption patterns as predictors, and the cognitive task performance as a dependent variable, revealed that cognitive task performance worsened with age. However, we found that the frequency of consuming different types of foods (healthy versus unhealthy dietary patterns) moderates the effects of age on cognitive functioning. Red meat and animal fat consumption were negatively correlated with cognitive performance, and this relation was dependent on the age of our participants. Conversely, white meat and fish consumption were positively related to memory. Different indices of dietary patterns (both positive and negative) were stronger predictors of cognitive performance in the older adult group. We interpret our results as evidence that diet may be a protective (or worsening) factor in age-related cognitive decline.
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Affiliation(s)
- Aleksandra Bramorska
- SWPS Institute of Psychology, University of Social Sciences and Humanities, 03-815 Warsaw, Poland; (W.Z.); (W.P.); (K.K.); (A.B.)
- Faculty of Information Technology, Polish-Japanese Academy of Information Technology, 02-008 Warsaw, Poland
| | - Wanda Zarzycka
- SWPS Institute of Psychology, University of Social Sciences and Humanities, 03-815 Warsaw, Poland; (W.Z.); (W.P.); (K.K.); (A.B.)
| | - Wiktoria Podolecka
- SWPS Institute of Psychology, University of Social Sciences and Humanities, 03-815 Warsaw, Poland; (W.Z.); (W.P.); (K.K.); (A.B.)
| | - Katarzyna Kuc
- SWPS Institute of Psychology, University of Social Sciences and Humanities, 03-815 Warsaw, Poland; (W.Z.); (W.P.); (K.K.); (A.B.)
| | - Aneta Brzezicka
- SWPS Institute of Psychology, University of Social Sciences and Humanities, 03-815 Warsaw, Poland; (W.Z.); (W.P.); (K.K.); (A.B.)
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A Negative Energy Balance Is Associated with Metabolic Dysfunctions in the Hypothalamus of a Humanized Preclinical Model of Alzheimer's Disease, the 5XFAD Mouse. Int J Mol Sci 2021; 22:ijms22105365. [PMID: 34065168 PMCID: PMC8161294 DOI: 10.3390/ijms22105365] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Revised: 05/15/2021] [Accepted: 05/16/2021] [Indexed: 12/19/2022] Open
Abstract
Increasing evidence links metabolic disorders with neurodegenerative processes including Alzheimer’s disease (AD). Late AD is associated with amyloid (Aβ) plaque accumulation, neuroinflammation, and central insulin resistance. Here, a humanized AD model, the 5xFAD mouse model, was used to further explore food intake, energy expenditure, neuroinflammation, and neuroendocrine signaling in the hypothalamus. Experiments were performed on 6-month-old male and female full transgenic (Tg5xFAD/5xFAD), heterozygous (Tg5xFAD/-), and non-transgenic (Non-Tg) littermates. Although histological analysis showed absence of Aβ plaques in the hypothalamus of 5xFAD mice, this brain region displayed increased protein levels of GFAP and IBA1 in both Tg5xFAD/- and Tg5xFAD/5xFAD mice and increased expression of IL-1β in Tg5xFAD/5xFAD mice, suggesting neuroinflammation. This condition was accompanied by decreased body weight, food intake, and energy expenditure in both Tg5xFAD/- and Tg5xFAD/5xFAD mice. Negative energy balance was associated with altered circulating levels of insulin, GLP-1, GIP, ghrelin, and resistin; decreased insulin and leptin hypothalamic signaling; dysregulation in main metabolic sensors (phosphorylated IRS1, STAT5, AMPK, mTOR, ERK2); and neuropeptides controlling energy balance (NPY, AgRP, orexin, MCH). These results suggest that glial activation and metabolic dysfunctions in the hypothalamus of a mouse model of AD likely result in negative energy balance, which may contribute to AD pathogenesis development.
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Alves SS, Silva-Junior RMPD, Servilha-Menezes G, Homolak J, Šalković-Petrišić M, Garcia-Cairasco N. Insulin Resistance as a Common Link Between Current Alzheimer's Disease Hypotheses. J Alzheimers Dis 2021; 82:71-105. [PMID: 34024838 DOI: 10.3233/jad-210234] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Almost 115 years ago, Alois Alzheimer described Alzheimer's disease (AD) for the first time. Since then, many hypotheses have been proposed. However, AD remains a severe health public problem. The current medical approaches for AD are limited to symptomatic interventions and the complexity of this disease has led to a failure rate of approximately 99.6%in AD clinical trials. In fact, no new drug has been approved for AD treatment since 2003. These failures indicate that we are failing in mimicking this disease in experimental models. Although most studies have focused on the amyloid cascade hypothesis of AD, the literature has made clear that AD is rather a multifactorial disorder. Therefore, the persistence in a single theory has resulted in lost opportunities. In this review, we aim to present the striking points of the long scientific path followed since the description of the first AD case and the main AD hypotheses discussed over the last decades. We also propose insulin resistance as a common link between many other hypotheses.
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Affiliation(s)
- Suélen Santos Alves
- Department of Neurosciences and Behavioral Sciences, Ribeirão Preto Medical School - University of São Paulo (FMRP-USP), Ribeirão Preto, São Paulo, Brazil
| | - Rui Milton Patrício da Silva-Junior
- Department of Internal Medicine, Ribeirão Preto Medical School -University of São Paulo (FMRP-USP), Ribeirão Preto, São Paulo, Brazil.,Department of Physiology, Ribeirão Preto Medical School - University of São Paulo (FMRP-USP), Ribeirão Preto, São Paulo, Brazil
| | - Gabriel Servilha-Menezes
- Department of Physiology, Ribeirão Preto Medical School - University of São Paulo (FMRP-USP), Ribeirão Preto, São Paulo, Brazil
| | - Jan Homolak
- Department of Pharmacology, University of Zagreb School of Medicine, Zagreb, Croatia.,Croatian Institute for Brain Research, University of Zagreb School of Medicine, Zagreb, Croatia
| | - Melita Šalković-Petrišić
- Department of Pharmacology, University of Zagreb School of Medicine, Zagreb, Croatia.,Croatian Institute for Brain Research, University of Zagreb School of Medicine, Zagreb, Croatia
| | - Norberto Garcia-Cairasco
- Department of Neurosciences and Behavioral Sciences, Ribeirão Preto Medical School - University of São Paulo (FMRP-USP), Ribeirão Preto, São Paulo, Brazil.,Department of Physiology, Ribeirão Preto Medical School - University of São Paulo (FMRP-USP), Ribeirão Preto, São Paulo, Brazil
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32
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de Medeiros SF, Rodgers RJ, Norman RJ. Adipocyte and steroidogenic cell cross-talk in polycystic ovary syndrome. Hum Reprod Update 2021; 27:771-796. [PMID: 33764457 DOI: 10.1093/humupd/dmab004] [Citation(s) in RCA: 49] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2020] [Revised: 01/08/2021] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Metabolic and endocrine alterations in women with polycystic ovary syndrome (PCOS) affect adipose tissue mass and distribution. PCOS is characterised by hyperandrogenism, obesity and adipocyte dysfunction. Hyperandrogenism in PCOS drives dysfunctional adipocyte secretion of potentially harmful adipocytokines. Glucocorticoids and sex-steroids modulate adipocyte development and function. For their part, adipocyte products interact with adrenal and ovarian steroidogenic cells. Currently, the relationship between adipocyte and steroidogenic cells is not clear, and for these reasons, it is important to elucidate the interrelationship between these cells in women with and without PCOS. OBJECTIVE AND RATIONALE This comprehensive review aims to assess current knowledge regarding the interrelationship between adipocytes and adrenal and ovarian steroidogenic cells in animal models and humans with or without PCOS. SEARCH METHODS We searched for articles published in English and Portuguese in PubMed. Keywords were as follows: polycystic ovary syndrome, steroidogenesis, adrenal glands, theca cells, granulosa cells, adipocytes, adipocytokines, obesity, enzyme activation, and cytochrome P450 enzymes. We expanded the search into the references from the retrieved articles. OUTCOMES Glucocorticoids and sex-steroids modulate adipocyte differentiation and function. Dysfunctional adipocyte products play important roles in the metabolic and endocrine pathways in animals and women with PCOS. Most adipokines participate in the regulation of the hypothalamic-pituitary-adrenal and ovarian axes. In animal models of PCOS, hyperinsulinemia and poor fertility are common; various adipokines modulate ovarian steroidogenesis, depending on the species. Women with PCOS secrete unbalanced levels of adipocyte products, characterised by higher levels of leptin and lower levels of adiponectin. Leptin expression positively correlates with body mass index, waist/hip ratio and levels of total cholesterol, triglyceride, luteinising hormone, oestradiol and androgens. Leptin inhibits the production of oestradiol and, in granulosa cells, may modulate 17-hydroxylase and aromatase enzyme activities. Adiponectin levels negatively correlate with fat mass, body mass index, waist-hip ratio, glucose, insulin and triglycerides, and decrease androgen production by altering expression of luteinising hormone receptor, steroidogenic acute regulatory protein, cholesterol-side-chain cleavage enzyme and 17-hydroxylase. Resistin expression positively correlates with body mass index and testosterone, and promotes the expression of 17-hydroxylase enzyme in theca cells. The potential benefits of adipokines in the treatment of women with PCOS require more investigation. WIDER IMPLICATIONS The current data regarding the relationship between adipocyte products and steroidogenic cells are conflicting in animals and humans. Polycystic ovary syndrome is an excellent model to investigate the interrelationship among adipocyte and steroidogenic cells. Women with PCOS manifest some pathological conditions associated with hyperandrogenism and adipocyte products. In animals, cross-talk between cells may vary according to species, and the current review suggests opportunities to test new medications to prevent or even reverse several harmful sequelae of PCOS in humans. Further studies are required to investigate the possible therapeutic application of adipokines in women with obese and non-obese PCOS. Meanwhile, when appropriate, metformin use alone, or associated with flutamide, may be considered for therapeutic purposes.
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Affiliation(s)
- Sebastião Freitas de Medeiros
- Department of Gynecology and Obstetrics, Medical School, Federal University of Mato Grosso; and Tropical Institute of Reproductive Medicine,Cuiabá, MT, Brazil
| | - Raymond Joseph Rodgers
- Paediatrics and Reproductive Health, The University of Adelaide, Adelaide, South Australia, Australia
| | - Robert John Norman
- Robinson Research Institute Adelaide Medical School, Adelaide, South Australia, Australia
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Melo HM, Seixas da Silva GDS, Sant'Ana MR, Teixeira CVL, Clarke JR, Miya Coreixas VS, de Melo BC, Fortuna JTS, Forny-Germano L, Ledo JH, Oliveira MS, Figueiredo CP, Pardossi-Piquard R, Checler F, Delgado-García JM, Gruart A, Velloso LA, Balthazar MLF, Cintra DE, Ferreira ST, De Felice FG. Palmitate Is Increased in the Cerebrospinal Fluid of Humans with Obesity and Induces Memory Impairment in Mice via Pro-inflammatory TNF-α. Cell Rep 2021; 30:2180-2194.e8. [PMID: 32075735 DOI: 10.1016/j.celrep.2020.01.072] [Citation(s) in RCA: 80] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2018] [Revised: 10/08/2019] [Accepted: 01/22/2020] [Indexed: 12/26/2022] Open
Abstract
Obesity has been associated with cognitive decline, atrophy of brain regions related to learning and memory, and higher risk of developing dementia. However, the molecular mechanisms underlying these neurological alterations are still largely unknown. Here, we investigate the effects of palmitate, a saturated fatty acid present at high amounts in fat-rich diets, in the brain. Palmitate is increased in the cerebrospinal fluid (CSF) of overweight and obese patients with amnestic mild cognitive impairment. In mice, intracerebroventricular infusion of palmitate impairs synaptic plasticity and memory. Palmitate induces astroglial and microglial activation in the mouse hippocampus, and its deleterious impact is mediated by microglia-derived tumor necrosis factor alpha (TNF-α) signaling. Our results establish that obesity is associated with increases in CSF palmitate. By defining a pro-inflammatory mechanism by which abnormal levels of palmitate in the brain impair memory, the results further suggest that anti-inflammatory strategies may attenuate memory impairment in obesity.
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Affiliation(s)
- Helen M Melo
- Institute of Medical Biochemistry Leopoldo de Meis, Federal University of Rio de Janeiro, Rio de Janeiro, RJ 21941-902, Brazil
| | - Gisele da S Seixas da Silva
- Federal Institute of Education, Science and Technology of Rio de Janeiro, Rio de Janeiro, RJ 20270-021, Brazil
| | - Marcella Ramos Sant'Ana
- Laboratory of Nutritional Genomics (LabGeN), School of Applied Sciences and CELN - Nutrigenomics and Lipids Research Center, School of Applied Sciences, University of Campinas (UNICAMP), Limeira, SP 13484-350, Brazil
| | - Camila Vieira Ligo Teixeira
- Brazilian Institute of Neuroscience and Neurotechnology (BRAINN) and Department of Neurology, Neuroimaging Laboratory, University of Campinas (UNICAMP), Campinas, SP 13083-887, Brazil
| | - Julia R Clarke
- School of Pharmacy, Federal University of Rio de Janeiro, Rio de Janeiro, RJ 21941-902, Brazil
| | - Vivian S Miya Coreixas
- Institute of Medical Biochemistry Leopoldo de Meis, Federal University of Rio de Janeiro, Rio de Janeiro, RJ 21941-902, Brazil
| | - Bruno C de Melo
- Institute of Medical Biochemistry Leopoldo de Meis, Federal University of Rio de Janeiro, Rio de Janeiro, RJ 21941-902, Brazil
| | - Juliana T S Fortuna
- Institute of Medical Biochemistry Leopoldo de Meis, Federal University of Rio de Janeiro, Rio de Janeiro, RJ 21941-902, Brazil
| | - Leticia Forny-Germano
- Institute of Medical Biochemistry Leopoldo de Meis, Federal University of Rio de Janeiro, Rio de Janeiro, RJ 21941-902, Brazil
| | - José Henrique Ledo
- Institute of Medical Biochemistry Leopoldo de Meis, Federal University of Rio de Janeiro, Rio de Janeiro, RJ 21941-902, Brazil
| | - Maíra S Oliveira
- Institute of Medical Biochemistry Leopoldo de Meis, Federal University of Rio de Janeiro, Rio de Janeiro, RJ 21941-902, Brazil
| | - Claudia P Figueiredo
- School of Pharmacy, Federal University of Rio de Janeiro, Rio de Janeiro, RJ 21941-902, Brazil
| | - Raphaelle Pardossi-Piquard
- Université Côte d'Azur, INSERM, CNRS/UMR7275, IPMC, team labeled "Laboratory of Excellence (LABEX) Distalz," 660 route des Lucioles, 06560 Sophia-Antipolis, Valbonne, France
| | - Frédéric Checler
- Université Côte d'Azur, INSERM, CNRS/UMR7275, IPMC, team labeled "Laboratory of Excellence (LABEX) Distalz," 660 route des Lucioles, 06560 Sophia-Antipolis, Valbonne, France
| | | | - Agnès Gruart
- Division of Neuroscience, Pablo de Olavide University, Seville 41013, Spain
| | - Licio A Velloso
- Laboratory of Cell Signalling, Obesity and Comorbidities Research Centre, University of Campinas, Campinas, SP 13084-761, Brazil
| | - Marcio L F Balthazar
- Brazilian Institute of Neuroscience and Neurotechnology (BRAINN) and Department of Neurology, Neuroimaging Laboratory, University of Campinas (UNICAMP), Campinas, SP 13083-887, Brazil
| | - Dennys E Cintra
- Laboratory of Nutritional Genomics (LabGeN), School of Applied Sciences and CELN - Nutrigenomics and Lipids Research Center, School of Applied Sciences, University of Campinas (UNICAMP), Limeira, SP 13484-350, Brazil
| | - Sergio T Ferreira
- Institute of Medical Biochemistry Leopoldo de Meis, Federal University of Rio de Janeiro, Rio de Janeiro, RJ 21941-902, Brazil; Institute of Biophysics Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro, RJ 21941-902, Brazil
| | - Fernanda G De Felice
- Institute of Medical Biochemistry Leopoldo de Meis, Federal University of Rio de Janeiro, Rio de Janeiro, RJ 21941-902, Brazil; Centre for Neuroscience Studies and Department of Psychiatry, Queen's University, Kingston, ON K7L 3N6, Canada.
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Wu Z, Xi P, Zhang Y, Wang H, Xue J, Sun X, Tian D. LKB1 up-regulation inhibits hypothalamic inflammation and attenuates diet-induced obesity in mice. Metabolism 2021; 116:154694. [PMID: 33358943 DOI: 10.1016/j.metabol.2020.154694] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/07/2020] [Revised: 12/11/2020] [Accepted: 12/15/2020] [Indexed: 12/15/2022]
Abstract
BACKGROUND Diet-induced obesity (DIO) is associated with chronic, low-grade inflammation in the hypothalamus. The inflammatory pathway of the hypothalamus is activated during obesity, and inhibition of activation of the inflammatory pathway can partially reverse obesity. Therefore, exploring new targets for inhibiting hypothalamic inflammation will provide new ideas for the prevention and treatment of obesity. Liver kinase B1 (LKB1), a serine/threonine kinase, is a tumor suppressor and metabolic regulator. Recent studies have shown that LKB1 has a certain anti-inflammatory effect. However, a role of LKB1 in the regulation of hypothalamic inflammation remains unclear. Therefore, we examined whether LKB1 overexpression in the hypothalamus could weaken the hypothalamic inflammation and inhibit the development of obesity. METHODS LKB1 overexpressing adeno-associated virus (AAV) particles were injected stereotactically into the third ventricle (3 V) of C57BL/6 mice fed with HFD. We assessed changes in body mass and adiposity, food intake, hypothalamic inflammatory markers, and energy and glucose metabolism. RESULTS LKB1 up-regulation in hypothalamus attenuated diet-induced hypothalamic inflammation, reduced food intake and body weight gain. In addition, the overexpression of hypothalamic LKB1 increased the insulin sensitivity and improved whole-body lipid metabolism, which attenuated hepatic fat accumulation and serum lipid levels. CONCLUSION Hypothalamic LKB1 up-regulation attenuates hypothalamic inflammation, and protects against hypothalamic inflammation induced damage to melanocortin system, resulting in lower food intake and lower fat mass accumulation, which consequently protects mice from the development of obesity. Our data suggest LKB1 as a novel negative regulator of hypothalamic inflammation, and also a potentially important target for treating other inflammatory diseases.
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Affiliation(s)
- Zhaoxia Wu
- Department of Clinical Laboratory Diagnostics, Tianjin Medical University, Tianjin 300203, China
| | - Pengjiao Xi
- Department of Clinical Laboratory Diagnostics, Tianjin Medical University, Tianjin 300203, China
| | - Yan Zhang
- Department of Clinical Laboratory Diagnostics, Tianjin Medical University, Tianjin 300203, China
| | - Haomin Wang
- Department of Human Anatomy and Histology, Tianjin Medical University, Tianjin 300070, China
| | - Jie Xue
- Department of Human Anatomy and Histology, Tianjin Medical University, Tianjin 300070, China
| | - Xuguo Sun
- Department of Clinical Laboratory Diagnostics, Tianjin Medical University, Tianjin 300203, China
| | - Derun Tian
- Department of Clinical Laboratory Diagnostics, Tianjin Medical University, Tianjin 300203, China; Department of Human Anatomy and Histology, Tianjin Medical University, Tianjin 300070, China.
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Monfort-Pires M, U-Din M, Nogueira GA, de Almeida-Faria J, Sidarta-Oliveira D, Sant'Ana MR, De Lima-Júnior JC, Cintra DE, de Souza HP, Ferreira SRG, Sapienza MT, Virtanen KA, Velloso LA. Short Dietary Intervention with Olive Oil Increases Brown Adipose Tissue Activity in Lean but not Overweight Subjects. J Clin Endocrinol Metab 2021; 106:472-484. [PMID: 33180910 DOI: 10.1210/clinem/dgaa824] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2020] [Indexed: 01/09/2023]
Abstract
BACKGROUND The brown adipose tissue (BAT) is a potential target for the treatment of obesity and metabolic disorders. Its activation by cold exposure or adrenergic drugs can increase systemic insulin sensitivity and improve lipid metabolism; however, little is known about the effects of specific dietary components on BAT activity. OBJECTIVES We asked if a short-term (4 weeks) dietary intervention with olive oil could modify BAT activity in lean and overweight/obese volunteers. DESIGN This was a 4-week open clinical trial in which all participants underwent a dietary intervention with extra-virgin olive oil supplementation. As the initial intake of olive oil was controlled all the participants were controls of themselves. RESULTS The intervention resulted in significant increase in blood monounsaturated fatty acid levels, which was accompanied by increased BAT activity in lean but not in overweight/obese volunteers. In the lean group, an increase in leptin was detected after the intervention, and low leptin values at the beginning of the study were predictive of greater BAT activity after intervention. In addition, increase in leptin concentration was associated with increased BAT activity. Three known endogenous mediators of BAT activity, secretin, fibroblast growth factor 21 (FGF21), and 12,13-dihydroxy-9Z-octadecenoic acid (12,13-diHOME) were increased by intervention in lean, whereas only secretin and FGF21 were increased in subjects with excessive weight. CONCLUSION This study provides clinical evidence for the impact of monounsaturated fatty acids on BAT activity and an advance in the understanding of the beneficial health effects of olive oil.
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Affiliation(s)
- Milena Monfort-Pires
- Laboratory of Cell Signaling, Obesity and Comorbidities Research Center, State University of Campinas (UNICAMP), Campinas, São Paulo, Brazil
| | - Mueez U-Din
- Turku PET Centre, Turku University Hospital, Turku, Finland
| | - Guilherme A Nogueira
- Laboratory of Cell Signaling, Obesity and Comorbidities Research Center, State University of Campinas (UNICAMP), Campinas, São Paulo, Brazil
| | - Juliana de Almeida-Faria
- Laboratory of Cell Signaling, Obesity and Comorbidities Research Center, State University of Campinas (UNICAMP), Campinas, São Paulo, Brazil
| | - Davi Sidarta-Oliveira
- Laboratory of Cell Signaling, Obesity and Comorbidities Research Center, State University of Campinas (UNICAMP), Campinas, São Paulo, Brazil
| | - Marcella Ramos Sant'Ana
- Nutritional Genomics Laboratory, LabGeN, School of Applied Sciences, UNICAMP, Limeira, São Paulo, Brazil
| | - José C De Lima-Júnior
- Laboratory of Cell Signaling, Obesity and Comorbidities Research Center, State University of Campinas (UNICAMP), Campinas, São Paulo, Brazil
| | - Dennys E Cintra
- Nutritional Genomics Laboratory, LabGeN, School of Applied Sciences, UNICAMP, Limeira, São Paulo, Brazil
| | | | - Sandra R G Ferreira
- Department of Epidemiology, School of Public Health - University of São Paulo, São Paulo, SP, Brazil
| | - Marcelo Tatit Sapienza
- Division of Nuclear Medicine, Department of Radiology and Oncology, Medical School of University of São Paulo (FMUSP), São Paulo, Brazil
| | - Kirsi A Virtanen
- Turku PET Centre, Turku University Hospital, Turku, Finland
- Clinical Nutrition, Institute of Public Health and Clinical Nutrition, University of Eastern Finland (UEF), Kuopio, Finland
| | - Licio A Velloso
- Laboratory of Cell Signaling, Obesity and Comorbidities Research Center, State University of Campinas (UNICAMP), Campinas, São Paulo, Brazil
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Komleva Y, Chernykh A, Lopatina O, Gorina Y, Lokteva I, Salmina A, Gollasch M. Inflamm-Aging and Brain Insulin Resistance: New Insights and Role of Life-style Strategies on Cognitive and Social Determinants in Aging and Neurodegeneration. Front Neurosci 2021; 14:618395. [PMID: 33519369 PMCID: PMC7841337 DOI: 10.3389/fnins.2020.618395] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2020] [Accepted: 12/10/2020] [Indexed: 12/13/2022] Open
Abstract
Over the past decades, the human life span has dramatically increased, and therefore, a steady increase in diseases associated with age (such as Alzheimer's disease and Parkinson's disease) is expected. In these neurodegenerative diseases, there is a cognitive decline and memory loss, which accompany increased systemic inflammation, the inflamm-aging, and the insulin resistance. Despite numerous studies of age-related pathologies, data on the contribution of brain insulin resistance and innate immunity components to aging are insufficient. Recently, much research has been focused on the consequences of nutrients and adiposity- and nutrient-related signals in brain aging and cognitive decline. Moreover, given the role of metainflammation in neurodegeneration, lifestyle interventions such as calorie restriction may be an effective way to break the vicious cycle of metainflammation and have a role in social behavior. The various effects of calorie restriction on metainflammation, insulin resistance, and neurodegeneration have been described. Less attention has been paid to the social determinants of aging and the possible mechanism by which calorie restriction might influence social behavior. The purpose of this review is to discuss current knowledge in the interdisciplinary field of geroscience-immunosenescence, inflamm-aging, and metainflammation-which makes a significant contribution to aging. A substantial part of the review is devoted to frontiers in the brain insulin resistance in relation to neuroinflammation. In addition, we summarize new data on potential mechanisms of calorie restriction that influence as a lifestyle intervention on the social brain. This knowledge can be used to initiate successful aging and slow the onset of neurodegenerative diseases.
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Affiliation(s)
- Yulia Komleva
- Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany
- Experimental and Clinical Research Center (ECRC), Charité - Universitätsmedizin Berlin, Berlin, Germany
- Department of Biochemistry, Medical, Pharmaceutical & Toxicological Chemistry, Krasnoyarsk State Medical University named after Professor V.F. Voyno-Yasenetsky, Ministry of Health of the Russian Federation, Krasnoyarsk, Russia
- Research Institute of Molecular Medicine and Pathobiochemistry, Krasnoyarsk State Medical University named after Professor V.F. Voyno-Yasenetsky, Ministry of Health of the Russian Federation, Krasnoyarsk, Russia
| | - Anatoly Chernykh
- Research Institute of Molecular Medicine and Pathobiochemistry, Krasnoyarsk State Medical University named after Professor V.F. Voyno-Yasenetsky, Ministry of Health of the Russian Federation, Krasnoyarsk, Russia
| | - Olga Lopatina
- Department of Biochemistry, Medical, Pharmaceutical & Toxicological Chemistry, Krasnoyarsk State Medical University named after Professor V.F. Voyno-Yasenetsky, Ministry of Health of the Russian Federation, Krasnoyarsk, Russia
- Research Institute of Molecular Medicine and Pathobiochemistry, Krasnoyarsk State Medical University named after Professor V.F. Voyno-Yasenetsky, Ministry of Health of the Russian Federation, Krasnoyarsk, Russia
| | - Yana Gorina
- Department of Biochemistry, Medical, Pharmaceutical & Toxicological Chemistry, Krasnoyarsk State Medical University named after Professor V.F. Voyno-Yasenetsky, Ministry of Health of the Russian Federation, Krasnoyarsk, Russia
- Research Institute of Molecular Medicine and Pathobiochemistry, Krasnoyarsk State Medical University named after Professor V.F. Voyno-Yasenetsky, Ministry of Health of the Russian Federation, Krasnoyarsk, Russia
| | - Irina Lokteva
- Medical Center “Private Practice”, Krasnoyarsk, Russia
| | - Alla Salmina
- Experimental and Clinical Research Center (ECRC), Charité - Universitätsmedizin Berlin, Berlin, Germany
- Department of Biochemistry, Medical, Pharmaceutical & Toxicological Chemistry, Krasnoyarsk State Medical University named after Professor V.F. Voyno-Yasenetsky, Ministry of Health of the Russian Federation, Krasnoyarsk, Russia
- Research Institute of Molecular Medicine and Pathobiochemistry, Krasnoyarsk State Medical University named after Professor V.F. Voyno-Yasenetsky, Ministry of Health of the Russian Federation, Krasnoyarsk, Russia
| | - Maik Gollasch
- Experimental and Clinical Research Center (ECRC), Charité - Universitätsmedizin Berlin, Berlin, Germany
- Greifswald Medical School, University of Greifswald, Greifswald, Germany
- Geriatric Medicine Center, Wolgast Hospital, Wolgast, Germany
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Anklam CFV, Lissarassa YPS, dos Santos AB, Costa-Beber LC, Sulzbacher LM, Goettems-Fiorin PB, Heck TG, Frizzo MN, Ludwig MS. Oxidative and Cellular Stress Markers in Postmenopause Women with Diabetes: The Impact of Years of Menopause. J Diabetes Res 2021; 2021:3314871. [PMID: 34568498 PMCID: PMC8460375 DOI: 10.1155/2021/3314871] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/26/2021] [Accepted: 08/28/2021] [Indexed: 02/08/2023] Open
Abstract
Women live approximately one-third of their lives in postmenopause. Among postmenopausal women, type 2 diabetes mellitus (DM2) is one of the most prevalent chronic diseases. These conditions promote alterations in the oxidative, metabolic, and immune-inflammatory profiles marked by higher extracellular 72 kDa-heat shock protein (eHSP72). Here, we investigated whether the time of menopause is associated with oxidative cellular stress marker levels in postmenopausal women with DM2. Sixty-four women were recruited (56.7 ± 12.6 years old) in the pre- (n = 22) and postmenopause (n = 42) period, with (n = 19) or without DM2 (n = 45), and a fasting blood collection was made for the evaluation of metabolic, oxidative, and inflammatory markers. We found that menopause and DM2 influenced metabolic and oxidative parameters and presented synergistic effects on the plasma lipoperoxidation levels. Also, postmenopausal women had the highest eHSP72 concentration levels associated with the years in postmenopause. We conclude that the time of menopause impacts the markers of cellular stress and increases the risk of oxidative stress, mainly when it is associated with DM2.
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Affiliation(s)
- Carolain Felipin Vincensi Anklam
- Research Group in Physiology, Department of Life Sciences, Regional University of Northwestern Rio Grande Do Sul State (UNIJUI), Rua do Comércio, 3000 Bairro Universitário Ijuí RS, Brazil 98700-000
- Postgraduate Program in Integral Attention to Health (PPGAIS-UNIJUÍ/UNICRUZ), Ijuí, RS, Brazil
| | - Yana Picinin Sandri Lissarassa
- Research Group in Physiology, Department of Life Sciences, Regional University of Northwestern Rio Grande Do Sul State (UNIJUI), Rua do Comércio, 3000 Bairro Universitário Ijuí RS, Brazil 98700-000
- Postgraduate Program in Integral Attention to Health (PPGAIS-UNIJUÍ/UNICRUZ), Ijuí, RS, Brazil
| | - Analú Bender dos Santos
- Research Group in Physiology, Department of Life Sciences, Regional University of Northwestern Rio Grande Do Sul State (UNIJUI), Rua do Comércio, 3000 Bairro Universitário Ijuí RS, Brazil 98700-000
- Postgraduate Program in Integral Attention to Health (PPGAIS-UNIJUÍ/UNICRUZ), Ijuí, RS, Brazil
| | - Lílian Corrêa Costa-Beber
- Research Group in Physiology, Department of Life Sciences, Regional University of Northwestern Rio Grande Do Sul State (UNIJUI), Rua do Comércio, 3000 Bairro Universitário Ijuí RS, Brazil 98700-000
- Postgraduate Program in Integral Attention to Health (PPGAIS-UNIJUÍ/UNICRUZ), Ijuí, RS, Brazil
| | - Lucas Machado Sulzbacher
- Research Group in Physiology, Department of Life Sciences, Regional University of Northwestern Rio Grande Do Sul State (UNIJUI), Rua do Comércio, 3000 Bairro Universitário Ijuí RS, Brazil 98700-000
- Postgraduate Program in Integral Attention to Health (PPGAIS-UNIJUÍ/UNICRUZ), Ijuí, RS, Brazil
| | - Pauline Brendler Goettems-Fiorin
- Research Group in Physiology, Department of Life Sciences, Regional University of Northwestern Rio Grande Do Sul State (UNIJUI), Rua do Comércio, 3000 Bairro Universitário Ijuí RS, Brazil 98700-000
- Postgraduate Program in Integral Attention to Health (PPGAIS-UNIJUÍ/UNICRUZ), Ijuí, RS, Brazil
| | - Thiago Gomes Heck
- Research Group in Physiology, Department of Life Sciences, Regional University of Northwestern Rio Grande Do Sul State (UNIJUI), Rua do Comércio, 3000 Bairro Universitário Ijuí RS, Brazil 98700-000
- Postgraduate Program in Integral Attention to Health (PPGAIS-UNIJUÍ/UNICRUZ), Ijuí, RS, Brazil
- Postgraduate Program in Mathematical and Computational Modeling (PPGMMC-UNIJUÍ), Ijuí, RS, Brazil
| | - Matias Nunes Frizzo
- Research Group in Physiology, Department of Life Sciences, Regional University of Northwestern Rio Grande Do Sul State (UNIJUI), Rua do Comércio, 3000 Bairro Universitário Ijuí RS, Brazil 98700-000
- Postgraduate Program in Integral Attention to Health (PPGAIS-UNIJUÍ/UNICRUZ), Ijuí, RS, Brazil
| | - Mirna Stela Ludwig
- Research Group in Physiology, Department of Life Sciences, Regional University of Northwestern Rio Grande Do Sul State (UNIJUI), Rua do Comércio, 3000 Bairro Universitário Ijuí RS, Brazil 98700-000
- Postgraduate Program in Integral Attention to Health (PPGAIS-UNIJUÍ/UNICRUZ), Ijuí, RS, Brazil
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Abstract
Over the past decade, hypothalamic microinflammation has been studied and appreciated as a core mechanism involved in the advancement of metabolic syndrome and aging. Accumulating evidence suggests that atypical microinflammatory insults disturb hypothalamic regulation resulting in metabolic imbalance and aging progression, establishing a common causality for these two pathophysiologic statuses. Studies have causally linked these changes to activation of key proinflammatory pathways, especially NF-κB signaling within the hypothalamus, which leads to hypothalamic neuronal dysregulation, astrogliosis, microgliosis, and loss of adult hypothalamic neural stem/progenitor cells. While hypothalamic microinflammation is a complex, multifaceted process, initial work has been done to reveal how it contributes to the pathogenesis of metabolic syndrome and aging, and studies inhibiting hypothalamic microinflammation through targeting proinflammatory signaling pathways have shown to be beneficial against these disorders and diseases. In this chapter, we provide a broad overview on hypothalamic microinflammation, focusing on its features, inducers, and shared pathogenic roles in metabolic syndrome and aging.
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Affiliation(s)
- Dongsheng Cai
- Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY, United States.
| | - Sinan Khor
- Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY, United States
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39
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Sergi D, Williams LM. Potential relationship between dietary long-chain saturated fatty acids and hypothalamic dysfunction in obesity. Nutr Rev 2020; 78:261-277. [PMID: 31532491 DOI: 10.1093/nutrit/nuz056] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Diet-induced hypothalamic inflammation, which leads to hypothalamic dysfunction and a loss of regulation of energy balance, is emerging as a potential driver of obesity. Excessive intake of long-chain saturated fatty acids is held to be the causative dietary component in hypothalamic inflammation. This review summarizes current evidence on the role of long-chain saturated fatty acids in promoting hypothalamic inflammation and the related induction of central insulin and leptin insensitivity. Particularly, the present review focuses on the molecular mechanisms linking long-chain saturated fatty acids and hypothalamic inflammation, emphasizing the metabolic fate of fatty acids and the resulting lipotoxicity, which is a key driver of hypothalamic dysfunction. In conclusion, long-chain saturated fatty acids are key nutrients that promote hypothalamic inflammation and dysfunction by fostering the build-up of lipotoxic lipid species, such as ceramide. Furthermore, when long-chain saturated fatty acids are consumed in combination with high levels of refined carbohydrates, the proinflammatory effects are exacerbated via a mechanism that relies on the formation of advanced glycation end products.
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Affiliation(s)
- Domenico Sergi
- Nutrition and Health Substantiation Group, Nutrition and Health Program, Health and Biosecurity, Commonwealth Scientific and Industrial Research Organisation (CSIRO), Adelaide, South Australia, Australia
| | - Lynda M Williams
- Rowett Institute, University of Aberdeen, Foresterhill, Aberdeen, United Kingdom
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40
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Fu Y, Kaneko K, Lin HY, Mo Q, Xu Y, Suganami T, Ravn P, Fukuda M. Gut Hormone GIP Induces Inflammation and Insulin Resistance in the Hypothalamus. Endocrinology 2020; 161:5865317. [PMID: 32603429 PMCID: PMC7410368 DOI: 10.1210/endocr/bqaa102] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/11/2020] [Accepted: 06/24/2020] [Indexed: 02/08/2023]
Abstract
The hypothalamus plays a critical role in controlling energy balance. High-fat diet (HFD) feeding increases the gene expression of proinflammatory mediators and decreases insulin actions in the hypothalamus. Here, we show that a gut-derived hormone, glucose-dependent insulinotropic polypeptide (GIP), whose levels are elevated during diet-induced obesity, promotes and mediates hypothalamic inflammation and insulin resistance during HFD-induced obesity. Unbiased ribonucleic acid sequencing of GIP-stimulated hypothalami revealed that hypothalamic pathways most affected by intracerebroventricular (ICV) GIP stimulation were related to inflammatory-related responses. Subsequent analysis demonstrated that GIP administered either peripherally or centrally, increased proinflammatory-related factors such as Il-6 and Socs3 in the hypothalamus, but not in the cortex of C57BL/6J male mice. Consistently, hypothalamic activation of IκB kinase-β inflammatory signaling was induced by ICV GIP. Further, hypothalamic levels of proinflammatory cytokines and Socs3 were significantly reduced by an antagonistic GIP receptor (GIPR) antibody and by GIPR deficiency. Additionally, centrally administered GIP reduced anorectic actions of insulin in the brain and diminished insulin-induced phosphorylation of Protein kinase B and Glycogen synthase kinase 3β in the hypothalamus. Collectively, these findings reveal a previously unrecognized role for brain GIP signaling in diet-induced inflammation and insulin resistance in the hypothalamus.
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Affiliation(s)
- Yukiko Fu
- Children’s Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, Texas
- Department of Molecular Medicine and Metabolism, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan
| | - Kentaro Kaneko
- Children’s Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, Texas
| | - Hsiao-Yun Lin
- Children’s Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, Texas
| | - Qianxing Mo
- Dan L Duncan Cancer Center and Center for Cell Gene & Therapy, Baylor College of Medicine, Houston, Texas
- Present address: Department of Biostatistics & Bioinformatics, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida 33612
| | - Yong Xu
- Children’s Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, Texas
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas
| | - Takayoshi Suganami
- Department of Molecular Medicine and Metabolism, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan
| | - Peter Ravn
- AstraZeneca, R&D BioPharmaceuticals Unit, Department of Antibody Discovery and Protein Engineering, Cambridge, UK
| | - Makoto Fukuda
- Children’s Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, Texas
- Correspondence: Makoto Fukuda, Children’s Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA. E-mail:
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41
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Kalsbeek MJ, Wolff SE, Korpel NL, la Fleur SE, Romijn JA, Fliers E, Kalsbeek A, Swaab DF, Huitinga I, Hol EM, Yi CX. The impact of antidiabetic treatment on human hypothalamic infundibular neurons and microglia. JCI Insight 2020; 5:133868. [PMID: 32814716 PMCID: PMC7455135 DOI: 10.1172/jci.insight.133868] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2019] [Accepted: 07/08/2020] [Indexed: 12/22/2022] Open
Abstract
Animal studies indicate that hypothalamic dysfunction plays a major role in type 2 diabetes mellitus (T2DM) development, and that insulin resistance and inflammation are important mechanisms involved in this disorder. However, it remains unclear how T2DM and antidiabetic treatments affect the human hypothalamus. Here, we characterized the proopiomelanocortin (POMC) immunoreactive (-ir) neurons, the neuropeptide-Y-ir (NPY-ir) neurons, the ionized calcium-binding adapter molecule 1-ir (iba1-ir) microglia, and the transmembrane protein 119-ir (TMEM119-ir) microglia in the infundibular nucleus (IFN) of human postmortem hypothalamus of 32 T2DM subjects with different antidiabetic treatments and 17 matched nondiabetic control subjects. Compared with matched control subjects, T2DM subjects showed a decrease in the number of POMC-ir neurons, but no changes in NPY-ir neurons or microglia. Interestingly, T2DM subjects treated with the antidiabetic drug metformin had fewer NPY-ir neurons and microglia than T2DM subjects not treated with metformin. We found that the number of microglia correlated with the number of NPY-ir neurons, but only in T2DM subjects. These results indicate that different changes in POMC and NPY neurons and microglial cells in the IFN accompany T2DM. In addition, T2DM treatment modality is associated with highly selective changes in hypothalamic neurons and microglial cells.
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Affiliation(s)
- Martin Jt Kalsbeek
- Laboratory of Endocrinology, and.,Department of Endocrinology and Metabolism, Amsterdam University Medical Center (UMC), University of Amsterdam, Amsterdam, Netherlands.,Netherlands Institute for Neuroscience, an Institute of the Royal Netherlands Academy of Arts and Sciences, Amsterdam, Netherlands
| | - Samantha Ec Wolff
- Laboratory of Endocrinology, and.,Department of Endocrinology and Metabolism, Amsterdam University Medical Center (UMC), University of Amsterdam, Amsterdam, Netherlands.,Netherlands Institute for Neuroscience, an Institute of the Royal Netherlands Academy of Arts and Sciences, Amsterdam, Netherlands
| | - Nikita L Korpel
- Laboratory of Endocrinology, and.,Department of Endocrinology and Metabolism, Amsterdam University Medical Center (UMC), University of Amsterdam, Amsterdam, Netherlands.,Netherlands Institute for Neuroscience, an Institute of the Royal Netherlands Academy of Arts and Sciences, Amsterdam, Netherlands
| | - Susanne E la Fleur
- Laboratory of Endocrinology, and.,Department of Endocrinology and Metabolism, Amsterdam University Medical Center (UMC), University of Amsterdam, Amsterdam, Netherlands.,Netherlands Institute for Neuroscience, an Institute of the Royal Netherlands Academy of Arts and Sciences, Amsterdam, Netherlands
| | - Johannes A Romijn
- Department of Medicine, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands
| | - Eric Fliers
- Department of Endocrinology and Metabolism, Amsterdam University Medical Center (UMC), University of Amsterdam, Amsterdam, Netherlands
| | - Andries Kalsbeek
- Laboratory of Endocrinology, and.,Department of Endocrinology and Metabolism, Amsterdam University Medical Center (UMC), University of Amsterdam, Amsterdam, Netherlands.,Netherlands Institute for Neuroscience, an Institute of the Royal Netherlands Academy of Arts and Sciences, Amsterdam, Netherlands
| | - Dick F Swaab
- Netherlands Institute for Neuroscience, an Institute of the Royal Netherlands Academy of Arts and Sciences, Amsterdam, Netherlands
| | - Inge Huitinga
- Netherlands Institute for Neuroscience, an Institute of the Royal Netherlands Academy of Arts and Sciences, Amsterdam, Netherlands
| | - Elly M Hol
- Department of Translational Neuroscience, University Medical Center Utrecht Brain Center, Utrecht University, Utrecht, Netherlands
| | - Chun-Xia Yi
- Laboratory of Endocrinology, and.,Department of Endocrinology and Metabolism, Amsterdam University Medical Center (UMC), University of Amsterdam, Amsterdam, Netherlands.,Netherlands Institute for Neuroscience, an Institute of the Royal Netherlands Academy of Arts and Sciences, Amsterdam, Netherlands
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42
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Cansell C, Stobbe K, Sanchez C, Le Thuc O, Mosser CA, Ben-Fradj S, Leredde J, Lebeaupin C, Debayle D, Fleuriot L, Brau F, Devaux N, Benani A, Audinat E, Blondeau N, Nahon JL, Rovère C. Dietary fat exacerbates postprandial hypothalamic inflammation involving glial fibrillary acidic protein-positive cells and microglia in male mice. Glia 2020; 69:42-60. [PMID: 32659044 DOI: 10.1002/glia.23882] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2019] [Revised: 06/10/2020] [Accepted: 06/11/2020] [Indexed: 12/15/2022]
Abstract
In humans, obesity is associated with brain inflammation, glial reactivity, and immune cells infiltration. Studies in rodents have shown that glial reactivity occurs within 24 hr of high-fat diet (HFD) consumption, long before obesity development, and takes place mainly in the hypothalamus (HT), a crucial brain structure for controlling body weight. Here, we sought to characterize the postprandial HT inflammatory response to 1, 3, and 6 hr of exposure to either a standard diet (SD) or HFD. HFD exposure increased gene expression of astrocyte and microglial markers (glial fibrillary acidic protein [GFAP] and Iba1, respectively) compared to SD-treated mice and induced morphological modifications of microglial cells in HT. This remodeling was associated with higher expression of inflammatory genes and differential regulation of hypothalamic neuropeptides involved in energy balance regulation. DREADD and PLX5622 technologies, used to modulate GFAP-positive or microglial cells activity, respectively, showed that both glial cell types are involved in hypothalamic postprandial inflammation, with their own specific kinetics and reactiveness to ingested foods. Thus, recurrent exacerbated postprandial inflammation in the brain might promote obesity and needs to be characterized to address this worldwide crisis.
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Affiliation(s)
- Céline Cansell
- IPMC, CNRS, Université Côte d'Azur, IPMC, CNRS, Valbonne, France
| | - Katharina Stobbe
- IPMC, CNRS, Université Côte d'Azur, IPMC, CNRS, Valbonne, France
| | - Clara Sanchez
- IPMC, CNRS, Université Côte d'Azur, IPMC, CNRS, Valbonne, France
| | - Ophélia Le Thuc
- IPMC, CNRS, Université Côte d'Azur, IPMC, CNRS, Valbonne, France
| | - Coralie-Anne Mosser
- Laboratory of Neurophysiology and New Microscopies, INSERM, Université Paris Descartes, Paris, France
| | - Selma Ben-Fradj
- CSGA, AgroSup Dijon, CNRS, INRA, Université Bourgogne Franche-Comté, Dijon, France
| | - Joris Leredde
- IPMC, CNRS, Université Côte d'Azur, IPMC, CNRS, Valbonne, France
| | | | - Delphine Debayle
- IPMC, CNRS, Université Côte d'Azur, IPMC, CNRS, Valbonne, France
| | - Lucile Fleuriot
- IPMC, CNRS, Université Côte d'Azur, IPMC, CNRS, Valbonne, France
| | - Frédéric Brau
- IPMC, CNRS, Université Côte d'Azur, IPMC, CNRS, Valbonne, France
| | - Nadège Devaux
- IPMC, CNRS, Université Côte d'Azur, IPMC, CNRS, Valbonne, France
| | - Alexandre Benani
- CSGA, AgroSup Dijon, CNRS, INRA, Université Bourgogne Franche-Comté, Dijon, France
| | - Etienne Audinat
- IGF, CNRS, INSERM, Université de Montpellier, Montpellier, France
| | - Nicolas Blondeau
- IPMC, CNRS, Université Côte d'Azur, IPMC, CNRS, Valbonne, France
| | - Jean-Louis Nahon
- IPMC, CNRS, Université Côte d'Azur, IPMC, CNRS, Valbonne, France
| | - Carole Rovère
- IPMC, CNRS, Université Côte d'Azur, IPMC, CNRS, Valbonne, France
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43
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Nogueira G, Solon C, Carraro RS, Engel DF, Ramalho AF, Sidarta-Oliveira D, Gaspar RS, Bombassaro B, Vasques AC, Geloneze B, Vinolo MA, Donato Junior J, Velloso LA. Interleukin-17 acts in the hypothalamus reducing food intake. Brain Behav Immun 2020; 87:272-285. [PMID: 31863824 DOI: 10.1016/j.bbi.2019.12.012] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/06/2019] [Revised: 11/20/2019] [Accepted: 12/16/2019] [Indexed: 12/12/2022] Open
Abstract
Interleukin-17 (IL-17) is expressed in the intestine in response to changes in the gut microbiome landscape and plays an important role in intestinal and systemic inflammatory diseases. There is evidence that dietary factors can also modify the expression of intestinal IL-17. Here, we hypothesized that, similar to several other gut-produced factors, IL-17 may act in the hypothalamus to modulate food intake. We confirm that food intake increases IL-17 expression in the mouse ileum and human blood. There is no expression of IL-17 in the hypothalamus; however, IL-17 receptor A is expressed in both pro-opiomelanocortin (POMC) and agouti-related peptide (AgRP) neurons. Upon systemic injection, IL-17 promoted a rapid increase in hypothalamic POMC expression, which was followed by a late increase in the expression of AgRP. Both systemic and intracerebroventricular injections of IL-17 reduced calorie intake without affecting whole-body energy expenditure. Systemic but not intracerebroventricular injection of IL-17 increase brown adipose tissue temperature. Thus, IL-17 is a gut-produced factor that is controlled by diet and modulates food intake by acting in the hypothalamus. Our findings provide the first evidence of a cytokine that is acutely regulated by food intake and plays a role in the regulation of eating.
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Affiliation(s)
- Guilherme Nogueira
- Laboratory of Cell Signalling-Obesity and Comorbidities Research Center, University of Campinas, Campinas, Brazil
| | - Carina Solon
- Laboratory of Cell Signalling-Obesity and Comorbidities Research Center, University of Campinas, Campinas, Brazil
| | - Rodrigo S Carraro
- Laboratory of Cell Signalling-Obesity and Comorbidities Research Center, University of Campinas, Campinas, Brazil
| | - Daiane F Engel
- Laboratory of Cell Signalling-Obesity and Comorbidities Research Center, University of Campinas, Campinas, Brazil
| | - Albina F Ramalho
- Laboratory of Cell Signalling-Obesity and Comorbidities Research Center, University of Campinas, Campinas, Brazil
| | - Davi Sidarta-Oliveira
- Laboratory of Cell Signalling-Obesity and Comorbidities Research Center, University of Campinas, Campinas, Brazil
| | - Rodrigo S Gaspar
- Laboratory of Cell Signalling-Obesity and Comorbidities Research Center, University of Campinas, Campinas, Brazil
| | - Bruna Bombassaro
- Laboratory of Cell Signalling-Obesity and Comorbidities Research Center, University of Campinas, Campinas, Brazil
| | - Ana C Vasques
- Laboratory of Investigation in Metabolism and Diabetes, University of Campinas, Campinas, Brazil
| | - Bruno Geloneze
- Laboratory of Investigation in Metabolism and Diabetes, University of Campinas, Campinas, Brazil
| | - Marco A Vinolo
- Laboratory of Immunoinflammation, Department of Genetics, Evolution, Microbiology and Immunology, University of Campinas, Campinas, Brazil
| | - Jose Donato Junior
- Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, Brazil
| | - Licio A Velloso
- Laboratory of Cell Signalling-Obesity and Comorbidities Research Center, University of Campinas, Campinas, Brazil.
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44
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Lee TJ, Hargrave SL, Kinzig KP. Dual functions of CNS inflammation in food intake and metabolic regulation. Brain Res 2020; 1740:146859. [PMID: 32353432 DOI: 10.1016/j.brainres.2020.146859] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2019] [Revised: 04/08/2020] [Accepted: 04/25/2020] [Indexed: 01/22/2023]
Abstract
Western diet (WD) consumption induces chronic mild inflammation in the hypothalamus. However, metabolic consequences of increased hypothalamic inflammatory cytokines remain unclear. This research first aimed to examine whether increased proinflammatory cytokines in the brain influenced feeding or metabolism. Rats that received an intracerebroventricular third ventricle injection (i3vt) of 0.5 pg TNFα daily for six days consumed significantly more calories than saline-injected rats, with no differences between treatment groups in terms of body weight, blood triglycerides nor glucose regulation. Continuously infusing TNFα for three weeks decreased hepatic fatty acid synthase (FAS) and increased body weight and the epididymal adipose sterol regulatory element-binding protein 1c (SREBP-1c) gene expression. Differences were not due to food intake nor voluntary wheel running activity. The second aim of this research was to examine whether inhibition of inflammation signaling in the brain at early stage of switching from chow to WD would affect diet-induced obesity development. WD-fed rats with i3vt NFκB inhibitor had greater caloric intake than rats given i3vt saline. These studies suggest elevated inflammatory cytokines in the brain induce food intake acutely and favor fat storage and weight gain in the long term. However, in the early stage of WD consumption, hypothalamic inflammatory signaling inhibits caloric intake and may serve as a warning signal of energy imbalance.
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Affiliation(s)
- Tien-Jui Lee
- Department of Psychological Sciences, Purdue University, 703 Third Street, West Lafayette, IN 47907, United States.
| | - Sara L Hargrave
- Department of Psychological Sciences, Purdue University, 703 Third Street, West Lafayette, IN 47907, United States
| | - Kimberly P Kinzig
- Department of Psychological Sciences, Purdue University, 703 Third Street, West Lafayette, IN 47907, United States.
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45
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Teimouri E, Rainey-Smith SR, Bharadwaj P, Verdile G, Martins RN. Amla Therapy as a Potential Modulator of Alzheimer’s Disease Risk Factors and Physiological Change. J Alzheimers Dis 2020; 74:713-733. [PMID: 32083581 DOI: 10.3233/jad-191033] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Affiliation(s)
- Elham Teimouri
- Centre of Excellence for Alzheimer’s Disease Research and Care, School of Medical and Health Sciences, Edith Cowan University, Joondalup, Western Australia, Australia
| | - Stephanie R. Rainey-Smith
- Centre of Excellence for Alzheimer’s Disease Research and Care, School of Medical and Health Sciences, Edith Cowan University, Joondalup, Western Australia, Australia
- Sir James McCusker Alzheimer’s Disease Research Unit (Hollywood Private Hospital), Perth, Western Australia, Australia
| | - Prashant Bharadwaj
- Centre of Excellence for Alzheimer’s Disease Research and Care, School of Medical and Health Sciences, Edith Cowan University, Joondalup, Western Australia, Australia
- School of Biomedical Sciences, Curtin Health Innovation Research Institute, Faculty of Health Sciences, Curtin University, Bentley, Western Australia, Australia
| | - Giuseppe Verdile
- Sir James McCusker Alzheimer’s Disease Research Unit (Hollywood Private Hospital), Perth, Western Australia, Australia
- School of Biomedical Sciences, Curtin Health Innovation Research Institute, Faculty of Health Sciences, Curtin University, Bentley, Western Australia, Australia
| | - Ralph N. Martins
- Centre of Excellence for Alzheimer’s Disease Research and Care, School of Medical and Health Sciences, Edith Cowan University, Joondalup, Western Australia, Australia
- Sir James McCusker Alzheimer’s Disease Research Unit (Hollywood Private Hospital), Perth, Western Australia, Australia
- School of Psychiatry and Clinical Neurosciences, University of Western Australia, Crawley, Western Australia, Australia
- Department of Biomedical Sciences, Macquarie University, North Ryde, New South Wales, Australia
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Role of c-Jun N-terminal Kinase (JNK) in Obesity and Type 2 Diabetes. Cells 2020; 9:cells9030706. [PMID: 32183037 PMCID: PMC7140703 DOI: 10.3390/cells9030706] [Citation(s) in RCA: 121] [Impact Index Per Article: 24.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2019] [Revised: 02/16/2020] [Accepted: 03/11/2020] [Indexed: 12/13/2022] Open
Abstract
Obesity has been described as a global epidemic and is a low-grade chronic inflammatory disease that arises as a consequence of energy imbalance. Obesity increases the risk of type 2 diabetes (T2D), by mechanisms that are not entirely clarified. Elevated circulating pro-inflammatory cytokines and free fatty acids (FFA) during obesity cause insulin resistance and ß-cell dysfunction, the two main features of T2D, which are both aggravated with the progressive development of hyperglycemia. The inflammatory kinase c-jun N-terminal kinase (JNK) responds to various cellular stress signals activated by cytokines, free fatty acids and hyperglycemia, and is a key mediator in the transition between obesity and T2D. Specifically, JNK mediates both insulin resistance and ß-cell dysfunction, and is therefore a potential target for T2D therapy.
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Nash Y, Frenkel D. Inflammation and insulin resistance in Alzheimer’s disease. GENETICS, NEUROLOGY, BEHAVIOR, AND DIET IN DEMENTIA 2020:389-405. [DOI: 10.1016/b978-0-12-815868-5.00025-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
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Lee CH, Kim HJ, Lee YS, Kang GM, Lim HS, Lee SH, Song DK, Kwon O, Hwang I, Son M, Byun K, Sung YH, Kim S, Kim JB, Choi EY, Kim YB, Kim K, Kweon MN, Sohn JW, Kim MS. Hypothalamic Macrophage Inducible Nitric Oxide Synthase Mediates Obesity-Associated Hypothalamic Inflammation. Cell Rep 2019; 25:934-946.e5. [PMID: 30355499 PMCID: PMC6284237 DOI: 10.1016/j.celrep.2018.09.070] [Citation(s) in RCA: 61] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2016] [Revised: 06/13/2018] [Accepted: 09/21/2018] [Indexed: 02/08/2023] Open
Abstract
Obesity-associated metabolic alterations are closely linked to low-grade
inflammation in peripheral organs, in which macrophages play a central role.
Using genetic labeling of myeloid lineage cells, we show that hypothalamic
macrophages normally reside in the perivascular area and circumventricular organ
median eminence. Chronic consumption of a high-fat diet (HFD) induces expansion
of the monocyte-derived macrophage pool in the hypothalamic arcuate nucleus
(ARC), which is significantly attributed to enhanced proliferation of
macrophages. Notably, inducible nitric oxide synthase (iNOS) is robustly
activated in ARC macrophages of HFD-fed obese mice. Hypothalamic macrophage iNOS
inhibition completely abrogates macrophage accumulation and activation,
proinflammatory cytokine overproduction, reactive astrogliosis,
blood-brain-barrier permeability, and lipid accumulation in the ARC of obese
mice. Moreover, central iNOS inhibition improves obesity-induced alterations in
systemic glucose metabolism without affecting adiposity. Our findings suggest a
critical role for hypothalamic macrophage-expressed iNOS in hypothalamic
inflammation and abnormal glucose metabolism in cases of overnutrition-induced
obesity. Lee et al. demonstrate in mice that, upon prolonged high-fat diet
feeding, hypothalamic macrophages proliferate, expand their pool, and sustain
hypothalamic inflammation. Moreover, they show that hypothalamic macrophage iNOS
inhibition diminishes macrophage activation, astrogliosis, blood-brain-barrier
permeability, and impaired glucose metabolism in diet-induced obese mice.
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Affiliation(s)
- Chan Hee Lee
- Biomedical Science and Engineering Interdisciplinary Program, Korea Advanced Institute of Science and Technology, Daejeon 34141, Korea; Asan Institute for Life Sciences, University of Ulsan College of Medicine, Seoul 05505, Korea
| | - Hyo Jin Kim
- Asan Institute for Life Sciences, University of Ulsan College of Medicine, Seoul 05505, Korea; Department of Biomedical Sciences, University of Ulsan College of Medicine, Seoul 05505, Korea
| | - Yong-Soo Lee
- Department of Convergence Medicine, University of Ulsan College of Medicine, Seoul 05505, Korea
| | - Gil Myoung Kang
- Asan Institute for Life Sciences, University of Ulsan College of Medicine, Seoul 05505, Korea
| | - Hyo Sun Lim
- Asan Institute for Life Sciences, University of Ulsan College of Medicine, Seoul 05505, Korea; Department of Biomedical Sciences, University of Ulsan College of Medicine, Seoul 05505, Korea
| | - Seung-Hwan Lee
- Department of Biomedical Sciences, University of Ulsan College of Medicine, Seoul 05505, Korea
| | - Do Kyeong Song
- Division of Endocrinology and Metabolism, Department of Internal Medicine, University of Ulsan College of Medicine, Seoul 05505, Korea
| | - Obin Kwon
- Division of Endocrinology and Metabolism, Department of Internal Medicine, University of Ulsan College of Medicine, Seoul 05505, Korea
| | - Injae Hwang
- National Creative Research Initiatives Center for Adipose Tissue Remodeling, School of Biological Sciences, Institute of Molecular Biology and Genetics, Seoul National University, Seoul 08826, Korea
| | - Myeongjoo Son
- Department of Anatomy and Cell Biology, Gachon University College of Medicine, Incheon 21565, Korea
| | - Kyunghee Byun
- Department of Anatomy and Cell Biology, Gachon University College of Medicine, Incheon 21565, Korea
| | - Young Hoon Sung
- Asan Institute for Life Sciences, University of Ulsan College of Medicine, Seoul 05505, Korea; Department of Convergence Medicine, University of Ulsan College of Medicine, Seoul 05505, Korea
| | - Seyun Kim
- Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon 34141, Korea
| | - Jae Bum Kim
- National Creative Research Initiatives Center for Adipose Tissue Remodeling, School of Biological Sciences, Institute of Molecular Biology and Genetics, Seoul National University, Seoul 08826, Korea
| | - Eun Young Choi
- Department of Biomedical Sciences, University of Ulsan College of Medicine, Seoul 05505, Korea
| | - Young-Bum Kim
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA
| | - Keetae Kim
- Department of New Biology, DGIST, Daegu 42988, Korea
| | - Mi-Na Kweon
- Department of Convergence Medicine, University of Ulsan College of Medicine, Seoul 05505, Korea
| | - Jong-Woo Sohn
- Biomedical Science and Engineering Interdisciplinary Program, Korea Advanced Institute of Science and Technology, Daejeon 34141, Korea; Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon 34141, Korea
| | - Min-Seon Kim
- Division of Endocrinology and Metabolism, Department of Internal Medicine, University of Ulsan College of Medicine, Seoul 05505, Korea.
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Nogueira PAS, Pereira MP, Soares JJG, de Assis Silva Gomes J, Ribeiro DL, Razolli DS, Velloso LA, Neto MB, Zanon RG. Swimming reduces fatty acids-associated hypothalamic damage in mice. J Chem Neuroanat 2019; 103:101713. [PMID: 31726089 DOI: 10.1016/j.jchemneu.2019.101713] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2019] [Revised: 09/20/2019] [Accepted: 11/09/2019] [Indexed: 12/28/2022]
Abstract
The arcuate and the paraventricular and lateral hypothalamic nuclei, related to hunger and satiety control, are generally compromised by excess fatty acids. In this situation, fatty acids cause inflammation via TLR4 (toll like receptor 4) and the nuclei become less responsive to the hormones leptin and insulin, contributing to the development of obesity. In this work, these nuclei were analyzed in animals fed with high-fat diet and submitted to swimming without and with load for two months. For this, frontal sections of the hypothalamus were immunolabelled with GFAP (glial fibrillary acidic protein), synaptophysin, IL-6 (interleukin 6) and TLR4. Also, proteins extracted from the hypothalamus were analyzed using Western blotting (GFAP and synaptophysin), fluorometric analysis for caspases 3 and 7, and CBA (cytometric bead array) for Th1, Th2, and Th17 profiles. The high-fat diet significantly caused overweight and, in the hypothalamus, decreased synapses and increased astrocytic reactivity. The swimming with load, especially 80 % of the maximum load, reduced those consequences. The high-fat diet increased TLR4 in the arcuate nucleus and the swimming exercise with 80 % of the maximum load showed a tendency of reducing this expression. Swimming did not significantly influence the inflammatory or anti-inflammatory cytokines in the hypothalamus or in plasma. The high-fat diet in sedentary animals increased the expression of caspases 3 and 7 and swimming practice reduced this increment to levels compatible with animals fed on a normal diet. The set of results conclude that the impact of swimming on the damage caused in the hypothalamus by a high-fat diet is positive. The different aspects analyzed in here point to better cellular viability and conservation of the synapses in the hypothalamic nuclei of overweight animals that practiced swimming with a load.
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Affiliation(s)
- Pedro Augusto Silva Nogueira
- Institute of Biomedical Science, Federal University of Uberlandia, Uberlandia, Minas Gerais, Brazil; Institute of Biology, University of Campinas, Campinas, São Paulo, Brazil; Laboratory of Cell Signaling, Department of Internal Medicine, University of Campinas, Campinas, São Paulo, Brazil
| | - Miriam Pimenta Pereira
- Institute of Biomedical Science, Federal University of Uberlandia, Uberlandia, Minas Gerais, Brazil
| | | | - Juliana de Assis Silva Gomes
- Laboratory of Cellular Interactions Biology, Department of Morphology, Institute of Biological Science, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - Daniele Lisboa Ribeiro
- Institute of Biomedical Science, Federal University of Uberlandia, Uberlandia, Minas Gerais, Brazil
| | - Daniela Soares Razolli
- Laboratory of Cell Signaling, Department of Internal Medicine, University of Campinas, Campinas, São Paulo, Brazil; Laboratory of Multidisciplinary Research, São Francisco University, Bragança Paulista, São Paulo, Brazil
| | - Licio Augusto Velloso
- Laboratory of Cell Signaling, Department of Internal Medicine, University of Campinas, Campinas, São Paulo, Brazil
| | - Morun Bernardino Neto
- Department of Basic and Environmental Sciences, University of São Paulo, Lorena, São Paulo, Brazil
| | - Renata Graciele Zanon
- Institute of Biomedical Science, Federal University of Uberlandia, Uberlandia, Minas Gerais, Brazil.
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Ferreira V, Grajales D, Valverde ÁM. Adipose tissue as a target for second-generation (atypical) antipsychotics: A molecular view. Biochim Biophys Acta Mol Cell Biol Lipids 2019; 1865:158534. [PMID: 31672575 DOI: 10.1016/j.bbalip.2019.158534] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2019] [Revised: 10/18/2019] [Accepted: 10/23/2019] [Indexed: 12/14/2022]
Abstract
Schizophrenia is a neuropsychiatric disorder that chronically affects 21 million people worldwide. Second-generation antipsychotics (SGAs) are the cornerstone in the management of schizophrenia. However, despite their efficacy in counteracting both positive and negative symptomatology of schizophrenia, recent clinical observations have described an increase in the prevalence of metabolic disturbances in patients treated with SGAs, including abnormal weight gain, hyperglycemia and dyslipidemia. While the molecular mechanisms responsible for these side-effects remain poorly understood, increasing evidence points to a link between SGAs and adipose tissue depots of white, brown and beige adipocytes. In this review, we survey the present knowledge in this area, with a particular focus on the molecular aspects of adipocyte biology including differentiation, lipid metabolism, thermogenic function and the browning/beiging process.
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Affiliation(s)
- Vitor Ferreira
- Instituto de Investigaciones Biomédicas Alberto Sols (CSIC-UAM), Madrid, Spain; CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), ISCIII, Madrid, Spain
| | - Diana Grajales
- Instituto de Investigaciones Biomédicas Alberto Sols (CSIC-UAM), Madrid, Spain; CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), ISCIII, Madrid, Spain
| | - Ángela M Valverde
- Instituto de Investigaciones Biomédicas Alberto Sols (CSIC-UAM), Madrid, Spain; CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), ISCIII, Madrid, Spain.
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