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1
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Bonfante ILP, Segantim HDS, Mendonça KNS, de Oliveira MAB, Monfort-Pires M, Duft RG, da Silva Mateus KC, Chacon-Mikahil MPT, Ramos CD, Velloso LA, Cavaglieri CR. Better cardiometabolic/inflammatory profile is associated with differences in the supraclavicular adipose tissue activity of individuals with T2DM. Endocrine 2025; 87:1011-1021. [PMID: 39627400 DOI: 10.1007/s12020-024-04122-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2024] [Accepted: 11/25/2024] [Indexed: 02/22/2025]
Abstract
PURPOSE Brown adipose tissue (BAT), located in the supraclavicular region, has been associated with a better cardiometabolic profile and reduced risk of developing non-communicable chronic diseases (NCD), in addition to being associated with a healthier phenotype in obesity. However, it is unknown whether greater supraclavicular adipose tissue activity could be associated with a healthier metabolic profile in people already diagnosed with type 2 diabetes (T2DM). Thus, the present work evaluated if supraclavicular adipose tissue activity is associated with metabolic and molecular markers in individuals with T2DM. METHODS Based on a cluster study, individuals with T2DM were divided into groups according to high or low-standard uptake value (SUV) evaluated in the supraclavicular adipose tissue area by [18F]-fluorodeoxyglucose and positron emission tomography-computed tomography (18F-FDG-PET/CT) after mild cold exposure). Functional, biochemical, inflammatory, and molecular markers were measured. RESULTS When we evaluated the whole sample, women showed higher SUV, which favored a difference between groups in sex-related markers. On the other hand, volunteers in the high-SUV group showed lower BMI, monocytes count, triglycerides/glucose index (TYG-index) and z score of metabolic syndrome (MS) values, as well as lower triglycerides, and VLDL concentrations. Moreover, they also had enhanced expression of thermogenic genes in subcutaneous fat. When analyzing only women, the differences in markers associated with sex disappear, and a lower count of leukocytes, platelets, along with lower TYG-index, z score of MS values, and triglycerides, VLDL, LDL, and TNFα concentrations were observed in women with the high SUV. In addition, higher expression of thermogenic genes and BECN1 were detected. CONCLUSION Higher supraclavicular adipose tissue SUV in individuals with T2DM is associated with a better cardiometabolic/inflammatory profile and expression of thermogenic genes. CLINICAL TRIAL REGISTRATION UTN: U1111-1202-1476 - 08/20/2020.
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Affiliation(s)
- Ivan Luiz Padilha Bonfante
- Laboratory of Exercise Physiology, School of Physical Education, University of Campinas, Campinas, SP, Brazil.
- Postdoctoral Researcher Program (PPPD), University of Campinas, Campinas, Brazil.
| | - Higor da Silva Segantim
- Higher Interdisciplinary Training Program (PROFIS), University of Campinas, Campinas, SP, Brazil
| | | | | | - Milena Monfort-Pires
- Laboratory of Cell Signaling, Department of Internal Medicine, University of Campinas, Campinas, SP, Brazil
- Obesity and Comorbidities Research Center, University of Campinas, Campinas, SP, Brazil
- Turku Pet Centre, University of Turku, Turku, Finland
| | - Renata Garbellini Duft
- Laboratory of Exercise Physiology, School of Physical Education, University of Campinas, Campinas, SP, Brazil
- The Rowett Institute of Nutrition and Health, University of Aberdeen, Ashgrove Rd W, Aberdeen, Scotland, UK
| | | | | | - Celso Darío Ramos
- Department of Radiology, University of Campinas, Campinas, SP, Brazil
| | - Licio Augusto Velloso
- Laboratory of Cell Signaling, Department of Internal Medicine, University of Campinas, Campinas, SP, Brazil
- Obesity and Comorbidities Research Center, University of Campinas, Campinas, SP, Brazil
| | - Cláudia Regina Cavaglieri
- Laboratory of Exercise Physiology, School of Physical Education, University of Campinas, Campinas, SP, Brazil
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Bednarczyk M, Dąbrowska-Szeja N, Łętowski D, Dzięgielewska-Gęsiak S, Waniczek D, Muc-Wierzgoń M. Relationship Between Dietary Nutrient Intake and Autophagy-Related Genes in Obese Humans: A Narrative Review. Nutrients 2024; 16:4003. [PMID: 39683397 PMCID: PMC11643440 DOI: 10.3390/nu16234003] [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: 09/24/2024] [Revised: 11/14/2024] [Accepted: 11/19/2024] [Indexed: 12/18/2024] Open
Abstract
Obesity is one of the world's major public health challenges. Its pathogenesis and comorbid metabolic disorders share common mechanisms, such as mitochondrial or endoplasmic reticulum dysfunction or oxidative stress, gut dysbiosis, chronic inflammation and altered autophagy. Numerous pro-autophagy dietary interventions are being investigated for their potential obesity-preventing or therapeutic effects. We summarize current data on the relationship between autophagy and obesity, and discuss various dietary interventions as regulators of autophagy-related genes in the prevention and ultimate treatment of obesity in humans, as available in scientific databases and published through July 2024. Lifestyle modifications (such as calorie restriction, intermittent fasting, physical exercise), including following a diet rich in flavonoids, antioxidants, specific fatty acids, specific amino acids and others, have shown a beneficial role in the induction of this process. The activation of autophagy through various nutritional interventions tends to elicit a consistent response, characterized by the induction of certain kinases (including AMPK, IKK, JNK1, TAK1, ULK1, and VPS34) or the suppression of others (like mTORC1), the deacetylation of proteins, and the alleviation of inhibitory interactions between BECN1 and members of the Bcl-2 family. Significant health/translational properties of many nutrients (nutraceuticals) can affect chronic disease risk through various mechanisms that include the activation or inhibition of autophagy. The role of nutritional intervention in the regulation of autophagy in obesity and its comorbidities is not yet clear, especially in obese individuals.
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Affiliation(s)
- Martyna Bednarczyk
- Department of Cancer Prevention, Faculty of Public Health, Medical University of Silesia in Katowice, 40-055 Katowice, Poland; (M.B.); (N.D.-S.); (D.Ł.)
| | - Nicola Dąbrowska-Szeja
- Department of Cancer Prevention, Faculty of Public Health, Medical University of Silesia in Katowice, 40-055 Katowice, Poland; (M.B.); (N.D.-S.); (D.Ł.)
| | - Dariusz Łętowski
- Department of Cancer Prevention, Faculty of Public Health, Medical University of Silesia in Katowice, 40-055 Katowice, Poland; (M.B.); (N.D.-S.); (D.Ł.)
| | - Sylwia Dzięgielewska-Gęsiak
- Department of Internal Diseases Propaedeutics and Emergency Medicine, Faculty of Public Health in Bytom, Medical University of Silesia in Katowice, 40-055 Katowice, Poland;
| | - Dariusz Waniczek
- Department of Oncological Surgery, Faculty of Medical Sciences in Zabrze, Medical University of Silesia in Katowice, 40-055 Katowice, Poland;
| | - Małgorzata Muc-Wierzgoń
- Department of Internal Diseases Propaedeutics and Emergency Medicine, Faculty of Public Health in Bytom, Medical University of Silesia in Katowice, 40-055 Katowice, Poland;
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Jakubek P, Pakula B, Rossmeisl M, Pinton P, Rimessi A, Wieckowski MR. Autophagy alterations in obesity, type 2 diabetes, and metabolic dysfunction-associated steatotic liver disease: the evidence from human studies. Intern Emerg Med 2024; 19:1473-1491. [PMID: 38971910 PMCID: PMC11364608 DOI: 10.1007/s11739-024-03700-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2024] [Accepted: 06/26/2024] [Indexed: 07/08/2024]
Abstract
Autophagy is an evolutionarily conserved process that plays a pivotal role in the maintenance of cellular homeostasis and its impairment has been implicated in the pathogenesis of various metabolic diseases including obesity, type 2 diabetes (T2D), and metabolic dysfunction-associated steatotic liver disease (MASLD). This review synthesizes the current evidence from human studies on autophagy alterations under these metabolic conditions. In obesity, most data point to autophagy upregulation during the initiation phase of autophagosome formation, potentially in response to proinflammatory conditions in the adipose tissue. Autophagosome formation appears to be enhanced under hyperglycemic or insulin-resistant conditions in patients with T2D, possibly acting as a compensatory mechanism to eliminate damaged organelles and proteins. Other studies have proposed that prolonged hyperglycemia and disrupted insulin signaling hinder autophagic flux, resulting in the accumulation of dysfunctional cellular components that can contribute to β-cell dysfunction. Evidence from patients with MASLD supports autophagy inhibition in disease progression. Nevertheless, given the available data, it is difficult to ascertain whether autophagy is enhanced or suppressed in these conditions because the levels of autophagy markers depend on the overall metabolism of specific organs, tissues, experimental conditions, or disease duration. Owing to these constraints, determining whether the observed shifts in autophagic activity precede or result from metabolic diseases remains challenging. Additionally, autophagy-modulating strategies are shortly discussed. To conclude, more studies investigating autophagy impairment are required to gain a more comprehensive understanding of its role in the pathogenesis of obesity, T2D, and MASLD and to unveil novel therapeutic strategies for these conditions.
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Affiliation(s)
- Patrycja Jakubek
- Laboratory of Mitochondrial Biology and Metabolism, Nencki Institute of Experimental Biology, Polish Academy of Sciences, 3 Pasteur St., 02-093, Warsaw, Poland.
| | - Barbara Pakula
- Laboratory of Mitochondrial Biology and Metabolism, Nencki Institute of Experimental Biology, Polish Academy of Sciences, 3 Pasteur St., 02-093, Warsaw, Poland
| | - Martin Rossmeisl
- Laboratory of Adipose Tissue Biology, Institute of Physiology of the Czech Academy of Sciences, Prague, Czech Republic
| | - Paolo Pinton
- Department of Medical Sciences, Section of Experimental Medicine, Laboratory for Technologies of Advanced Therapies, University of Ferrara, Ferrara, Italy
- Center of Research for Innovative Therapies in Cystic Fibrosis, University of Ferrara, 44121, Ferrara, Italy
| | - Alessandro Rimessi
- Department of Medical Sciences, Section of Experimental Medicine, Laboratory for Technologies of Advanced Therapies, University of Ferrara, Ferrara, Italy
- Center of Research for Innovative Therapies in Cystic Fibrosis, University of Ferrara, 44121, Ferrara, Italy
| | - Mariusz Roman Wieckowski
- Laboratory of Mitochondrial Biology and Metabolism, Nencki Institute of Experimental Biology, Polish Academy of Sciences, 3 Pasteur St., 02-093, Warsaw, Poland.
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Ji T, Fang B, Wu F, Liu Y, Cheng L, Li Y, Wang R, Zhu L. Diet Change Improves Obesity and Lipid Deposition in High-Fat Diet-Induced Mice. Nutrients 2023; 15:4978. [PMID: 38068835 PMCID: PMC10708053 DOI: 10.3390/nu15234978] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2023] [Revised: 11/14/2023] [Accepted: 11/27/2023] [Indexed: 12/18/2023] Open
Abstract
The number of obese people is increasing dramatically worldwide, and one of the major causes of obesity is excess energy due to high-fat diets. Several studies have shown that reducing food and energy intake represents a key intervention or treatment to combat overweight/obesity. Here, we conducted a 12-week energy-restricted dietary intervention for high-fat diet-induced obese mice (C57BL/6J) to investigate the effectiveness of diet change in improving obesity. The results revealed that the diet change from HFD to NFD significantly reduced weight gain and subcutaneous adipose tissue weight in high-fat diet-induced obese mice, providing scientific evidence for the effectiveness of diet change in improving body weight and fat deposition in obese individuals. Regarding the potential explanations for these observations, weight reduction may be attributed to the excessive enlargement of adipocytes in the white adipose tissue of obese mice that were inhibited. Diet change significantly promoted lipolysis in the adipose tissue (eWAT: Adrb3, Plin1, HSL, and CPTA1a; ingWAT: CPT1a) and liver (reduced content of nonesterified fatty acids), and reduced lipogenesis in ingWAT (Dgat2). Moreover, the proportion of proliferative stem cells in vWAT and sWAT changed dramatically with diet change. Overall, our study reveals the phenotypic, structural, and metabolic diversity of multiple tissues (vWAT and sWAT) in response to diet change and identifies a role for adipocyte stem cells in the tissue specificity of diet change.
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Affiliation(s)
| | - Bing Fang
- Key Laboratory of Precision Nutrition and Food Quality, Department of Nutrition and Health, China Agricultural University, Beijing 100193, China
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Verma J, Rai AK, Satija NK. Autophagy perturbation upon acute pyrethroid treatment impacts adipogenic commitment of mesenchymal stem cells. PESTICIDE BIOCHEMISTRY AND PHYSIOLOGY 2023; 195:105566. [PMID: 37666621 DOI: 10.1016/j.pestbp.2023.105566] [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: 04/01/2023] [Revised: 07/25/2023] [Accepted: 08/02/2023] [Indexed: 09/06/2023]
Abstract
Environmental chemical exposure can cause dysregulation in adipogenesis that can result in metabolic syndrome, which includes insulin resistance, type 2 diabetes, cardiovascular disease, as well as excessive body weight. The role of autophagy in adipocyte differentiation is debatable since both positive and negative effects have been reported. Type-I and type-II synthetic pyrethroids α-cypermethrin (CPM) and permethrin (PER), respectively, are reported to increase adipogenesis in vitro and in vivo. However, it is not known how these pyrethroids affect mesenchymal stem cells (MSCs). Thus, this study focused on evaluating the effect of pyrethroids (CPM and PER) pre-treatment (24 h) on MSC commitment and the regulatory role of autophagy in adipogenic lineage commitment. The formation of adipocytes was observed through nile red staining, perilipin expression by immunoflourescence, and adipogenic markers PPARγ, C/EBPα, and FABP4 by western blotting. It was found that the adipogenic differentiation ability of MSCs was significantly increased upon CPM or PER pre-treatment at 100 μM concentration as evident by lipid accumulation and enhanced expression of adipogenic markers. To assess the involvement of autophagy, the expression of p62 and LC3II were evaluated following pre-treatment. Immunoblotting results revealed an increased expression of p62 and LC3II in CPM or PER pretreated MSCs suggesting CPM and PER mediated inhibition of autophagy at 24 h. Further, an increase was observed in adipogenesis upon CPM or PER pre-treatment in combination with chloroquine, while use of rapamycin during pre-treatment abrogated the effect of CPM and PER. Thus, this study concludes that CPM or PER pre-treatment increases the adipogenic differentiation of MSCs. Since chloroquine also demonstrated similar adipogenic response, it further highlights that 24 h pre-treatment with autophagy modulators to inhibit basal autophagy primes MSCs towards adipogenic lineage.
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Affiliation(s)
- Julee Verma
- Systems Toxicology Group, Food, Drug & Chemical, Environment and Systems Toxicology Division, CSIR-Indian Institute of Toxicology Research, Vishvigyan Bhawan, 31, Mahatma Gandhi Marg, Lucknow 226001, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
| | - Ajit Kumar Rai
- Systems Toxicology Group, Food, Drug & Chemical, Environment and Systems Toxicology Division, CSIR-Indian Institute of Toxicology Research, Vishvigyan Bhawan, 31, Mahatma Gandhi Marg, Lucknow 226001, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
| | - Neeraj Kumar Satija
- Systems Toxicology Group, Food, Drug & Chemical, Environment and Systems Toxicology Division, CSIR-Indian Institute of Toxicology Research, Vishvigyan Bhawan, 31, Mahatma Gandhi Marg, Lucknow 226001, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India.
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Oh J, Park C, Kim S, Kim M, Kim CS, Jo W, Park S, Yi GS, Park J. High levels of intracellular endotrophin in adipocytes mediate COPII vesicle supplies to autophagosome to impair autophagic flux and contribute to systemic insulin resistance in obesity. Metabolism 2023:155629. [PMID: 37302692 DOI: 10.1016/j.metabol.2023.155629] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2023] [Revised: 05/25/2023] [Accepted: 06/08/2023] [Indexed: 06/13/2023]
Abstract
BACKGROUND AND AIMS Extracellular matrix (ECM) homeostasis plays a crucial role in metabolic plasticity and endocrine function of adipose tissue. High levels of intracellular endotrophin, a cleavage peptide of type VI collagen alpha 3 chain (Col6a3), have been frequently observed in adipocyte in obesity and diabetes. However, how endotrophin intracellularly traffics and influences metabolic homeostasis in adipocyte remains unknown. Therefore, we aimed to investigate the trafficking of endotrophin and its metabolic effects in adipocytes depending on lean or obese condition. METHODS We used doxycycline-inducible adipocyte-specific endotrophin overexpressed mice for a gain-of-function study and CRISPR-Cas9 system-based Col6a3-deficient mice for a loss-of-function study. Various molecular and biochemical techniques were employed to examine the effects of endotrophin on metabolic parameters. RESULTS In adipocytes during obesity, the majority of endosomal endotrophin escapes lysosomal degradation and is released into the cytosol to mediate direct interactions between SEC13, a major component of coat protein complex II (COPII) vesicles, and autophagy-related 7 (ATG7), leading to the increased formation of autophagosomes. Autophagosome accumulation disrupts the balance of autophagic flux, resulting in adipocyte death, inflammation, and insulin resistance. These adverse metabolic effects were ameliorated by either suppressing ATG7 with siRNA ex vivo or neutralizing endotrophin with monoclonal antibodies in vivo. CONCLUSIONS High levels of intracellular endotrophin-mediated autophagic flux impairment in adipocyte contribute to metabolic dysfunction such as apoptosis, inflammation, and insulin resistance in obesity.
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Affiliation(s)
- Jiyoung Oh
- Department of Biological Sciences, College of Information and Biotechnology, Ulsan National Institute of Science and Technology, Ulsan 44919, Republic of Korea
| | - Chanho Park
- Department of Biological Sciences, College of Information and Biotechnology, Ulsan National Institute of Science and Technology, Ulsan 44919, Republic of Korea
| | - Sahee Kim
- Department of Biological Sciences, College of Information and Biotechnology, Ulsan National Institute of Science and Technology, Ulsan 44919, Republic of Korea
| | - Min Kim
- Department of Biological Sciences, College of Information and Biotechnology, Ulsan National Institute of Science and Technology, Ulsan 44919, Republic of Korea
| | - Chu-Sook Kim
- Department of Biological Sciences, College of Information and Biotechnology, Ulsan National Institute of Science and Technology, Ulsan 44919, Republic of Korea
| | - Woobeen Jo
- Department of Biological Sciences, College of Information and Biotechnology, Ulsan National Institute of Science and Technology, Ulsan 44919, Republic of Korea
| | - Sungho Park
- Department of Biological Sciences, College of Information and Biotechnology, Ulsan National Institute of Science and Technology, Ulsan 44919, Republic of Korea
| | - Gwan-Su Yi
- Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology, Daejeon 34141, Republic of Korea
| | - Jiyoung Park
- Department of Biological Sciences, College of Information and Biotechnology, Ulsan National Institute of Science and Technology, Ulsan 44919, Republic of Korea.
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Zhu J, Wilding JP, Hu J. Adipocytes in obesity: A perfect reservoir for SARS-CoV-2? Med Hypotheses 2023; 171:111020. [PMID: 36742015 PMCID: PMC9889082 DOI: 10.1016/j.mehy.2023.111020] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2022] [Revised: 12/17/2022] [Accepted: 12/30/2022] [Indexed: 01/28/2023]
Abstract
Research evidence suggests that adipocytes in obesity might facilitate SARS-CoV-2 replication, for it was only found in adipose tissue of individuals with overweight or obesity but not lean individuals who died from COVID-19. As lipid metabolism is key to adipocyte function, and viruses are capable of exploiting and manipulating lipid metabolism of host cells for their own benefit of infection, we hypothesize that adipocytes could not only impair host immune defense against viral infection, but also facilitate SARS-CoV-2 entry, replication and assembly as a reservoir to boost the viral infection in obesity. The latter of which could mainly be mediated by SARS-CoV-2 hijacking the abnormal lipid metabolism in the adipocytes. If these were to be confirmed, an approach to combat COVID-19 in people with obesity by taking advantage of the abnormal lipid metabolism in adipocytes might be considered, as well as modifying lipid metabolism of other host cells as a potential adjunctive treatment for COVID-19.
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Key Words
- ACE2, angiotensin-converting enzyme 2
- ATP, adenosine triphosphate
- Adipocyte
- COVID-19, coronavirus disease 2019
- ER, endoplasmic reticulum
- ERGIC, ER-to-Golgi intermediate compartment
- FFAs, free fatty acids
- LDs, lipid droplets
- Lipid metabolism
- Obesity
- S protein, spike protein
- SARS-CoV-2, severe acute respiratory syndrome coronavirus 2
- Severe acute respiratory syndrome coronavirus 2
- TAGs, triacylglycerols
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Affiliation(s)
- JingJing Zhu
- Department of Endocrinology and Metabolism, the Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu, People’s Republic of China,Department of Cardiovascular and Metabolic Medicine, Institute of Life Course and Medical Sciences, University of Liverpool, United Kingdom
| | - John P.H. Wilding
- Department of Cardiovascular and Metabolic Medicine, Institute of Life Course and Medical Sciences, University of Liverpool, United Kingdom
| | - Ji Hu
- Department of Endocrinology and Metabolism, the Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu, People’s Republic of China,Corresponding author
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Adipokines as Regulators of Autophagy in Obesity-Linked Cancer. Cells 2022; 11:cells11203230. [PMID: 36291097 PMCID: PMC9600294 DOI: 10.3390/cells11203230] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2022] [Revised: 10/02/2022] [Accepted: 10/12/2022] [Indexed: 11/16/2022] Open
Abstract
Excess body weight and obesity have become significant risk factors for cancer development. During obesity, adipose tissue alters its biological function, deregulating the secretion of bioactive factors such as hormones, cytokines, and adipokines that promote an inflammatory microenvironment conducive to carcinogenesis and tumor progression. Adipokines regulate tumor processes such as apoptosis, proliferation, migration, angiogenesis, and invasion. Additionally, it has been found that they can modulate autophagy, a process implicated in tumor suppression in healthy tissue and cancer progression in established tumors. Since the tumor-promoting role of autophagy has been well described, the process has been suggested as a therapeutic target in cancer. However, the effects of targeting autophagy might depend on the tumor type and microenvironmental conditions, where circulating adipokines could influence the role of autophagy in cancer. Here, we review recent evidence related to the role of adipokines in cancer cell autophagy in an effort to understand the tumor response in the context of obesity under the assumption of an autophagy-targeting treatment.
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Li R, Li G, Hai Y, Li T, Bian Y, Ma T. The effect of aerobic exercise on the lipophagy of adipose tissue in obese male mice. Chem Phys Lipids 2022; 247:105225. [PMID: 35810833 DOI: 10.1016/j.chemphyslip.2022.105225] [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: 03/07/2022] [Revised: 05/27/2022] [Accepted: 07/06/2022] [Indexed: 01/18/2023]
Abstract
This article explores the obesity state and the changes in the level of lipophagy in adipose tissue after exercise to lose weight, so as to provide direction and basis for theoretical research on obesity prevention and control. We established a high-fat diet model of obese mice, and applied exercise intervention and intraperitoneal injection of chloroquine to inhibit autophagy. Long-term high-fat diet can cause obesity in mice, and the process of lipophagy is inhibited, which may be one of the reasons for fat accumulation. Eight weeks of aerobic exercise can effectively reduce the weight of obese mice and promote lipolysis; this process is mainly completed by lipase decomposition, in addition to require the participation of the lipophagy process.
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Affiliation(s)
- Rendong Li
- Physical Education Department, Shenyang University of Chemical Technology, Shenyang Economic and Technological Development Zone, Shenyang 110142, PR China.
| | - Guangkuan Li
- Department of Postgraduate, Shenyang Sport University, Shenyang 110102, PR China.
| | - Yan Hai
- Department of Postgraduate, Shenyang Sport University, Shenyang 110102, PR China.
| | - Tao Li
- Department of Postgraduate, Shenyang Sport University, Shenyang 110102, PR China.
| | - Yuanyuan Bian
- College of Food Science, Shenyang Agricultural University, Shenyang 110866, PR China.
| | - Tie Ma
- The College of Kinesiology, Shenyang Sport University, Shenyang 110102, PR China.
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Haslem L, Hays JM, Hays FA. p66Shc in Cardiovascular Pathology. Cells 2022; 11:cells11111855. [PMID: 35681549 PMCID: PMC9180016 DOI: 10.3390/cells11111855] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2022] [Revised: 05/30/2022] [Accepted: 06/01/2022] [Indexed: 02/06/2023] Open
Abstract
p66Shc is a widely expressed protein that governs a variety of cardiovascular pathologies by generating, and exacerbating, pro-apoptotic ROS signals. Here, we review p66Shc’s connections to reactive oxygen species, expression, localization, and discuss p66Shc signaling and mitochondrial functions. Emphasis is placed on recent p66Shc mitochondrial function discoveries including structure/function relationships, ROS identity and regulation, mechanistic insights, and how p66Shc-cyt c interactions can influence p66Shc mitochondrial function. Based on recent findings, a new p66Shc mitochondrial function model is also put forth wherein p66Shc acts as a rheostat that can promote or antagonize apoptosis. A discussion of how the revised p66Shc model fits previous findings in p66Shc-mediated cardiovascular pathology follows.
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Affiliation(s)
- Landon Haslem
- Biochemistry and Molecular Biology Department, College of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA; (L.H.); (J.M.H.)
| | - Jennifer M. Hays
- Biochemistry and Molecular Biology Department, College of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA; (L.H.); (J.M.H.)
| | - Franklin A. Hays
- Biochemistry and Molecular Biology Department, College of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA; (L.H.); (J.M.H.)
- Stephenson Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
- Harold Hamm Diabetes Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
- Correspondence:
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11
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Mechanisms underlying the effects of caloric restriction on hypertension. Biochem Pharmacol 2022; 200:115035. [DOI: 10.1016/j.bcp.2022.115035] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2022] [Revised: 04/07/2022] [Accepted: 04/07/2022] [Indexed: 11/20/2022]
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12
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Xu Q, Mariman EC, Blaak EE, Jocken JW. Pharmacological agents targeting autophagy and their effects on lipolysis in human adipocytes. Mol Cell Endocrinol 2022; 544:111555. [PMID: 35031432 DOI: 10.1016/j.mce.2022.111555] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2021] [Revised: 12/12/2021] [Accepted: 01/04/2022] [Indexed: 11/17/2022]
Abstract
Adipose tissue of metabolically compromised humans with obesity is often characterized by impaired regulation of autophagy pathway. However, data on the role of autophagy in human adipocyte lipid catabolism is scarce. Therefore, we investigated the effect of pharmacological agents (including 3-methyladenine (3MA), bafilomycin A1 (BAF), chloroquine (CQ) and lalistat-2 (L-stat), that target different stages of the autophagy pathway on lipid hydrolysis in differentiated human multipotent adipose-derived stem cells (hMADs). Glycerol and fatty acid release were measured as marker of lipid hydrolysis following starvation and β-adrenergic stimulation. Microtubule-associated protein light chain 3 ratio (LC3II/LC3I) and HSL phosphorylation (pHSL) were analyzed by Western blot. Our data indicate that pharmacological inhibition of the autophagy pathway reduced lipid hydrolysis in human adipocytes, although to a limited extent (10-15%). However, further research is needed to reveal the exact mechanism of action of these pharmacological agents and their interplay with cytosolic lipid breakdown in human adipocytes.
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Affiliation(s)
- Qing Xu
- Department of Human Biology, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University Medical Centre(+), Maastricht, the Netherlands
| | - Edwin Cm Mariman
- Department of Human Biology, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University Medical Centre(+), Maastricht, the Netherlands
| | - Ellen E Blaak
- Department of Human Biology, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University Medical Centre(+), Maastricht, the Netherlands
| | - Johan We Jocken
- Department of Human Biology, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University Medical Centre(+), Maastricht, the Netherlands.
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13
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Bonfante ILP, Monfort-Pires M, Duft RG, da Silva Mateus KC, de Lima Júnior JC, Dos Santos Trombeta JC, Finardi EAR, Brunelli DT, Morari J, de Lima JAB, Bellotto ML, de Araújo TMF, Ramos CD, Chacon-Mikahil MPT, Velloso LA, Cavaglieri CR. Combined training increases thermogenic fat activity in patients with overweight and type 2 diabetes. Int J Obes (Lond) 2022; 46:1145-1154. [PMID: 35173278 DOI: 10.1038/s41366-022-01086-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2021] [Revised: 01/26/2022] [Accepted: 01/28/2022] [Indexed: 11/10/2022]
Abstract
BACKGROUND Exercise is an important strategy in the management of diabetes. Experimental studies have shown that exercise acts, at least in part, by inducing the production of myokines that improve metabolic control and activate brown/beige adipose tissue depots. Combined training (CT) is recommended by the major diabetes guidelines due to its metabolic and cardiovascular benefits, however, its impact on brown/beige adipose tissue activities has never been tested in humans with overweight and type 2 diabetes (T2D). Here, we evaluated the effects of 16-week combined training (CT) program on brown adipose tissue activity; browning and autophagy markers, and serum pro-thermogenic/inflammatory inducers in patients with overweight and T2D. METHODS Thirty-four patients with overweight and T2D were assigned to either a control group (CG) or a combined training group (CTG) in a randomized and controlled study. Functional/fitness parameters, anthropometry/body composition parameters, blood hormone/biochemical parameters, thermogenic/autophagic gene expression in subcutaneous adipose tissue were evaluated before and at the end of the intervention. In addition, cold-induced 18-Fluoroxyglucose Positron Emission Computed Tomography (18F-FDG PET/CT) was performed in the training group before and after the end of the intervention. RESULTS CT increased cervical/supraclavicular brown adipose tissue (BAT) thermogenic activity (p = 0.03) as well as in perirenal adipose tissue (p = 0.02). In addition, CT increased the expression of genes related to thermogenic profile (TMEM26: + 95%, p = 0.04; and EPSTI1: + 26%, p = 0.03) and decreased autophagic genes (ULK1: -15%, p = 0.04; LC3: -5%, p = 0.02; and ATG4: -22%, p < 0.001) in subcutaneous adipose tissue. There were positive correlations between Δ% BAT activity with Δ% of post training energy expenditure cold exposure, HDL-c, IL4, adiponectin, irisin, meteorin-like, and TMEM26 and ZIC1 genes, besides negative correlations with LDL-c, total cholesterol and C-reactive protein. CONCLUSION This is the first evidence of the beneficial actions of CT on adipose tissue thermogenic activity in humans, and it adds important support for the recommendation of CT as a strategy in the management of diabetes.
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Affiliation(s)
- Ivan Luiz Padilha Bonfante
- Laboratory of Exercise Physiology, School of Physical Education, University of Campinas, Campinas, SP, 13083-970, Brazil. .,Federal Institute of Education, Science and Technology of São Paulo, Hortolândia campus, Hortolândia, SP, 13183-091, Brazil.
| | - Milena Monfort-Pires
- Laboratory of Cell Signaling, Department of Internal Medicine, University of Campinas, Campinas, SP, 13084-970, Brazil.,Obesity and Comorbidities Research Center, University of Campinas, Campinas, SP, 13084-970, Brazil
| | - Renata Garbellini Duft
- Laboratory of Exercise Physiology, School of Physical Education, University of Campinas, Campinas, SP, 13083-970, Brazil
| | - Keryma Chaves da Silva Mateus
- Laboratory of Exercise Physiology, School of Physical Education, University of Campinas, Campinas, SP, 13083-970, Brazil
| | - José Carlos de Lima Júnior
- Laboratory of Cell Signaling, Department of Internal Medicine, University of Campinas, Campinas, SP, 13084-970, Brazil.,Obesity and Comorbidities Research Center, University of Campinas, Campinas, SP, 13084-970, Brazil
| | | | | | - Diego Trevisan Brunelli
- Laboratory of Exercise Physiology, School of Physical Education, University of Campinas, Campinas, SP, 13083-970, Brazil
| | - Joseane Morari
- Laboratory of Cell Signaling, Department of Internal Medicine, University of Campinas, Campinas, SP, 13084-970, Brazil.,Obesity and Comorbidities Research Center, University of Campinas, Campinas, SP, 13084-970, Brazil
| | | | - Maria Luisa Bellotto
- Laboratory of Exercise Physiology, School of Physical Education, University of Campinas, Campinas, SP, 13083-970, Brazil
| | - Thiago Matos Ferreira de Araújo
- Laboratory of Cell Signaling, Department of Internal Medicine, University of Campinas, Campinas, SP, 13084-970, Brazil.,Obesity and Comorbidities Research Center, University of Campinas, Campinas, SP, 13084-970, Brazil
| | - Celso Darío Ramos
- Department of Radiology, University of Campinas, Campinas, SP, 13084-970, Brazil
| | | | - Licio Augusto Velloso
- Laboratory of Cell Signaling, Department of Internal Medicine, University of Campinas, Campinas, SP, 13084-970, Brazil.,Obesity and Comorbidities Research Center, University of Campinas, Campinas, SP, 13084-970, Brazil
| | - Cláudia Regina Cavaglieri
- Laboratory of Exercise Physiology, School of Physical Education, University of Campinas, Campinas, SP, 13083-970, Brazil.
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14
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Abad-Jiménez Z, López-Domènech S, García-Gargallo C, Vezza T, Gómez-Abril SÁ, Morillas C, Díaz-Pozo P, Falcón R, Bañuls C, Víctor VM, Rocha M. Roux-en-Y Gastric Bypass Modulates AMPK, Autophagy and Inflammatory Response in Leukocytes of Obese Patients. Biomedicines 2022; 10:biomedicines10020430. [PMID: 35203639 PMCID: PMC8962362 DOI: 10.3390/biomedicines10020430] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2022] [Revised: 02/07/2022] [Accepted: 02/08/2022] [Indexed: 11/16/2022] Open
Abstract
Obesity is characterized by low-grade chronic inflammation, metabolic overload, and impaired endothelial and cardiovascular function. Roux-en-Y gastric bypass (RYGB) results in amelioration of the pro-oxidant status of leukocytes and the metabolic profile. Nevertheless, little is known about the precise mechanism that drives systemic and metabolic improvements following bariatric surgery. In this cohort study, we investigated the effect of RYGB on molecular pathways involving energy homeostasis in leukocytes in 43 obese subjects one year after surgery. In addition to clinical and biochemical parameters, we determined protein expression of systemic proinflammatory cytokines by Luminex®, different markers of inflammation, endoplasmic reticulum (ER) stress, autophagy/mitophagy by western blot, and mitochondrial membrane potential by fluorescence imaging. Bariatric surgery induced an improvement in metabolic outcomes that was accompanied by a systemic drop in hsCRP, IL6, and IL1β levels, and a slowing down of intracellular inflammatory pathways in leukocytes (NF-κB and MCP-1), an increase in AMPK content, a reduction of ER stress (ATF6 and CHOP), augmented autophagy/mitophagy markers (Beclin 1, ATG5, LC3-I, LC3-II, NBR1, and PINK1), and a decrease of mitochondrial membrane potential. These findings shed light on the specific molecular mechanisms by which RYGB facilitates metabolic improvements, highlighting the relevance of pathways involving energy homeostasis as key mediators of these outcomes. In addition, since leukocytes are particularly exposed to physiological changes, they could be used in routine clinical practice as a good sensor of the whole body’s responses.
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Affiliation(s)
- Zaida Abad-Jiménez
- Department of Endocrinology and Nutrition, University Hospital Doctor Peset, Foundation for the Promotion of Health and Biomedical Research in the Valencian Region (FISABIO), 46017 Valencia, Spain; (Z.A.-J.); (C.G.-G.); (T.V.); (C.M.); (P.D.-P.); (R.F.); (C.B.)
| | - Sandra López-Domènech
- Department of Endocrinology and Nutrition, University Hospital Doctor Peset, Foundation for the Promotion of Health and Biomedical Research in the Valencian Region (FISABIO), 46017 Valencia, Spain; (Z.A.-J.); (C.G.-G.); (T.V.); (C.M.); (P.D.-P.); (R.F.); (C.B.)
- Correspondence: (S.L.-D.); (V.M.V.); (M.R.); Tel.: +34-96-318-91-32 (M.R.)
| | - Celia García-Gargallo
- Department of Endocrinology and Nutrition, University Hospital Doctor Peset, Foundation for the Promotion of Health and Biomedical Research in the Valencian Region (FISABIO), 46017 Valencia, Spain; (Z.A.-J.); (C.G.-G.); (T.V.); (C.M.); (P.D.-P.); (R.F.); (C.B.)
| | - Teresa Vezza
- Department of Endocrinology and Nutrition, University Hospital Doctor Peset, Foundation for the Promotion of Health and Biomedical Research in the Valencian Region (FISABIO), 46017 Valencia, Spain; (Z.A.-J.); (C.G.-G.); (T.V.); (C.M.); (P.D.-P.); (R.F.); (C.B.)
| | - Segundo Ángel Gómez-Abril
- Department of General and Digestive System Surgery, University Hospital Doctor Peset, Foundation for the Promotion of Health and Biomedical Research in the Valencian Region (FISABIO), 46017 Valencia, Spain;
- Department of Surgery, Faculty of Medicine and Dentistry, University of Valencia, Av Blasco Ibáñez 13, 46010 Valencia, Spain
| | - Carlos Morillas
- Department of Endocrinology and Nutrition, University Hospital Doctor Peset, Foundation for the Promotion of Health and Biomedical Research in the Valencian Region (FISABIO), 46017 Valencia, Spain; (Z.A.-J.); (C.G.-G.); (T.V.); (C.M.); (P.D.-P.); (R.F.); (C.B.)
| | - Pedro Díaz-Pozo
- Department of Endocrinology and Nutrition, University Hospital Doctor Peset, Foundation for the Promotion of Health and Biomedical Research in the Valencian Region (FISABIO), 46017 Valencia, Spain; (Z.A.-J.); (C.G.-G.); (T.V.); (C.M.); (P.D.-P.); (R.F.); (C.B.)
| | - Rosa Falcón
- Department of Endocrinology and Nutrition, University Hospital Doctor Peset, Foundation for the Promotion of Health and Biomedical Research in the Valencian Region (FISABIO), 46017 Valencia, Spain; (Z.A.-J.); (C.G.-G.); (T.V.); (C.M.); (P.D.-P.); (R.F.); (C.B.)
| | - Celia Bañuls
- Department of Endocrinology and Nutrition, University Hospital Doctor Peset, Foundation for the Promotion of Health and Biomedical Research in the Valencian Region (FISABIO), 46017 Valencia, Spain; (Z.A.-J.); (C.G.-G.); (T.V.); (C.M.); (P.D.-P.); (R.F.); (C.B.)
| | - Víctor M. Víctor
- Department of Endocrinology and Nutrition, University Hospital Doctor Peset, Foundation for the Promotion of Health and Biomedical Research in the Valencian Region (FISABIO), 46017 Valencia, Spain; (Z.A.-J.); (C.G.-G.); (T.V.); (C.M.); (P.D.-P.); (R.F.); (C.B.)
- CIBERehd-Department of Pharmacology, University of Valencia, Av Blasco Ibáñez 15, 46010 Valencia, Spain
- Department of Physiology, Faculty of Medicine and Dentistry, University of Valencia, Av Blasco Ibáñez 13, 46010 Valencia, Spain
- Correspondence: (S.L.-D.); (V.M.V.); (M.R.); Tel.: +34-96-318-91-32 (M.R.)
| | - Milagros Rocha
- Department of Endocrinology and Nutrition, University Hospital Doctor Peset, Foundation for the Promotion of Health and Biomedical Research in the Valencian Region (FISABIO), 46017 Valencia, Spain; (Z.A.-J.); (C.G.-G.); (T.V.); (C.M.); (P.D.-P.); (R.F.); (C.B.)
- CIBERehd-Department of Pharmacology, University of Valencia, Av Blasco Ibáñez 15, 46010 Valencia, Spain
- Correspondence: (S.L.-D.); (V.M.V.); (M.R.); Tel.: +34-96-318-91-32 (M.R.)
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15
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Jia Z, Chen X, Chen J, Zhang L, Oprescu SN, Luo N, Xiong Y, Yue F, Kuang S. ACSS3 in brown fat drives propionate catabolism and its deficiency leads to autophagy and systemic metabolic dysfunction. Clin Transl Med 2022; 12:e665. [PMID: 35184387 PMCID: PMC8858619 DOI: 10.1002/ctm2.665] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2021] [Revised: 11/11/2021] [Accepted: 11/17/2021] [Indexed: 11/22/2022] Open
Abstract
Propionate is a gut microbial metabolite that has been reported to have controversial effects on metabolic health. Here we show that propionate is activated by acyl-CoA synthetase short-chain family member 3 (ACSS3), located on the mitochondrial inner membrane in brown adipocytes. Knockout of Acss3 gene (Acss3-/- ) in mice reduces brown adipose tissue (BAT) mass but increases white adipose tissue (WAT) mass, leading to glucose intolerance and insulin resistance that are exacerbated by high-fat diet (HFD). Intriguingly, Acss3-/- or HFD feeding significantly elevates propionate levels in BAT and serum, and propionate supplementation induces autophagy in cultured brown and white adipocytes. The elevated levels of propionate in Acss3-/- mice similarly drive adipocyte autophagy, and pharmacological inhibition of autophagy using hydroxychloroquine ameliorates obesity, hepatic steatosis and insulin resistance of the Acss3-/- mice. These results establish ACSS3 as the key enzyme for propionate metabolism and demonstrate that accumulation of propionate promotes obesity and Type 2 diabetes through triggering adipocyte autophagy.
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Affiliation(s)
- Zhihao Jia
- Department of Animal SciencesPurdue UniversityWest LafayetteIndiana
| | - Xiyue Chen
- Department of Animal SciencesPurdue UniversityWest LafayetteIndiana
| | - Jingjuan Chen
- Department of Animal SciencesPurdue UniversityWest LafayetteIndiana
| | - Lijia Zhang
- Department of Animal SciencesPurdue UniversityWest LafayetteIndiana
| | - Stephanie N. Oprescu
- Department of Animal SciencesPurdue UniversityWest LafayetteIndiana
- Department of Biological SciencesPurdue UniversityWest LafayetteIndiana
| | - Nanjian Luo
- Department of Animal SciencesPurdue UniversityWest LafayetteIndiana
| | - Yan Xiong
- Department of Animal SciencesPurdue UniversityWest LafayetteIndiana
| | - Feng Yue
- Department of Animal SciencesPurdue UniversityWest LafayetteIndiana
| | - Shihuan Kuang
- Department of Animal SciencesPurdue UniversityWest LafayetteIndiana
- Center for Cancer ResearchPurdue UniversityWest LafayetteIndiana
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16
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Sekar M, Thirumurugan K. Autophagy: a molecular switch to regulate adipogenesis and lipolysis. Mol Cell Biochem 2022; 477:727-742. [PMID: 35022960 DOI: 10.1007/s11010-021-04324-w] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2021] [Accepted: 12/01/2021] [Indexed: 12/16/2022]
Abstract
Obesity is a complex epidemic disease caused by an imbalance of adipose tissue function that results in hyperglycemia, hyperlipidemia and insulin resistance which further develop into type 2 diabetes, cardiovascular disease and nonalcoholic fatty liver disease/nonalcoholic steatohepatitis. Adipose tissue is responsible for fat storage; white adipose tissue stores excess energy as fat for availability during starvation, whereas brown adipose tissue regulates thermogenesis through fat oxidation using uncoupling protein 1. However, hypertrophic fat storage results in inflammation and increase the chances for obesity which triggers autophagy genes and lipolytic enzymes to regulate lipid metabolism. Autophagy degrades cargo molecule with the help of lysosome and redistributes the energy back to the cell. Autophagy regulates adipocyte differentiation by modulating master regulators of adipogenesis. Adipogenesis is the process which stores excessive energy in the form of lipid droplets. Lipid droplets (LD) are dynamic cellular organelles that store toxic free-fatty acids into neutral triglycerides in adipose tissue. LD activates both lipolysis and lipophagy to degrade excess triglycerides. In obese tissue, autophagy is activated via pro-inflammatory cytokines produced by surplus fat stored in the adipose tissue. This review focused on the process of autophagy and adipogenesis and the transcription factors that regulate lipogenesis and lipolysis in the adipose tissue. We have also discussed about the importance of autophagic regulation within adipose tissue which controls the onset of obesity and its associated diseases.
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Affiliation(s)
- Mouliganesh Sekar
- Structural Biology Lab, Centre for Biomedical Research, School of Biosciences & Technology, Vellore Institute of Technology, Vellore, Tamil Nadu, India
| | - Kavitha Thirumurugan
- Structural Biology Lab, Centre for Biomedical Research, School of Biosciences & Technology, Vellore Institute of Technology, Vellore, Tamil Nadu, India.
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17
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Zhu L, Liu L. New Insights Into the Interplay Among Autophagy, the NLRP3 Inflammasome and Inflammation in Adipose Tissue. Front Endocrinol (Lausanne) 2022; 13:739882. [PMID: 35432210 PMCID: PMC9008752 DOI: 10.3389/fendo.2022.739882] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/12/2021] [Accepted: 03/09/2022] [Indexed: 12/12/2022] Open
Abstract
Obesity is a feature of metabolic syndrome with chronic inflammation in obese subjects, characterized by adipose tissue (AT) expansion, proinflammatory factor overexpression, and macrophage infiltration. Autophagy modulates inflammation in the enlargement of AT as an essential step for maintaining the balance in energy metabolism and waste elimination. Signaling originating from dysfunctional AT, such as AT containing hypertrophic adipocytes and surrounding macrophages, activates NOD-like receptor family 3 (NLRP3) inflammasome. There are interactions about altered autophagy and NLRP3 inflammasome activation during the progress in obesity. We summarize the current studies and potential mechanisms associated with autophagy and NLRP3 inflammasome in AT inflammation and aim to provide further evidence for research on obesity and obesity-related complications.
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Affiliation(s)
- Liyuan Zhu
- Department of Cardiovascular Medicine, The Second Xiangya Hospital, Central South University, Changsha, China
- Research Institute of Blood Lipid and Atherosclerosis, Central South University, Changsha, China
- Modern Cardiovascular Disease Clinical Technology Research Center of Hunan Province, Changsha, China
- Cardiovascular Disease Research Center of Hunan Province, Changsha, China
| | - Ling Liu
- Department of Cardiovascular Medicine, The Second Xiangya Hospital, Central South University, Changsha, China
- Research Institute of Blood Lipid and Atherosclerosis, Central South University, Changsha, China
- Modern Cardiovascular Disease Clinical Technology Research Center of Hunan Province, Changsha, China
- Cardiovascular Disease Research Center of Hunan Province, Changsha, China
- *Correspondence: Ling Liu,
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18
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Faghfouri AH, Khajebishak Y, Payahoo L, Faghfuri E, Alivand M. PPAR-gamma agonists: Potential modulators of autophagy in obesity. Eur J Pharmacol 2021; 912:174562. [PMID: 34655597 DOI: 10.1016/j.ejphar.2021.174562] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2021] [Revised: 09/21/2021] [Accepted: 10/11/2021] [Indexed: 12/15/2022]
Abstract
Autophagy pathways are involved in the pathogenesis of some obesity related health problems. As obesity is a nutrient sufficiency condition, autophagy process can be altered in obesity through AMP activated protein kinase (AMPK) inhibition. Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) as the main modulator of adipogenesis process can be effective in the regulation of obesity related phenotypes. As well, it has been revealed that PPAR-gamma and its agonists can regulate autophagy in different normal or cancer cells. However, their effects on autophagy modulation in obesity have been investigated in the limited number of studies. In the current comprehensive mechanistic review, we aimed to investigate the possible mechanisms of action of PPAR-gamma on the process of autophagy in obesity through narrating the effects of PPAR-gamma on autophagy in the non-obesity conditions. Moreover, mode of action of PPAR-gamma agonists on autophagy related implications comprehensively reviewed in the various studies. Understanding the different effects of PPAR-gamma agonists on autophagy in obesity can help to develop a new approach to management of obesity.
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Affiliation(s)
- Amir Hossein Faghfouri
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Community Nutrition, Faculty of Nutrition, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Yaser Khajebishak
- Department of Nutrition, Maragheh University of Medical Sciences, Maragheh, I.R., Iran
| | - Laleh Payahoo
- Department of Nutrition, Maragheh University of Medical Sciences, Maragheh, I.R., Iran
| | - Elnaz Faghfuri
- Digestive Disease Research Center, Ardabil University of Medical Sciences, Ardabil, Iran.
| | - Mohammadreza Alivand
- Department of Medical Genetics, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
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19
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Impact of Bariatric Surgery on Adipose Tissue Biology. J Clin Med 2021; 10:jcm10235516. [PMID: 34884217 PMCID: PMC8658722 DOI: 10.3390/jcm10235516] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2021] [Revised: 11/20/2021] [Accepted: 11/22/2021] [Indexed: 02/07/2023] Open
Abstract
Bariatric surgery (BS) procedures are actually the most effective intervention to help subjects with severe obesity achieve significant and sustained weight loss. White adipose tissue (WAT) is increasingly recognized as the largest endocrine organ. Unhealthy WAT expansion through adipocyte hypertrophy has pleiotropic effects on adipocyte function and promotes obesity-associated metabolic complications. WAT dysfunction in obesity encompasses an altered adipokine secretome, unresolved inflammation, dysregulated autophagy, inappropriate extracellular matrix remodeling and insufficient angiogenic potential. In the last 10 years, accumulating evidence suggests that BS can improve the WAT function beyond reducing the fat depot sizes. The causal relationships between improved WAT function and the health benefits of BS merits further investigation. This review summarizes the current knowledge on the short-, medium- and long-term outcomes of BS on the WAT composition and function.
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20
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Sakane S, Hikita H, Shirai K, Myojin Y, Sasaki Y, Kudo S, Fukumoto K, Mizutani N, Tahata Y, Makino Y, Yamada R, Kodama T, Sakamori R, Tatsumi T, Takehara T. White Adipose Tissue Autophagy and Adipose-Liver Crosstalk Exacerbate Nonalcoholic Fatty Liver Disease in Mice. Cell Mol Gastroenterol Hepatol 2021; 12:1683-1699. [PMID: 34303881 PMCID: PMC8551788 DOI: 10.1016/j.jcmgh.2021.07.008] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/29/2020] [Revised: 07/06/2021] [Accepted: 07/08/2021] [Indexed: 12/12/2022]
Abstract
BACKGROUND & AIMS Although nonalcoholic fatty liver disease (NAFLD) is closely associated with obesity, the role of adipose tissue in NAFLD is not well-understood. Because autophagy has been reported to be involved in the degradation of lipid droplets, we investigated the role of adipose tissue autophagy in the liver pathogenesis of NAFLD. METHODS C57BL/6J mice and adipocyte-specific Atg7-knockout mice (Adipoq-Atg7 KO mice) were fed a high-fat diet (HFD). RESULTS HFD feeding for up to 4 months increased both inguinal and epididymal white adipose tissue (iWAT and eWAT, respectively; the former represents subcutaneous fat, and the latter represents visceral fat) in mice. After HFD feeding, autophagy flux in both types of white adipose tissue was increased, and the levels of Rubicon, a negative autophagy regulator, were decreased, suggesting autophagy promotion. Adipoq-Atg7 KO mice exhibited suppressed autophagy in both iWAT and eWAT. Adipocyte-specific Atg7 KO enhanced HFD-induced iWAT hypertrophy. On the other hand, eWAT levels in Adipoq-Atg7 KO mice were increased after 1 month of HFD feeding but decreased after 4 months of HFD feeding compared with those in wild-type controls. Cleaved caspase 3 and JNK pathway protein expression in eWAT was increased without cytokine elevation in Adipoq-Atg7 KO mice fed an HFD compared with wild-type mice fed an HFD. Adipocyte-specific Atg7 KO decreased serum free fatty acid levels and ameliorated HFD-induced steatosis, liver inflammation, and fibrosis. CONCLUSIONS Autophagy was enhanced in the white adipose tissues of mice fed an HFD. Autophagy inhibition in white adipose tissues ameliorated the liver pathology of NAFLD via adipose-liver crosstalk.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | | | | | | | | | - Tetsuo Takehara
- Correspondence Address correspondence to: Tetsuo Takehara, MD, PhD, 2-2 Yamadaoka, Suita, Osaka, 565-0871 Japan. fax: +81-6-6879-3629.
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21
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Frendo-Cumbo S, Tokarz VL, Bilan PJ, Brumell JH, Klip A. Communication Between Autophagy and Insulin Action: At the Crux of Insulin Action-Insulin Resistance? Front Cell Dev Biol 2021; 9:708431. [PMID: 34336862 PMCID: PMC8319997 DOI: 10.3389/fcell.2021.708431] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2021] [Accepted: 06/24/2021] [Indexed: 01/18/2023] Open
Abstract
Insulin is a paramount anabolic hormone that promotes energy-storage in adipose tissue, skeletal muscle and liver, and these responses are significantly attenuated in insulin resistance leading to type 2 diabetes. Contrasting with insulin's function, macroautophagy/autophagy is a physiological mechanism geared to the degradation of intracellular components for the purpose of energy production, building-block recycling or tissue remodeling. Given that both insulin action and autophagy are dynamic phenomena susceptible to the influence of nutrient availability, it is perhaps not surprising that there is significant interaction between these two major regulatory mechanisms. This review examines the crosstalk between autophagy and insulin action, with specific focus on dysregulated autophagy as a cause or consequence of insulin resistance.
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Affiliation(s)
- Scott Frendo-Cumbo
- Cell Biology Program, Hospital for Sick Children, Toronto, ON, Canada
- Department of Physiology, University of Toronto, Toronto, ON, Canada
| | - Victoria L. Tokarz
- Cell Biology Program, Hospital for Sick Children, Toronto, ON, Canada
- Department of Physiology, University of Toronto, Toronto, ON, Canada
| | - Philip J. Bilan
- Cell Biology Program, Hospital for Sick Children, Toronto, ON, Canada
| | - John H. Brumell
- Cell Biology Program, Hospital for Sick Children, Toronto, ON, Canada
- Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada
- Institute of Medical Science, University of Toronto, Toronto, ON, Canada
- SickKids Inflammatory Bowel Disease (IBD) Centre, Hospital for Sick Children, Toronto, ON, Canada
| | - Amira Klip
- Cell Biology Program, Hospital for Sick Children, Toronto, ON, Canada
- Department of Physiology, University of Toronto, Toronto, ON, Canada
- Department of Biochemistry, University of Toronto, Toronto, ON, Canada
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22
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Mechanisms linking endoplasmic reticulum (ER) stress and microRNAs to adipose tissue dysfunction in obesity. Crit Rev Biochem Mol Biol 2021; 56:455-481. [PMID: 34182855 DOI: 10.1080/10409238.2021.1925219] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Over accumulation of lipids in adipose tissue disrupts metabolic homeostasis by affecting cellular processes. Endoplasmic reticulum (ER) stress is one such process affected by obesity. Biochemical and physiological alterations in adipose tissue due to obesity interfere with adipose ER functions causing ER stress. This is in line with increased irregularities in other cellular processes such as inflammation and autophagy, affecting overall metabolic integrity within adipocytes. Additionally, microRNAs (miRNAs), which can post-transcriptionally regulate genes, are differentially modulated in obesity. A better understanding and identification of such miRNAs could be used as novel therapeutic targets to fight against diseases. In this review, we discuss ways in which ER stress participates as a common molecular process in the pathogenesis of obesity-associated metabolic disorders. Moreover, our review discusses detailed underlying mechanisms through which ER stress and miRNAs contribute to metabolic alteration in adipose tissue in obesity. Hence, identifying mechanistic involvement of miRNAs-ER stress cross-talk in regulating adipose function during obesity could be used as a potential therapeutic approach to combat chronic diseases, including obesity.
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Tetrahydrocurcumin Ameliorates Skin Inflammation by Modulating Autophagy in High-Fat Diet-Induced Obese Mice. BIOMED RESEARCH INTERNATIONAL 2021; 2021:6621027. [PMID: 34222477 PMCID: PMC8219437 DOI: 10.1155/2021/6621027] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/26/2020] [Accepted: 05/29/2021] [Indexed: 01/06/2023]
Abstract
Obesity can induce chronic low-grade inflammation via oxidative stress. Tetrahydrocurcumin (THC) is a major curcumin metabolite with anti-inflammatory and antioxidant effects, but little is known about its effects on the skin of obese individuals. Thus, the aim of this study was to investigate the effects of THC on inflammatory cytokine production, oxidative stress, and autophagy in the skin of mice with high-fat diet- (HFD-) induced obesity. Eight-week-old C57BL/6J mice were fed a regular diet, HFD (60% of total calories from fat), or HFD supplemented with THC (100 mg/kg/day orally) for 12 weeks. We measured their body weights during the experimental period. After 12-week treatments, we performed western blotting and real-time polymerase chain reaction analyses on skin samples to evaluate the expression of inflammatory cytokines, oxidative stress markers, and autophagy markers. We observed higher tumor necrosis factor-α (TNF-α), NADPH oxidase 2 (Nox2), Nox4, and phosphorylated p65 levels; lower nuclear factor erythroid 2-related factor 2 (Nrf2) expression; and higher light chain 3 (LC3), autophagy-related 5 (Atg5), and Beclin 1 expression in the skin of HFD mice compared to the corresponding levels in the skin of mice fed with regular diet. THC administration decreased TNF-α, Nox2, Nox4, and phosphorylated p65 levels and activated the Nrf2 pathway. Interestingly, THC administration suppressed the expression of the autophagy markers LC3, Atg5, and Beclin 1. Overall, HFD-fed mice exhibited an elevation in inflammation, oxidative stress, and autophagy in their skin. THC ameliorated obesity-related skin pathology, and therefore, it is a potential therapeutic agent for obesity-related inflammatory skin diseases.
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Behl T, Sehgal A, Bala R, Chadha S. Understanding the molecular mechanisms and role of autophagy in obesity. Mol Biol Rep 2021; 48:2881-2895. [PMID: 33797660 DOI: 10.1007/s11033-021-06298-w] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2020] [Accepted: 03/17/2021] [Indexed: 12/14/2022]
Abstract
Vital for growth, proliferation, subsistence, and thermogenesis, autophagy is the biological cascade, which confers defence against aging and various pathologies. Current research has demonstrated de novo activity of autophagy in stimulation of biological events. There exists a significant association between autophagy activation and obesity, encompassing expansion of adipocytes which facilitates β cell activity. The main objective of the manuscript is to enumerate intrinsic role of autophagy in obesity and associated complications. The peer review articles published till date were searched using medical databases like PubMed and MEDLINE for research, primarily in English language. Obesity is characterized by adipocytic hypertrophy and hyperplasia, which leads to imbalance of lipid absorption, free fatty acid release, and mitochondrial activity. Detailed evaluation of obesity progression is necessary for its treatment and related comorbidities. Data collected in regard to etiological sustaining of obesity, has revealed hypothesized energy misbalance and neuro-humoral dysfunction, which is stimulated by autophagy. Autophagy regulates chief salvaging events for protein clustering, excessive triglycerides, and impaired mitochondria which is accompanied by oxidative and genotoxic stress in mammals. Autophagy is a homeostatic event, which regulates biological process by eliminating lethal cells and reprocessing physiological constituents, comprising of proteins and fat. Unquestionably, autophagy impairment is involved in metabolic syndromes, like obesity. According to an individual's metabolic outline, autophagy activation is essential for metabolism and activity of the adipose tissue and to retard metabolic syndrome i.e. obesity. The manuscript summarizes the perception of current knowledge on autophagy stimulation and its effect on the obesity.
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Affiliation(s)
- Tapan Behl
- Chitkara College of Pharmacy, Chitkara University, Punjab, India.
| | - Aayush Sehgal
- Chitkara College of Pharmacy, Chitkara University, Punjab, India
| | - Rajni Bala
- Chitkara College of Pharmacy, Chitkara University, Punjab, India
| | - Swati Chadha
- Chitkara College of Pharmacy, Chitkara University, Punjab, India
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Kouroumalis E, Voumvouraki A, Augoustaki A, Samonakis DN. Autophagy in liver diseases. World J Hepatol 2021; 13:6-65. [PMID: 33584986 PMCID: PMC7856864 DOI: 10.4254/wjh.v13.i1.6] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/09/2020] [Revised: 12/10/2020] [Accepted: 12/26/2020] [Indexed: 02/06/2023] Open
Abstract
Autophagy is the liver cell energy recycling system regulating a variety of homeostatic mechanisms. Damaged organelles, lipids and proteins are degraded in the lysosomes and their elements are re-used by the cell. Investigations on autophagy have led to the award of two Nobel Prizes and a health of important reports. In this review we describe the fundamental functions of autophagy in the liver including new data on the regulation of autophagy. Moreover we emphasize the fact that autophagy acts like a two edge sword in many occasions with the most prominent paradigm being its involvement in the initiation and progress of hepatocellular carcinoma. We also focused to the implication of autophagy and its specialized forms of lipophagy and mitophagy in the pathogenesis of various liver diseases. We analyzed autophagy not only in well studied diseases, like alcoholic and nonalcoholic fatty liver and liver fibrosis but also in viral hepatitis, biliary diseases, autoimmune hepatitis and rare diseases including inherited metabolic diseases and also acetaminophene hepatotoxicity. We also stressed the different consequences that activation or impairment of autophagy may have in hepatocytes as opposed to Kupffer cells, sinusoidal endothelial cells or hepatic stellate cells. Finally, we analyzed the limited clinical data compared to the extensive experimental evidence and the possible future therapeutic interventions based on autophagy manipulation.
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Affiliation(s)
- Elias Kouroumalis
- Liver Research Laboratory, University of Crete Medical School, Heraklion 71110, Greece
| | - Argryro Voumvouraki
- 1 Department of Internal Medicine, AHEPA University Hospital, Thessaloniki 54636, Greece
| | - Aikaterini Augoustaki
- Department of Gastroenterology and Hepatology, University Hospital of Crete, Heraklion 71110, Greece
| | - Dimitrios N Samonakis
- Department of Gastroenterology and Hepatology, University Hospital of Crete, Heraklion 71110, Greece.
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Role of Flavonoids in The Interactions among Obesity, Inflammation, and Autophagy. Pharmaceuticals (Basel) 2020; 13:ph13110342. [PMID: 33114725 PMCID: PMC7692407 DOI: 10.3390/ph13110342] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2020] [Revised: 10/22/2020] [Accepted: 10/23/2020] [Indexed: 12/19/2022] Open
Abstract
Nowadays, obesity is considered as one of the main concerns for public health worldwide, since it encompasses up to 39% of overweight and 13% obese (WHO) adults. It develops because of the imbalance in the energy intake/expenditure ratio, which leads to excess nutrients and results in dysfunction of adipose tissue. The hypertrophy of adipocytes and the nutrients excess trigger the induction of inflammatory signaling through various pathways, among others, an increase in the expression of pro-inflammatory adipocytokines, and stress of the endoplasmic reticulum (ER). A better understanding of obesity and preventing its complications are beneficial for obese patients on two facets: treating obesity, and treating and preventing the pathologies associated with it. Hitherto, therapeutic itineraries in most cases are based on lifestyle modifications, bariatric surgery, and pharmacotherapy despite none of them have achieved optimal results. Therefore, diet can play an important role in the prevention of adiposity, as well as the associated disorders. Recent results have shown that flavonoids intake have an essential role in protecting against oxidative damage phenomena, and presents biochemical and pharmacological functions beneficial to human health. This review summarizes the current knowledge of the anti-inflammatory actions and autophagic flux of natural flavonoids, and their molecular mechanisms for preventing and/or treating obesity.
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Systemic Oxidative Stress and Visceral Adipose Tissue Mediators of NLRP3 Inflammasome and Autophagy Are Reduced in Obese Type 2 Diabetic Patients Treated with Metformin. Antioxidants (Basel) 2020; 9:antiox9090892. [PMID: 32967076 PMCID: PMC7555880 DOI: 10.3390/antiox9090892] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2020] [Revised: 09/15/2020] [Accepted: 09/18/2020] [Indexed: 12/17/2022] Open
Abstract
Obesity is a low-grade inflammatory condition affecting a range of individuals, from metabolically healthy obese (MHO) subjects to type 2 diabetes (T2D) patients. Metformin has been shown to display anti-inflammatory properties, though the underlying molecular mechanisms are unclear. To study whether the effects of metformin are mediated by changes in the inflammasome complex and autophagy in visceral adipose tissue (VAT) of obese patients, a biopsy of VAT was obtained from a total of 68 obese patients undergoing gastric bypass surgery. The patients were clustered into two groups: MHO patients and T2D patients treated with metformin. Patients treated with metformin showed decreased levels of all analyzed serum pro-inflammatory markers (TNFα, IL6, IL1β and MCP1) and a downwards trend in IL18 levels associated with a lower production of oxidative stress markers in leukocytes (mitochondrial ROS and myeloperoxidase (MPO)). A reduction in protein levels of MCP1, NFκB, NLRP3, ASC, ATG5, Beclin1 and CHOP and an increase in p62 were also observed in the VAT of the diabetic group. This downregulation of both the NLRP3 inflammasome and autophagy in VAT may be associated with the improved inflammatory profile and leukocyte homeostasis seen in obese T2D patients treated with metformin with respect to MHO subjects and endorses the cardiometabolic protective effect of this drug.
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Zhang X, Wu D, Wang C, Luo Y, Ding X, Yang X, Silva F, Arenas S, Weaver JM, Mandell M, Deretic V, Liu M. Sustained activation of autophagy suppresses adipocyte maturation via a lipolysis-dependent mechanism. Autophagy 2020; 16:1668-1682. [PMID: 31840569 PMCID: PMC8386625 DOI: 10.1080/15548627.2019.1703355] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Dysregulation of macroautophagy/autophagy is implicated in obesity and insulin resistance. However, it remains poorly defined how autophagy regulates adipocyte development. Using adipose-specific rptor/raptor knockout (KO), atg7 KO and atg7 rptor double-KO mice, we show that inhibiting MTORC1 by RPTOR deficiency led to autophagic sequestration of lipid droplets, formation of LD-containing lysosomes, and elevation of basal and isoproterenol-induced lipolysis in vivo and in primary adipocytes. Despite normal differentiation at an early phase, progressive degradation and shrinkage of cellular LDs and downregulation of adipogenic markers PPARG and PLIN1 occurred in terminal differentiation of rptor KO adipocytes, which was rescued by inhibiting lipolysis or lysosome. In contrast, inactivating autophagy by depletion of ATG7 protected adipocytes against RPTOR deficiency-induced formation of LD-containing lysosomes, LD degradation, and downregulation of adipogenic markers in vitro. Ultimately, atg7 rptor double-KO mice displayed decreased lipolysis, restored adipose tissue development, and upregulated thermogenic gene expression in brown and inguinal adipose tissue compared to RPTOR-deficient mice in vivo. Collectively, our study demonstrates that autophagy plays an important role in regulating adipocyte maturation via a lipophagy and lipolysis-dependent mechanism. ABBREVIATIONS ATG7: autophagy related 7; BAT: brown adipose tissue; CEBPB/C/EBPβ: CCAAT enhancer binding protein beta; DGAT1: diacylglycerol O-acyltransferase 1; eWAT: epididymal white adipose tissue; iWAT: inguinal white adipose tissue; KO: knockout; LD: lipid droplet; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; MTOR: mechanistic target of rapamycin kinase; MTORC1: mechanistic target of rapamycin kinase complex 1; PLIN1: perepilin 1; PNPLA2/ATGL: patatin-like phospholipase domain containing 2; PPARG/PPARγ: peroxisome proliferator activated receptor gamma; RPTOR: regulatory associated protein of MTOR complex1; TG: triglyceride; ULK1: unc-51 like kinase 1; UCP1: uncoupling protein 1; WAT: white adipose tissue.
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Affiliation(s)
- Xing Zhang
- Department of Biochemistry and Molecular Biology, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, USA
| | - Dandan Wu
- Department of Biochemistry and Molecular Biology, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, USA
| | - Chunqing Wang
- Department of Biochemistry and Molecular Biology, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, USA
| | - Yan Luo
- Department of Biochemistry and Molecular Biology, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, USA
| | - Xiaofeng Ding
- Department of Biochemistry and Molecular Biology, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, USA
| | - Xin Yang
- Department of Biochemistry and Molecular Biology, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, USA
| | - Floyd Silva
- Department of Biochemistry and Molecular Biology, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, USA
| | - Sara Arenas
- Department of Biochemistry and Molecular Biology, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, USA
| | - John Michael Weaver
- Autophagy Inflammation and Metabolism Center for Biomedical Research Excellence, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, USA
| | - Michael Mandell
- Autophagy Inflammation and Metabolism Center for Biomedical Research Excellence, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, USA,Department of Molecular Genetics and Microbiology, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, USA
| | - Vojo Deretic
- Autophagy Inflammation and Metabolism Center for Biomedical Research Excellence, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, USA,Department of Molecular Genetics and Microbiology, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, USA
| | - Meilian Liu
- Department of Biochemistry and Molecular Biology, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, USA,CONTACT Meilian Liu Department of Biochemistry and Molecular Biology, University of New Mexico Health Sciences Center, Albuquerque, USA
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Balbuena-Pecino S, Lutfi E, Riera-Heredia N, Gasch-Navalón E, Vélez EJ, Gutiérrez J, Capilla E, Navarro I. Genistein Induces Adipogenic and Autophagic Effects in Rainbow Trout ( Oncorhynchus mykiss) Adipose Tissue: In Vitro and In Vivo Models. Int J Mol Sci 2020; 21:E5884. [PMID: 32824312 PMCID: PMC7461592 DOI: 10.3390/ijms21165884] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2020] [Revised: 08/07/2020] [Accepted: 08/14/2020] [Indexed: 02/08/2023] Open
Abstract
Soybeans are one of the most used alternative dietary ingredients in aquafeeds. However, they contain phytoestrogens like genistein (GE), which can have an impact on fish metabolism and health. This study aimed to investigate the in vitro and in vivo effects of GE on lipid metabolism, apoptosis, and autophagy in rainbow trout (Oncorhynchus mykiss). Primary cultured preadipocytes were incubated with GE at different concentrations, 10 or 100 μM, and 1 μM 17β-estradiol (E2). Furthermore, juveniles received an intraperitoneal injection of GE at 5 or 50 µg/g body weight, or E2 at 5 µg/g. In vitro, GE 100 μM increased lipid accumulation and reduced cell viability, apparently involving an autophagic process, indicated by the higher LC3-II protein levels, and higher lc3b and cathepsin d transcript levels achieved after GE 10 μM. In vivo, GE 50 µg/g upregulated the gene expression of fatty acid synthase (fas) and glyceraldehyde-3-phosphate dehydrogenase in adipose tissue, suggesting enhanced lipogenesis, whereas it increased hormone-sensitive lipase in liver, indicating a lipolytic response. Besides, autophagy-related genes increased in the tissues analyzed mainly after GE 50 µg/g treatment. Overall, these findings suggest that an elevated GE administration could lead to impaired adipocyte viability and lipid metabolism dysregulation in rainbow trout.
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Affiliation(s)
| | | | | | | | | | | | | | - Isabel Navarro
- Departament de Biologia Cellular, Fisiologia i Immunologia, Facultat de Biologia, Universitat de Barcelona, 08028 Barcelona, Spain; (S.B.-P.); (E.L.); (N.R.-H.); (E.G.-N.); (E.J.V.); (J.G.); (E.C.)
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30
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Clemente-Postigo M, Tinahones A, El Bekay R, Malagón MM, Tinahones FJ. The Role of Autophagy in White Adipose Tissue Function: Implications for Metabolic Health. Metabolites 2020; 10:metabo10050179. [PMID: 32365782 PMCID: PMC7281383 DOI: 10.3390/metabo10050179] [Citation(s) in RCA: 51] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2020] [Revised: 04/27/2020] [Accepted: 04/28/2020] [Indexed: 02/07/2023] Open
Abstract
White adipose tissue (WAT) is a highly adaptive endocrine organ that continuously remodels in response to nutritional cues. WAT expands to store excess energy by increasing adipocyte number and/or size. Failure in WAT expansion has serious consequences on metabolic health resulting in altered lipid, glucose, and inflammatory profiles. Besides an impaired adipogenesis, fibrosis and low-grade inflammation also characterize dysfunctional WAT. Nevertheless, the precise mechanisms leading to impaired WAT expansibility are yet unresolved. Autophagy is a conserved and essential process for cellular homeostasis, which constitutively allows the recycling of damaged or long-lived proteins and organelles, but is also highly induced under stress conditions to provide nutrients and remove pathogens. By modulating protein and organelle content, autophagy is also essential for cell remodeling, maintenance, and survival. In this line, autophagy has been involved in many processes affected during WAT maladaptation, including adipogenesis, adipocyte, and macrophage function, inflammatory response, and fibrosis. WAT autophagy dysregulation is related to obesity and diabetes. However, it remains unclear whether WAT autophagy alteration in obese and diabetic patients are the cause or the consequence of WAT malfunction. In this review, current data regarding these issues are discussed, focusing on evidence from human studies.
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Affiliation(s)
- Mercedes Clemente-Postigo
- Department of Cell Biology, Physiology and Immunology, Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC)-Reina Sofia University Hospital, University of Cordoba, Edificio IMIBIC, Av. Menéndez Pidal s/n, 14004 Córdoba, Spain;
- Correspondence: (M.C.-P.); (F.J.T.); Tel.: +34-957213728 (M.C.-P.); +34-951032648 (F.J.T.)
| | - Alberto Tinahones
- Unidad de Gestión Clínica de Endocrinología y Nutrición (Hospital Universitario Virgen de la Victoria), Instituto de Investigación Biomédica de Málaga (IBIMA), Universidad de Málaga, Campus Teatinos s/n, 29010 Málaga, Spain;
| | - Rajaa El Bekay
- Unidad de Gestión Clínica de Endocrinología y Nutrición (Hospital Universitario Regional de Málaga), Instituto de Investigación Biomédica de Málaga (IBIMA), Universidad de Málaga, Campus Teatinos s/n, 29010 Málaga, Spain;
- Centro de Investigación Biomédica en Red (CIBER) Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain
| | - María M. Malagón
- Department of Cell Biology, Physiology and Immunology, Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC)-Reina Sofia University Hospital, University of Cordoba, Edificio IMIBIC, Av. Menéndez Pidal s/n, 14004 Córdoba, Spain;
- Centro de Investigación Biomédica en Red (CIBER) Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain
| | - Francisco J. Tinahones
- Unidad de Gestión Clínica de Endocrinología y Nutrición (Hospital Universitario Virgen de la Victoria), Instituto de Investigación Biomédica de Málaga (IBIMA), Universidad de Málaga, Campus Teatinos s/n, 29010 Málaga, Spain;
- Centro de Investigación Biomédica en Red (CIBER) Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain
- Correspondence: (M.C.-P.); (F.J.T.); Tel.: +34-957213728 (M.C.-P.); +34-951032648 (F.J.T.)
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31
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Nasution LS, Jusuf AA, Jusman SW, Sadikin M. Hypoxia and autophagic response of obese adult rat adipocytes which differ in nutritional state during childhood. J Clin Biochem Nutr 2020; 66:132-138. [PMID: 32231409 DOI: 10.3164/jcbn.19-74] [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: 08/25/2019] [Accepted: 09/29/2019] [Indexed: 11/22/2022] Open
Abstract
The prevalence of obesity in adults is increasing worldwide, which is problematic since obesity is associated with degenerative diseases. Nowadays Indonesia is facing an interesting phenomenon since there are adults who have been obese since childhood and others who conversely were undernourished while young. The biological differences of these two types of obesities are not well understood. This study aims to analyse the difference in the size and number of visceral adipocytes, HIF-1α, HIF-2α and MAP1LC3A/LC3 in obese adult rat groups that were undernourished at a young age compared to groups who were normal or even already fat from childhood. We analyzed Hif-1α, Hif-2α, Lc3 mRNA by RT-qPCR; HIF-1α, HIF-2α, MAP1LC3A/LC3 protein level by ELISA. The HIF-1α and HIF-2α protein level of visceral adipocytes derived from the group of rat which were undernourished while young increased significantly compared to the group which was overnourished. The visceral adipocytes of the group which was overnourished since childhood showed an increase in Hif-2α mRNA level. The Lc3 mRNA of the rat group which were undernourished since young increased significantly compared to rat group which was obese since childhood.
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Affiliation(s)
- Lailan Safina Nasution
- Doctoral Programme in Biomedical Sciences, Faculty of Medicine, Universitas Indonesia, Salemba Raya 4 Jakarta 10430, Indonesia.,Department of Nutrition, Faculty of Medicine, Universitas Muhammadiyah Jakarta, K.H. Ahmad Dahlan Jakarta 15419, Indonesia
| | - Ahmad Aulia Jusuf
- Department of Histology, Faculty of Medicine, Universitas Indonesia, Salemba Raya 4 Jakarta 10430, Indonesia
| | - Sri Widia Jusman
- Department of Biochemistry and Molecular Biology, Faculty of Medicine, Universitas Indonesia, Salemba Raya 4 Jakarta 10430, Indonesia.,Center of Hypoxia and Oxidative Stress Studies, Department of Biochemistry and Molecular Biology, Faculty of Medicine, Universitas Indonesia, Salemba Raya 4 Jakarta 10430, Indonesia
| | - Mohamad Sadikin
- Department of Biochemistry and Molecular Biology, Faculty of Medicine, Universitas Indonesia, Salemba Raya 4 Jakarta 10430, Indonesia.,Center of Hypoxia and Oxidative Stress Studies, Department of Biochemistry and Molecular Biology, Faculty of Medicine, Universitas Indonesia, Salemba Raya 4 Jakarta 10430, Indonesia
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32
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Menikdiwela KR, Ramalingam L, Rasha F, Wang S, Dufour JM, Kalupahana NS, Sunahara KKS, Martins JO, Moustaid-Moussa N. Autophagy in metabolic syndrome: breaking the wheel by targeting the renin-angiotensin system. Cell Death Dis 2020; 11:87. [PMID: 32015340 PMCID: PMC6997396 DOI: 10.1038/s41419-020-2275-9] [Citation(s) in RCA: 62] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2019] [Revised: 01/08/2020] [Accepted: 01/09/2020] [Indexed: 12/12/2022]
Abstract
Metabolic syndrome (MetS) is a complex, emerging epidemic which disrupts the metabolic homeostasis of several organs, including liver, heart, pancreas, and adipose tissue. While studies have been conducted in these research areas, the pathogenesis and mechanisms of MetS remain debatable. Lines of evidence show that physiological systems, such as the renin-angiotensin system (RAS) and autophagy play vital regulatory roles in MetS. RAS is a pivotal system known for controlling blood pressure and fluid balance, whereas autophagy is involved in the degradation and recycling of cellular components, including proteins. Although RAS is activated in MetS, the interrelationship between RAS and autophagy varies in glucose homeostatic organs and their cross talk is poorly understood. Interestingly, autophagy is attenuated in the liver during MetS, whereas autophagic activity is induced in adipose tissue during MetS, indicating tissue-specific discordant roles. We discuss in vivo and in vitro studies conducted in metabolic tissues and dissect their tissue-specific effects. Moreover, our review will focus on the molecular mechanisms by which autophagy orchestrates MetS and the ways future treatments could target RAS in order to achieve metabolic homeostasis.
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Affiliation(s)
- Kalhara R Menikdiwela
- Department of Nutritional Sciences, Texas Tech University, Lubbock, TX, USA
- Obesity Research Institute, Texas Tech University, Lubbock, TX, USA
| | - Latha Ramalingam
- Department of Nutritional Sciences, Texas Tech University, Lubbock, TX, USA
- Obesity Research Institute, Texas Tech University, Lubbock, TX, USA
| | - Fahmida Rasha
- Department of Nutritional Sciences, Texas Tech University, Lubbock, TX, USA
- Obesity Research Institute, Texas Tech University, Lubbock, TX, USA
| | - Shu Wang
- Department of Nutritional Sciences, Texas Tech University, Lubbock, TX, USA
- Obesity Research Institute, Texas Tech University, Lubbock, TX, USA
| | - Jannette M Dufour
- Obesity Research Institute, Texas Tech University, Lubbock, TX, USA
- Department of Cell Biology and Biochemistry, Texas Tech University Health Sciences Center, Lubbock, TX, USA
| | - Nishan S Kalupahana
- Department of Nutritional Sciences, Texas Tech University, Lubbock, TX, USA
- Obesity Research Institute, Texas Tech University, Lubbock, TX, USA
- Department of Physiology, Faculty of Medicine, University of Peradeniya, Peradeniya, Sri Lanka
| | - Karen K S Sunahara
- Department of Experimental Physiopatholgy, Medical School University of São Paulo, São Paulo, Brazil
| | - Joilson O Martins
- Laboratory of Immunoendocrinology, Department of Clinical and Toxicological Analyses, School of Pharmaceutical Sciences of University Sao Paulo (FCF/USP), São Paulo, Brazil
| | - Naima Moustaid-Moussa
- Department of Nutritional Sciences, Texas Tech University, Lubbock, TX, USA.
- Obesity Research Institute, Texas Tech University, Lubbock, TX, USA.
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33
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Xu Q, Mariman ECM, Goossens GH, Blaak EE, Jocken JWE. Cathepsin gene expression in abdominal subcutaneous adipose tissue of obese/overweight humans. Adipocyte 2020; 9:246-252. [PMID: 32486882 PMCID: PMC7469552 DOI: 10.1080/21623945.2020.1775035] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/02/2023] Open
Abstract
Cathepsin L1 (CTSL1) and B (CTSB) are lysosomal proteases, of which the expression and activity are impaired in adipose tissue (AT) of obese rodents, indicating AT lysosomal dysfunction. Here we assess the relation between abdominal subcutaneous AT (SCAT) CTSL1 and CTSB gene expression (qRT-PCR), body composition and tissue-specific insulin resistance in 77 overweight/obese (BMI: 225.6-38.6 kg/m2) well phenotyped men and women (61 M/16 F). A two-step hyperinsulinemic-euglycemic clamp was performed to assess AT, hepatic and skeletal muscle insulin sensitivity. Our data show that reduced CTSB expression is associated with markers of insulin resistance (standardized β = -0.561, p < 0.001), independent of adiposity, while CTSL1 expression is only associated with markers of body composition. Our data suggest the presence of lysosomal dysfunction in SCAT of obese humans with an impaired glucose homoeostasis. However, this needs to be investigated in more detail in future mechanistic studies.
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Affiliation(s)
- Qing Xu
- Department of Human Biology, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University Medical Centre+, Maastricht, The Netherlands
| | - Edwin C. M. Mariman
- Department of Human Biology, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University Medical Centre+, Maastricht, The Netherlands
| | - Gijs H. Goossens
- Department of Human Biology, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University Medical Centre+, Maastricht, The Netherlands
| | - Ellen E. Blaak
- Department of Human Biology, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University Medical Centre+, Maastricht, The Netherlands
| | - Johan W. E. Jocken
- Department of Human Biology, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University Medical Centre+, Maastricht, The Netherlands
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Shepard CR. TLR9 in MAFLD and NASH: At the Intersection of Inflammation and Metabolism. Front Endocrinol (Lausanne) 2020; 11:613639. [PMID: 33584545 PMCID: PMC7880160 DOI: 10.3389/fendo.2020.613639] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/02/2020] [Accepted: 12/10/2020] [Indexed: 12/15/2022] Open
Abstract
Toll-Like Receptor 9 (TLR9) is an ancient receptor integral to the primordial functions of inflammation and metabolism. TLR9 functions to regulate homeostasis in a healthy system under acute stress. The literature supports that overactivation of TLR9 under the chronic stress of obesity is a critical driver of the pathogenesis of NASH and NASH-associated fibrosis. Research has focused on the core contributions of the parenchymal and non-parenchymal cells in the liver, adipose, and gut compartments. TLR9 is activated by endogenous circulating mitochondrial DNA (mtDNA). Chronically elevated circulating levels of mtDNA, caused by the stress of overnutrition, are observed in obesity, metabolic dysfunction-associated fatty liver disease (MAFLD), and NASH. Clinical evidence is supportive of TLR9 overactivation as a driver of disease. The role of TLR9 in metabolism and energy regulation may have an underappreciated contribution in the pathogenesis of NASH. Antagonism of TLR9 in NASH and NASH-associated fibrosis could be an effective therapeutic strategy to target both the inflammatory and metabolic components of such a complex disease.
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Chung KW, Chung HY. The Effects of Calorie Restriction on Autophagy: Role on Aging Intervention. Nutrients 2019; 11:nu11122923. [PMID: 31810345 PMCID: PMC6950580 DOI: 10.3390/nu11122923] [Citation(s) in RCA: 66] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2019] [Revised: 11/23/2019] [Accepted: 11/29/2019] [Indexed: 12/13/2022] Open
Abstract
Autophagy is an important housekeeping process that maintains a proper cellular homeostasis under normal physiologic and/or pathologic conditions. It is responsible for the disposal and recycling of metabolic macromolecules and damaged organelles through broad lysosomal degradation processes. Under stress conditions, including nutrient deficiency, autophagy is substantially activated to maintain proper cell function and promote cell survival. Altered autophagy processes have been reported in various aging studies, and a dysregulated autophagy is associated with various age-associated diseases. Calorie restriction (CR) is regarded as the gold standard for many aging intervention methods. Although it is clear that CR has diverse effects in counteracting aging process, the exact mechanisms by which it modulates those processes are still controversial. Recent advances in CR research have suggested that the activation of autophagy is linked to the observed beneficial anti-aging effects. Evidence showed that CR induced a robust autophagy response in various metabolic tissues, and that the inhibition of autophagy attenuated the anti-aging effects of CR. The mechanisms by which CR modulates the complex process of autophagy have been investigated in depth. In this review, several major advances related to CR’s anti-aging mechanisms and anti-aging mimetics will be discussed, focusing on the modification of the autophagy response.
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Affiliation(s)
- Ki Wung Chung
- College of Pharmacy, Kyungsung University, Busan 48434, Korea
- Correspondence: (K.W.C.); (H.Y.C.); Tel.: +82-51-663-4884 (K.W.C.); +82-51-510-2814 (H.Y.C.)
| | - Hae Young Chung
- College of Pharmacy, Pusan National University, Busan 462414, Korea
- Correspondence: (K.W.C.); (H.Y.C.); Tel.: +82-51-663-4884 (K.W.C.); +82-51-510-2814 (H.Y.C.)
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TP53INP2 Promotes Bovine Adipocytes Differentiation Through Autophagy Activation. Animals (Basel) 2019; 9:ani9121060. [PMID: 31810209 PMCID: PMC6940805 DOI: 10.3390/ani9121060] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2019] [Revised: 11/15/2019] [Accepted: 11/27/2019] [Indexed: 02/06/2023] Open
Abstract
Simple Summary In this article explore the role of the bovine TP53INP2 gene in adipocyte differentiation and its function in autophagy during the early stage of adipocyte differentiation. In our work we found that a novel, important autophagy related protein TP53INP2 can activate autophagy during the early stage of differentiation in bovine adipocytes and positively regulate adipocyte differentiation by affecting autophagy. Furthermore, we demonstrated that peroxisome proliferator-activated receptor gamma (PPARγ) also contributed to the function of TP53INP2 in modulating adipocyte differentiation. The study of the function of bovine TP53INP2 gene on adipocyte differentiation has not been reported, therefore, we have decided to focus on Qinchuan cattle, one of the five important cattle breeds in China. We propose that the TP53INP2 gene may affect the meat quality of Qinchuan cattle by regulating lipid deposition, and may shed new light on the developmental mechanisms of adipose development. Abstract Tumor protein p53 inducible nuclear protein 2 (TP53INP2) is a key positive regulator of autophagy, and it has been shown to modulate adipocyte differentiation. However, the molecular mechanism involved in autophagy regulation during adipocyte differentiation has not been clarified. Our experiments were intended to investigate whether TP53INP2 is involved in the regulation of autophagy during bovine adipocyte differentiation and how TP53INP2 affects the differentiation of bovine adipocytes. In our research, using RT-qPCR and Western blot methods, we found that the overexpression of TP53INP2 resulted in the upregulation of adipogenesis and autophagy-related genes, and autophagy flux and the degree of differentiation were detected by LipidTOX™ Deep Red Neutral Lipid staining and dansylcadaverine staining, respectively. The knockdown of TP53INP2 produced results that were the inverse of those produced by the overexpression of TP53INP2. Overall, our results suggested that TP53INP2 can activate autophagy during the early stage of differentiation in bovine adipocytes and positively regulate adipocyte differentiation by affecting autophagy. Additionally, peroxisome proliferator-activated receptor gamma (PPARγ) also contributed to the function of TP53INP2 in modulating adipocyte differentiation.
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Goldstein N, Haim Y, Mattar P, Hadadi-Bechor S, Maixner N, Kovacs P, Blüher M, Rudich A. Leptin stimulates autophagy/lysosome-related degradation of long-lived proteins in adipocytes. Adipocyte 2019; 8:51-60. [PMID: 30676227 PMCID: PMC6768270 DOI: 10.1080/21623945.2019.1569447] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Obesity, a condition most commonly associated with hyper-leptinemia, is also characterized by increased expression of autophagy genes and likely autophagic activity in human adipose tissue (AT). Indeed, circulating leptin levels were previously shown to positively associate with the expression levels of autophagy genes such as Autophagy related gene-5 (ATG5). Here we hypothesized that leptin acts in an autocrine-paracrine manner to increase autophagy in two major AT cell populations, adipocytes and macrophages. We followed the dynamics of autophagosomes following acute leptin administration with or without a leptin receptor antagonist (SMLA) using high-throughput live-cell imaging in murine epididymal adipocyte and macrophage (RAW264.7) cell-lines. In macrophages leptin exerted only a mild effect on autophagy dynamics, tending to attenuate autophagosomes growth rate. In contrast, leptin-treated adipocytes exhibited a moderate, ~20% increase in the rate of autophagosome growth, an effect that was blocked by SMLA. This finding corresponded to mild increases in mRNA and protein expression of key autophagy genes. Interestingly, a long-lived proteins degradation assay uncovered a robust, >2-fold leptin-mediated stimulation of the autophagy/lysosome-related (bafilomycin-inhibited) activity, which was entirely blocked by SMLA. Collectively, leptin regulates autophagy in a cell-type specific manner. In adipocytes, autophagosome dynamics is moderately enhanced, but even more pronounced stimulation is seen in autophagy-related long-lived protein degradation. These findings suggest a causal link between obesity-associated hyperleptinemia and elevated adipocyte and AT autophagy-related processes.
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Affiliation(s)
- Nir Goldstein
- Department of Clinical Biochemistry and Pharmacology, Ben-Gurion University of the Negev, Beer-Sheva, Israel
| | - Yulia Haim
- Department of Clinical Biochemistry and Pharmacology, Ben-Gurion University of the Negev, Beer-Sheva, Israel
- The National Institute of Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer-Sheva, Israel
| | - Pamela Mattar
- Department of Clinical Biochemistry and Pharmacology, Ben-Gurion University of the Negev, Beer-Sheva, Israel
| | - Sapir Hadadi-Bechor
- Department of Clinical Biochemistry and Pharmacology, Ben-Gurion University of the Negev, Beer-Sheva, Israel
- The National Institute of Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer-Sheva, Israel
| | - Nitzan Maixner
- Department of Clinical Biochemistry and Pharmacology, Ben-Gurion University of the Negev, Beer-Sheva, Israel
| | - Peter Kovacs
- Department of Medicine, University of Leipzig, Leipzig, Germany
| | - Matthias Blüher
- Department of Medicine, University of Leipzig, Leipzig, Germany
| | - Assaf Rudich
- Department of Clinical Biochemistry and Pharmacology, Ben-Gurion University of the Negev, Beer-Sheva, Israel
- The National Institute of Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer-Sheva, Israel
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Pedro JMBS, Sica V, Madeo F, Kroemer G. Acyl-CoA-binding protein (ACBP): the elusive 'hunger factor' linking autophagy to food intake. Cell Stress 2019; 3:312-318. [PMID: 31656948 PMCID: PMC6789435 DOI: 10.15698/cst2019.10.200] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2019] [Revised: 09/19/2019] [Accepted: 09/20/2019] [Indexed: 12/13/2022] Open
Abstract
The best-known appetite-regulating factors identified in rodents are leptin, an appetite inhibitor, and ghrelin, an appetite stimulator. Rare cases of loss-of-functions mutations affecting leptin and its receptor, as well as polymorphisms concerning ghrelin and its receptor, have been documented in human obesity, apparently validating the relevance of leptin and ghrelin for human physiology. Paradoxically, however, the overwhelming majority of obese individuals manifest high leptin and low ghrelin plasma levels, suggesting that both factors are not directly disease-relevant. We recently discovered that acyl-CoA-binding protein (ACBP), also known as diazepam-binding inhibitor (DBI), acts as an efficient lipogenic and appetite stimulator in mice. Indeed, in response to starvation, ACBP/DBI is released from tissues in an autophagy-dependent fashion and increases in the plasma. Intravenous injection of ACBP/DBI stimulates feeding behavior through a reduction of circulating glucose levels, and consequent activation of orexigenic neurons in the hypothalamus. In contrast, neutralization of ACBP/DBI abolishes the hyperphagia observed after starvation of mice. Of note, ACBP/DBI is increased in the plasma of obese persons and mice, pointing to a convergence (rather than divergence) between its role in appetite stimulation and human obesity. Based on our results, we postulate a novel 'hunger reflex' in which starvation induces a surge in extracellular ACBP/DBI, which in turn stimulates feeding behavior. Thus, ACBP/DBI might be the elusive 'hunger factor' that explains increased food uptake in obesity.
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Affiliation(s)
- José Manuel Bravo-San Pedro
- INSERM U1138, Centre de Recherche des Cordeliers, Sorbonne Université, Université de Paris, 15 rue de l'école de médecine 75006, Paris, France
- Team “Metabolism, Cancer & Immunity” labellisée par la Ligue contre le Cancer, Paris, France
- Cell Biology and Metabolomics platforms, Gustave Roussy Cancer Campus, Villejuif, France
| | - Valentina Sica
- INSERM U1138, Centre de Recherche des Cordeliers, Sorbonne Université, Université de Paris, 15 rue de l'école de médecine 75006, Paris, France
- Team “Metabolism, Cancer & Immunity” labellisée par la Ligue contre le Cancer, Paris, France
- Cell Biology and Metabolomics platforms, Gustave Roussy Cancer Campus, Villejuif, France
| | - Frank Madeo
- Institute of Molecular Biosciences, NAWI Graz, University of Graz, Graz, 8010, Austria
- BioTechMed Graz, Graz, 8010, Austria
| | - Guido Kroemer
- INSERM U1138, Centre de Recherche des Cordeliers, Sorbonne Université, Université de Paris, 15 rue de l'école de médecine 75006, Paris, France
- Team “Metabolism, Cancer & Immunity” labellisée par la Ligue contre le Cancer, Paris, France
- Cell Biology and Metabolomics platforms, Gustave Roussy Cancer Campus, Villejuif, France
- Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP, Paris, France
- Suzhou Institute for Systems Medicine, Chinese Academy of Sciences, Suzhou, China
- Karolinska Institute, Department of Women's and Children's Health, Karolinska University Hospital, Stockholm, Sweden
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Shin J, Syme C, Wang D, Richer L, Pike GB, Gaudet D, Paus T, Pausova Z. Novel Genetic Locus of Visceral Fat and Systemic Inflammation. J Clin Endocrinol Metab 2019; 104:3735-3742. [PMID: 30942860 PMCID: PMC6642667 DOI: 10.1210/jc.2018-02656] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/11/2018] [Accepted: 03/28/2019] [Indexed: 11/19/2022]
Abstract
CONTEXT Visceral fat (VF), more than fat elsewhere in the body [mostly subcutaneous fat (SF)], promotes systemic inflammation and related disease. The mechanisms of preferentially visceral accumulation of body fat are largely unknown. OBJECTIVE To identify genetic loci and mechanistic pathways of preferential accumulation of VF and associated low-grade systemic inflammation. DESIGN Genome-wide association study (GWAS). SETTING AND PARTICIPANTS Population-based cohort of 1586 adolescents (aged 12 to 19 years) and adults (aged 36 to 65 years). MAIN OUTCOME MEASURES Abdominal VF and SF were measured with MRI, total body fat (TBF) was assessed with bioimpedance, and low-grade systemic inflammation was examined by serum C-reactive protein (CRP) measurement. RESULTS This GWAS of preferential accumulation of VF identified a significant locus on chromosome 6 at rs803522 (P = 1.1 × 10-9 or 4.3 × 10-10 for VF adjusted for SF or TBF, respectively). The major allele was associated with more VF; the association was similar in adolescents and adults. The allele was also associated with higher CRP level, but this association was stronger in adults than adolescents (P for interaction = 4.5 × 10-3). In adults, VF was a significant mediator (P = 1.9× 10-4) in the association between the locus and CRP, explaining 30% of the mediation. The locus was near ATG5, encoding an autophagy molecule reported to modulate adipocyte size and macrophage polarization. CONCLUSION A genetic locus near ATG5 regulates preferential accumulation of VF (vs SF) in youth and adulthood and contributes to the development of systemic inflammation in adulthood.
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Affiliation(s)
- Jean Shin
- The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada
- Department of Physiology, University of Toronto, Toronto, Ontario, Canada
- Department of Nutritional Sciences, University of Toronto, Toronto, Ontario, Canada
| | - Catriona Syme
- The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada
- Department of Physiology, University of Toronto, Toronto, Ontario, Canada
- Department of Nutritional Sciences, University of Toronto, Toronto, Ontario, Canada
| | - Dominic Wang
- The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada
- Department of Physiology, University of Toronto, Toronto, Ontario, Canada
- Department of Nutritional Sciences, University of Toronto, Toronto, Ontario, Canada
| | - Louis Richer
- Department of Health Sciences, Université du Québec à Chicoutimi, Chicoutimi, Quebec, Canada
| | - G Bruce Pike
- Department of Radiology and Clinical Neurosciences, University of Calgary, Calgary, Alberta, Canada
| | - Daniel Gaudet
- Lipidology Unit, Community Genomic Medicine Centre and ECOGENE-21, Department of Medicine, Université de Montréal, Saguenay, Quebec, Canada
| | - Tomas Paus
- Bloorview Research Institute, Holland Bloorview Kids Rehabilitation Hospital, Toronto, Ontario, Canada
- Departments of Psychology and Psychiatry, University of Toronto, Toronto, Ontario, Canada
| | - Zdenka Pausova
- The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada
- Department of Physiology, University of Toronto, Toronto, Ontario, Canada
- Department of Nutritional Sciences, University of Toronto, Toronto, Ontario, Canada
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Abstract
Significance: Alterations in adipose tissue function have profound consequences on whole body energy homeostasis because this tissue is central for fat accumulation, energy expenditure, glucose and insulin metabolism, and hormonal regulation. With the obesity reaching epidemic proportions globally, it is important to understand the mechanisms leading to adipose tissue malfunction. Recent Advances: Autophagy has originally been viewed as an adaptive response to cellular stress, but in recent years this process was shown to regulate important cellular processes. In adipose tissue, autophagy is a key regulator of white adipose tissue (WAT) and brown adipose tissue (BAT) adipogenesis, and dysregulated autophagy impairs fat accumulation both in vitro and in vivo. Animal studies have also suggested an important role for autophagy and mitophagy during the transition from beige to white fat. Human studies have provided evidence for altered autophagy in WAT, and these alterations correlated with the degree of insulin resistance. Critical Issues: Despite these important advances in the study of autophagy in adipose tissue, we still do not understand the physiological role of autophagy in mature white and brown adipocytes. Furthermore, several human studies involving autophagy assessment were performed on whole adipose tissue, which complicates the interpretation of the results considering the cellular heterogeneity of this tissue. Future Directions: Future studies will undoubtedly expand our understanding of the role of autophagy in fully differentiated adipocytes, and uncover novel cross-talks between this tissue and other organs in regulating lipid metabolism, redox signaling, energy homeostasis, and insulin sensitivity.
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Affiliation(s)
- Maroua Ferhat
- Program in Molecular Medicine, Department of Nutrition and Integrative Physiology, College of Health, University of Utah, Salt Lake City, Utah
| | - Katsuhiko Funai
- Program in Molecular Medicine, Department of Nutrition and Integrative Physiology, College of Health, University of Utah, Salt Lake City, Utah
| | - Sihem Boudina
- Program in Molecular Medicine, Department of Nutrition and Integrative Physiology, College of Health, University of Utah, Salt Lake City, Utah
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Sun M, Tan Y, Rexiati M, Dong M, Guo W. Obesity is a common soil for premature cardiac aging and heart diseases - Role of autophagy. Biochim Biophys Acta Mol Basis Dis 2019; 1865:1898-1904. [DOI: 10.1016/j.bbadis.2018.09.004] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2018] [Revised: 08/22/2018] [Accepted: 09/04/2018] [Indexed: 12/31/2022]
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Abstract
Autophagy plays a key role in cellular homeostasis since it allows optimal cellular functioning and provides energy under conditions of stress. Initial is revealed that alterations of macroautophagy disturb adipogenic differentiation in cultured cells, and in mice, leading to a drastic reduction of adipose tissue depots. Nevertheless, more recent studies indicate that autophagy participates in the control of adipose tissue biology in a more complex manner. The protein TP53INP2 activates the formation of autophagosomes by binding to ATG8 proteins such as LC3 or GATE16, and its genetic elimination reduces but does not cancel this activity. TP53INP2 deficiency increases adipogenic differentiation and induces a gain in adiposity in the mouse. At the cellular level, TP53INP2 promotes the sequestration of the regulatory protein GSK3β in multivesicular bodies (MVBs) by a process that involves autophagic activity and the participation of the endosomal sorting complexes required for transport (ESCRT) machinery. Through this mechanism, TP53INP2 stabilizes and activates β-catenin, which in turn triggers the inhibition of adipogenesis. In summary, autophagic pathways provide a whole set of mechanisms that may regulate in an opposite way the biology of adipose tissue, and consequently, have a variable impact on the whole body adiposity. This concept may be extensible to other cell types.
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Affiliation(s)
- Montserrat Romero
- a Institute for Research in Biomedicine (IRB Barcelona) , The Barcelona Institute of Science and Technology , Barcelona , Spain.,b Departament de Bioquímica i Biologia Molecular , Facultat de Biologia , Barcelona , Spain.,c CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM) , Instituto de Salud Carlos III , Madrid , Spain
| | - Antonio Zorzano
- a Institute for Research in Biomedicine (IRB Barcelona) , The Barcelona Institute of Science and Technology , Barcelona , Spain.,b Departament de Bioquímica i Biologia Molecular , Facultat de Biologia , Barcelona , Spain.,c CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM) , Instituto de Salud Carlos III , Madrid , Spain
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Jeong JK, Lee JH, Kim SW, Hong JM, Seol JW, Park SY. Cellular prion protein regulates the differentiation and function of adipocytes through autophagy flux. Mol Cell Endocrinol 2019; 481:84-94. [PMID: 30513342 DOI: 10.1016/j.mce.2018.11.013] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/24/2018] [Revised: 11/06/2018] [Accepted: 11/23/2018] [Indexed: 02/06/2023]
Abstract
The role of autophagy modulation in adipogenic differentiation and the possible autophagy modulators targeting adipogenesis remain unclear. In this study, we investigated whether normal cellular prion protein (PrP<C>) is involved in the modulation of autophagy and affects adipogenic differentiation in vivo and in vitro. Surprisingly, autophagy flux signals were activated in the adipose tissue of prion protein-deficient mice and PrP<C>-deleted 3T3-L1 adipocytes. The activation of autophagy flux mediated by PrP<C> deletion was confirmed in the adipose tissue via transmission electron microscopy. Adipocyte differentiation factors were highly induced in prion protein-deficient adipose tissue and 3T3-L1 adipocytes. In addition, deletion of prion protein significantly increased visceral fat volume, body fat weight, adipocyte cell size, and body weight gain in Prnp-knockout mice and increased lipid accumulation in PrP<C> siRNA-transfected 3T3-L1 cells. However, the overexpression of prion protein using adenovirus inhibited the autophagic flux signals, lipid accumulation, and the PPAR-γ and C/EBP-α mRNA and protein expression levels in comparison to those in the control cells. Our results demonstrated that deletion of normal prion protein accelerated adipogenic differentiation and lipid accumulation mediated via autophagy flux activation.
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Affiliation(s)
- Jae-Kyo Jeong
- Biosafety Research Institute, College of Veterinary Medicine, Chonbuk National University, Iksan, Jeonbuk, 54596, Republic of Korea
| | - Ju-Hee Lee
- Biosafety Research Institute, College of Veterinary Medicine, Chonbuk National University, Iksan, Jeonbuk, 54596, Republic of Korea
| | - Sung-Wook Kim
- Biosafety Research Institute, College of Veterinary Medicine, Chonbuk National University, Iksan, Jeonbuk, 54596, Republic of Korea
| | - Jeong-Min Hong
- Biosafety Research Institute, College of Veterinary Medicine, Chonbuk National University, Iksan, Jeonbuk, 54596, Republic of Korea
| | - Jae-Won Seol
- Biosafety Research Institute, College of Veterinary Medicine, Chonbuk National University, Iksan, Jeonbuk, 54596, Republic of Korea
| | - Sang-Youel Park
- Biosafety Research Institute, College of Veterinary Medicine, Chonbuk National University, Iksan, Jeonbuk, 54596, Republic of Korea.
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Abstract
Sepsis was known to ancient Greeks since the time of great physician Hippocrates (460-377 BC) without exact information regarding its pathogenesis. With time and medical advances, it is now considered as a condition associated with organ dysfunction occurring in the presence of systemic infection as a result of dysregulation of the immune response. Still with this advancement, we are struggling for the development of target-based therapeutic approach for the management of sepsis. The advancement in understanding the immune system and its working has led to novel discoveries in the last 50 years, including different pattern recognition receptors. Inflammasomes are also part of these novel discoveries in the field of immunology which are <20 years old in terms of their first identification. They serve as important cytosolic pattern recognition receptors required for recognizing cytosolic pathogens, and their pathogen-associated molecular patterns play an important role in the pathogenesis of sepsis. The activation of both canonical and non-canonical inflammasome signaling pathways is involved in mounting a proinflammatory immune response via regulating the generation of IL-1β, IL-18, IL-33 cytokines and pyroptosis. In addition to pathogens and their pathogen-associated molecular patterns, death/damage-associated molecular patterns and other proinflammatory molecules involved in the pathogenesis of sepsis affect inflammasomes and vice versa. Thus, the present review is mainly focused on the inflammasomes, their role in the regulation of immune response associated with sepsis, and their targeting as a novel therapeutic approach.
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Affiliation(s)
- Vijay Kumar
- Children's Health Queensland Clinical Unit, School of Clinical Medicine, Faculty of Medicine, Mater Research, University of Queensland, Brisbane, Australia,
- School of Biomedical Sciences, Faculty of Medicine, University of Queensland, Brisbane, Australia,
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Regulation of obesity-associated metabolic disturbance by the antipsychotic drug olanzapine: Role of the autophagy-lysosome pathway. Biochem Pharmacol 2018; 158:114-125. [DOI: 10.1016/j.bcp.2018.10.001] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2018] [Accepted: 10/01/2018] [Indexed: 11/22/2022]
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Baseggio AM, Nuñez CEC, Dragano NRV, Lamas CA, Braga PADC, Lenquiste SA, Reyes FGR, Cagnon VHA, Júnior MRM. Jaboticaba peel extract decrease autophagy in white adipose tissue and prevents metabolic disorders in mice fed with a high-fat diet. PHARMANUTRITION 2018. [DOI: 10.1016/j.phanu.2018.06.006] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
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Wang Y, Tan J, Du H, Liu X, Wang S, Wu S, Yuan Z, Zhu X. Notch1 Inhibits Rosiglitazone-Induced Adipogenic Differentiation in Primary Thymic Stromal Cells. Front Pharmacol 2018; 9:1284. [PMID: 30483127 PMCID: PMC6240707 DOI: 10.3389/fphar.2018.01284] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2018] [Accepted: 10/18/2018] [Indexed: 12/26/2022] Open
Abstract
Adipocyte deposition is believed to be a primary characteristic of age-related thymic involution. Herein, we cultured primary thymic stromal cells (TSCs), used rosiglitazone, a potent peroxisome proliferator-activated receptor γ (PPARγ) agonist, to induce adipogenic differentiation, and investigated the differentially expressed genes during adipogenic differentiation by using RNA-sequencing analysis. Furthermore, the effects of Notch1 on rosiglitazone-induced adipogenic differentiation of TSCs as well as the underlying mechanisms were also investigated. As a result, we identified a total of 1737 differentially expressed genes, among which 965 genes were up-regulated and 772 genes were down-regulated in rosiglitazone-treated cells compared with control cells. Gene ontology (GO) enrichment analysis showed that the GO terms were enriched in metabolic process, intracellular, and protein binding. Kyoto encyclopedia of genes and genomes (KEGG) analysis showed that a number of pathways, including ubiquitin mediated proteolysis, PPAR signaling pathway, and mammalian target of rapamycin (mTOR) signaling pathway were predominantly over-represented. Meanwhile, overexpression of Notch1 suppressed and inhibition of Notch1 promoted rosiglitazone-induced adipogenic differentiation in TSCs, and the pro-adipogenic effects of the Notch inhibitor DAPT were associated with the activation of autophagy. Taken together, our results suggest that Notch1 is a key regulator in thymic adipogenesis and may serve as a potential target to hinder thymic adiposity in age-related thymic involution.
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Affiliation(s)
- Yajun Wang
- Research Center, Shengjing Hospital of China Medical University, Shenyang, China
| | - Jianxin Tan
- State Key Laboratory of Reproductive Medicine, Department of Prenatal Diagnosis, The Affiliated Obstetrics and Gynecology Hospital of Nanjing Medical University, Nanjing Maternity and Child Health Care Hospital, Nanjing, China
| | - Hongmei Du
- Department of Medical Oncology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Xue Liu
- Research Center, Shengjing Hospital of China Medical University, Shenyang, China
| | - Siliang Wang
- Department of Medical Oncology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Simeng Wu
- Department of Blood Transfusion, Shengjing Hospital of China Medical University, Shenyang, China
| | - Zhe Yuan
- Department of Blood Transfusion, Shengjing Hospital of China Medical University, Shenyang, China
| | - Xike Zhu
- Research Center, Shengjing Hospital of China Medical University, Shenyang, China
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Autophagy in Metabolic Age-Related Human Diseases. Cells 2018; 7:cells7100149. [PMID: 30249977 PMCID: PMC6210409 DOI: 10.3390/cells7100149] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2018] [Revised: 09/20/2018] [Accepted: 09/21/2018] [Indexed: 02/08/2023] Open
Abstract
Autophagy is a highly conserved homeostatic cellular mechanism that mediates the degradation of damaged organelles, protein aggregates, and invading pathogens through a lysosome-dependent pathway. Over the last few years, specific functions of autophagy have been discovered in many tissues and organs; however, abnormal upregulation or downregulation of autophagy has been depicted as an attribute of a variety of pathologic conditions. In this review, we will describe the current knowledge on the role of autophagy, from its regulation to its physiological influence, in metabolic age-related disorders. Finally, we propose to discuss the therapeutic potential of pharmacological and nutritional modulators of autophagy to treat metabolic diseases.
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Lee H, Li H, Kweon M, Choi Y, Kim MJ, Ryu JH. Isobavachalcone from Angelica keiskei Inhibits Adipogenesis and Prevents Lipid Accumulation. Int J Mol Sci 2018; 19:ijms19061693. [PMID: 29882838 PMCID: PMC6032101 DOI: 10.3390/ijms19061693] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2018] [Revised: 06/02/2018] [Accepted: 06/04/2018] [Indexed: 12/12/2022] Open
Abstract
We isolated isobavachalcone (IBC) from Angelica keiskei (AK) as an anti-obesity component. IBC dose-dependently inhibited 3T3-L1 adipocyte differentiation by down-regulating adipogenic factors. At the mitotic clonal expansion stage (MCE), IBC caused cell cycle arrest in G0/G1 with decreased expression of cell cycle-regulating proteins. IBC also inhibited autophagic flux by inducing intracellular accumulation of LC3B and SQSTM1/p62 proteins while decreasing expression levels of regulating factors for autophagy initiation. In parallel with the inhibition of adipocyte differentiation, IBC decreased intrahepatic fat deposits and rescued the liver steatosis in high fat cholesterol diet-fed zebrafish. In this study, we found that IBC isolated from AK suppresses mitotic clonal expansion and autophagy flux of adipocytes and also shows anti-obesity activity in a high cholesterol-diet zebrafish model by decreasing intrahepatic fat deposits. These results suggest that IBC could be a leading pharmacological compound for the development of anti-obesity drugs.
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Affiliation(s)
- Hyejin Lee
- Research Center for Cell Fate Control and College of Pharmacy, Sookmyung Women’s University, 100 Chungparo 47-Gil, Yongsan-Gu, Seoul 04310, Korea; (H.L.); (H.L.); minson-_-@nate.com (M.K.)
| | - Hua Li
- Research Center for Cell Fate Control and College of Pharmacy, Sookmyung Women’s University, 100 Chungparo 47-Gil, Yongsan-Gu, Seoul 04310, Korea; (H.L.); (H.L.); minson-_-@nate.com (M.K.)
| | - Minson Kweon
- Research Center for Cell Fate Control and College of Pharmacy, Sookmyung Women’s University, 100 Chungparo 47-Gil, Yongsan-Gu, Seoul 04310, Korea; (H.L.); (H.L.); minson-_-@nate.com (M.K.)
| | - Youngsook Choi
- Research institute of women’s health, Sookmyung Women’s University, 100 Chungparo 47-Gil, Yongsan-Gu, Seoul 04310, Korea;
| | - Min Jung Kim
- Department of Biological Sciences, Sookmyung Women’s University, 100 Chungparo 47-Gil, Yongsan-Gu, Seoul 04310, Korea;
| | - Jae-Ha Ryu
- Research Center for Cell Fate Control and College of Pharmacy, Sookmyung Women’s University, 100 Chungparo 47-Gil, Yongsan-Gu, Seoul 04310, Korea; (H.L.); (H.L.); minson-_-@nate.com (M.K.)
- Correspondence: ; Tel.: +82-2-710-9568
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Bombassaro B, Ignacio-Souza LM, Nunez CE, Razolli DS, Pedro RM, Coope A, Araujo EP, Chaim EA, Velloso LA. A20 deubiquitinase controls PGC-1α expression in the adipose tissue. Lipids Health Dis 2018; 17:90. [PMID: 29678181 PMCID: PMC5909260 DOI: 10.1186/s12944-018-0740-6] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2017] [Accepted: 04/09/2018] [Indexed: 12/23/2022] Open
Abstract
BACKGROUND Peroxisome proliferator-activated receptor γ coactivator- 1alpha (PGC-1α) plays an important role in whole body metabolism and, particularly in glucose homeostasis. Its expression is highly regulated and, small variations in tissue levels can have a major impact in a number of physiological and pathological conditions. Recent studies have shown that the ubiquitin/proteasome system plays a role in the control of PGC-1α degradation. METHODS Here we evaluated the interaction of PGC-1α with the protein A20, which plays a dual-role in the control of the ubiquitin/proteasome system acting as a deubiquitinase and as an E3 ligase. We employed immunoprecipitation, quantitative real-time PCR and immunofluorescence staining to evaluate PGC-1α, A20, PPARγ and ubiquitin in the adipose tissue of humans and mice. RESULTS In distinct sites of the adipose tissue, A20 binds to PGC-1α. At least in the subcutaneous fat of humans and mice the levels of PGC-1α decrease during obesity, while its physical association with A20 increases. The inhibition of A20 leads to a reduction of PGC-1α and PPARγ expression, suggesting that A20 acts as a protective factor against PGC-1α disposal. CONCLUSION We provide evidence that mechanisms regulating PGC-1α ubiquitination are potentially involved in the control of the function of this transcriptional co-activator.
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Affiliation(s)
- Bruna Bombassaro
- Laboratory of Cell Signaling, Obesity and Comorbidities Research Center University of Campinas, Campinas, Brazil
| | - Leticia M Ignacio-Souza
- Laboratory of Cell Signaling, Obesity and Comorbidities Research Center University of Campinas, Campinas, Brazil
| | - Carla E Nunez
- Laboratory of Cell Signaling, Obesity and Comorbidities Research Center University of Campinas, Campinas, Brazil
| | - Daniela S Razolli
- Laboratory of Cell Signaling, Obesity and Comorbidities Research Center University of Campinas, Campinas, Brazil
| | - Rafael M Pedro
- Laboratory of Cell Signaling, Obesity and Comorbidities Research Center University of Campinas, Campinas, Brazil
| | - Andressa Coope
- Laboratory of Cell Signaling, Obesity and Comorbidities Research Center University of Campinas, Campinas, Brazil
| | - Eliana P Araujo
- Laboratory of Cell Signaling, Obesity and Comorbidities Research Center University of Campinas, Campinas, Brazil
| | - Elinton A Chaim
- Department of Surgery, University of Campinas, Campinas, Brazil
| | - Licio A Velloso
- Laboratory of Cell Signaling, Obesity and Comorbidities Research Center University of Campinas, Campinas, Brazil. .,Laboratory of Cell Signaling, Faculdade de Ciencias Medicas da Universidade Estadual de Campinas, Campinas, SP, 13084 970, Brazil.
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