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Abbasi K, Zarezadeh R, Valizadeh A, Mehdizadeh A, Hamishehkar H, Nouri M, Darabi M. White-brown adipose tissue interplay in polycystic ovary syndrome: Therapeutic avenues. Biochem Pharmacol 2024; 220:116012. [PMID: 38159686 DOI: 10.1016/j.bcp.2023.116012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2023] [Accepted: 12/22/2023] [Indexed: 01/03/2024]
Abstract
This study highlights the therapeutic potential of activating brown adipose tissue (BAT) for managing polycystic ovary syndrome (PCOS), a prevalent endocrine disorder associated with metabolic and reproductive abnormalities. BAT plays a crucial role in regulating energy expenditure and systemic insulin sensitivity, making it an attractive target for the treatment of obesity and metabolic diseases. Recent research suggests that impaired BAT function and mass may contribute to the link between metabolic disturbances and reproductive issues in PCOS. Additionally, abnormal white adipose tissue (WAT) can exacerbate these conditions by releasing adipokines and nonesterified fatty acids. In this review, we explored the impact of WAT changes on BAT function in PCOS and discussed the potential of BAT activation as a therapeutic strategy to improve PCOS symptoms. We propose that BAT activation holds promise for managing PCOS; however, further research is needed to confirm its efficacy and to develop clinically feasible methods for BAT activation.
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Affiliation(s)
- Khadijeh Abbasi
- Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Biochemistry and Clinical Laboratories, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Reza Zarezadeh
- Women's Reproductive Health Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Amir Valizadeh
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Amir Mehdizadeh
- Hematology and Oncology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Hamed Hamishehkar
- Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mohammad Nouri
- Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
| | - Masoud Darabi
- Department of Biochemistry and Clinical Laboratories, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran; Division of Experimental Oncology, Department of Hematology and Oncology, University Medical Center Schleswig-Holstein, Campus Lübeck, Germany.
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Yamagata K, Mizumoto T, Yoshizawa T. The Emerging Role of SIRT7 in Glucose and Lipid Metabolism. Cells 2023; 13:48. [PMID: 38201252 PMCID: PMC10778536 DOI: 10.3390/cells13010048] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2023] [Revised: 12/13/2023] [Accepted: 12/24/2023] [Indexed: 01/12/2024] Open
Abstract
Sirtuins (SIRT1-7 in mammals) are a family of NAD+-dependent lysine deacetylases and deacylases that regulate diverse biological processes, including metabolism, stress responses, and aging. SIRT7 is the least well-studied member of the sirtuins, but accumulating evidence has shown that SIRT7 plays critical roles in the regulation of glucose and lipid metabolism by modulating many target proteins in white adipose tissue, brown adipose tissue, and liver tissue. This review focuses on the emerging roles of SIRT7 in glucose and lipid metabolism in comparison with SIRT1 and SIRT6. We also discuss the possible implications of SIRT7 inhibition in the treatment of metabolic diseases such as type 2 diabetes and obesity.
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Affiliation(s)
- Kazuya Yamagata
- Department of Medical Biochemistry, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan; (T.M.); (T.Y.)
- Center for Metabolic Regulation of Healthy Aging, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan
| | - Tomoya Mizumoto
- Department of Medical Biochemistry, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan; (T.M.); (T.Y.)
| | - Tatsuya Yoshizawa
- Department of Medical Biochemistry, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan; (T.M.); (T.Y.)
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Abstract
Brown adipose tissue (BAT) displays the unique capacity to generate heat through uncoupled oxidative phosphorylation that makes it a very attractive therapeutic target for cardiometabolic diseases. Here, we review BAT cellular metabolism, its regulation by the central nervous and endocrine systems and circulating metabolites, the plausible roles of this tissue in human thermoregulation, energy balance, and cardiometabolic disorders, and the current knowledge on its pharmacological stimulation in humans. The current definition and measurement of BAT in human studies relies almost exclusively on BAT glucose uptake from positron emission tomography with 18F-fluorodeoxiglucose, which can be dissociated from BAT thermogenic activity, as for example in insulin-resistant states. The most important energy substrate for BAT thermogenesis is its intracellular fatty acid content mobilized from sympathetic stimulation of intracellular triglyceride lipolysis. This lipolytic BAT response is intertwined with that of white adipose (WAT) and other metabolic tissues, and cannot be independently stimulated with the drugs tested thus far. BAT is an interesting and biologically plausible target that has yet to be fully and selectively activated to increase the body's thermogenic response and shift energy balance. The field of human BAT research is in need of methods able to directly, specifically, and reliably measure BAT thermogenic capacity while also tracking the related thermogenic responses in WAT and other tissues. Until this is achieved, uncertainty will remain about the role played by this fascinating tissue in human cardiometabolic diseases.
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Affiliation(s)
- André C Carpentier
- Division of Endocrinology, Department of Medicine, Centre de recherche du Centre hospitalier universitaire de Sherbrooke, Université de Sherbrooke, Sherbrooke, Quebec, J1H 5N4, Canada
| | - Denis P Blondin
- Division of Neurology, Department of Medicine, Centre de recherche du Centre hospitalier universitaire de Sherbrooke, Université de Sherbrooke, Sherbrooke, Quebec, J1H 5N4, Canada
| | | | - Denis Richard
- Centre de recherche de l’Institut universitaire de cardiologie et de pneumologie de Québec, Université Laval, Quebec City, Quebec, G1V 4G5, Canada
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Arranz-Paraíso D, Sola Y, Baeza-Moyano D, Benítez-Martínez M, Melero-Tur S, González-Lezcano RA. Mitochondria and light: An overview of the pathways triggered in skin and retina with incident infrared radiation. JOURNAL OF PHOTOCHEMISTRY AND PHOTOBIOLOGY. B, BIOLOGY 2023; 238:112614. [PMID: 36469983 DOI: 10.1016/j.jphotobiol.2022.112614] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/26/2022] [Revised: 11/18/2022] [Accepted: 11/29/2022] [Indexed: 12/03/2022]
Abstract
Slightly more than half of the solar radiation that passes through the atmosphere and reaches the Earth's surface is infrared. Over the past few years, many papers have been published on the possible positive effects of receiving this part of the electromagnetic spectrum. In this article we analyse the role of mitochondria in the supposed effects of infrared light based on the published literature. It is claimed that ATP synthesis is stimulated, which has a positive effect on the skin by increasing fibroblast proliferation, anchorage and production of collagen fibres, procollagen, and various cytokines responsible for the wound healing process, such as keratinocyte growth factor. Currently there are infrared light emitting equipment whose manufacturers and the centres where this service or treatment is offered claim that they are used for skin rejuvenation among other positive effects. Based on the literature review, it is necessary to deepen the scientific study of the mechanism of absorption of infrared radiation through the skin to better understand its possible positive effects, the risks of overexposure and to improve consumer health protection.
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Affiliation(s)
- Daniel Arranz-Paraíso
- Área de conocimiento de Tecnología Farmacéutica, Departamento de Ciencias Farmacéuticas y de la Salud, Facultad de Farmacia, Universidad San Pablo-CEU, CEU Universities, Urbanización Montepríncipe, 28668 Alcorcón, Madrid, Spain.
| | - Yolanda Sola
- Group of Meteorology, Department of Applied Physics, Universitat de Barcelona, Martí i Franquès 1, 08028 Barcelona, Spain.
| | - David Baeza-Moyano
- Departamento de Química y Bioquímica, Facultad de Farmacia, Universidad San Pablo-CEU, CEU Universities, Urbanización Montepríncipe, 28668 Alcorcón, Madrid, Spain.
| | - Marta Benítez-Martínez
- Departamento de Química y Bioquímica, Facultad de Farmacia, Universidad San Pablo-CEU, CEU Universities, Urbanización Montepríncipe, 28668 Alcorcón, Madrid, Spain.
| | - Sofía Melero-Tur
- Departamento de arquitectura y diseño, Escuela Politécnica Superior, Universidad San Pablo-CEU, CEU Universities, Urbanización Montepríncipe, 28668 Alcorcón, Madrid, Spain.
| | - Roberto Alonso González-Lezcano
- Departamento de arquitectura y diseño, Escuela Politécnica Superior, Universidad San Pablo-CEU, CEU Universities, Urbanización Montepríncipe, 28668 Alcorcón, Madrid, Spain.
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Radugin FM, Timkina NV, Karonova TL. Metabolic properties of irisin in health and in diabetes mellitus. OBESITY AND METABOLISM 2022; 19:332-339. [DOI: 10.14341/omet12899] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/02/2024]
Abstract
Irisin is a polypeptide hormone of muscle tissue (myokine), the synthesis and secretion of which increase against the background of physical exertion, which plays a significant role in the metabolism of fat, muscle and bone tissues. It is known that irisin promotes the transformation of white adipose tissue into brown adipose tissue. It has also been experimentally proven that the introduction of irisin contributed to an increase in bone mass and the prevention of osteoporosis and muscular atrophy. There are works indicating a positive effect of irisin in the functioning of bone, fat and muscle tissues in humans. Diabetes mellitus (DM) is an independent risk factor for osteoporotic fractures and the development of specific diabetic myopathy, at the cellular level similar to the aging of muscle tissue, and type 2 diabetes is also associated with the presence of obesity. Thus, it is of particular interest to study the effect of irisin on the state of bone, muscle and adipose tissues and glucose homeostasis in patients with diabetes. This literature review highlights the biological functions of irisin in healthy people and patients with DM.
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Zhang Q, Ye R, Zhang YY, Fan CC, Wang J, Wang S, Chen S, Liu X. Brown Adipose Tissue and Novel Management Strategies for Polycystic Ovary Syndrome Therapy. Front Endocrinol (Lausanne) 2022; 13:847249. [PMID: 35663310 PMCID: PMC9160465 DOI: 10.3389/fendo.2022.847249] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/01/2022] [Accepted: 03/22/2022] [Indexed: 12/24/2022] Open
Abstract
Brown adipose tissue (BAT), a unique tissue, plays a key role in metabolism and energy expenditure through adaptive nonshivering thermogenesis. It has recently become a therapeutic target in the treatment of obesity and metabolic diseases. The thermogenic effect of BAT occurs through uncoupling protein-1 by uncoupling adenosine triphosphate (ATP) synthesis from energy substrate oxidation. The review discusses the recent developments and progress associated with the biology, function, and activation of BAT, with a focus on its therapeutic potential for the treatment of polycystic ovary syndrome (PCOS). The endocrine activity of brown adipocytes affects the energy balance and homeostasis of glucose and lipids, thereby affecting the association of BAT activity and the metabolic profile. PCOS is a complex reproductive and metabolic disorder of reproductive-age women. Functional abnormalities of adipose tissue (AT) have been reported in patients with PCOS. Numerous studies have shown that BAT could regulate the features of PCOS and that increases in BAT mass or activity were effective in the treatment of PCOS through approaches including cold stimulation, BAT transplantation and compound activation in various animal models. Therefore, BAT may be used as a novel management strategy for the patients with PCOS to improve women's health clinically. It is highly important to identify key brown adipokines for the discovery and development of novel candidates to establish an efficacious therapeutic strategy for patients with PCOS in the future.
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Affiliation(s)
- Qiaoli Zhang
- Department of Human Reproductive Medicine, Beijing Obstetrics and Gynecology Hospital, Beijing Maternal and Child Health Care Hospital, Capital Medical University, Beijing, China
| | - Rongcai Ye
- Key Laboratory of Animal Ecology and Conservation Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
| | - Yuan-Yuan Zhang
- Department of Reproductive Regulation (Family Planning), Beijing Obstetrics and Gynecology Hospital, Beijing Maternal and Child Health Care Hospital, Capital Medical University, Beijing, China
| | - Chen-Chen Fan
- Department of Obstetrics, Beijing Obstetrics and Gynecology Hospital, Beijing Maternal and Child Health Care Hospital, Capital Medical University, Beijing, China
| | - Jun Wang
- Department of Reproductive Regulation (Family Planning), Beijing Obstetrics and Gynecology Hospital, Beijing Maternal and Child Health Care Hospital, Capital Medical University, Beijing, China
| | - Shuyu Wang
- Department of Human Reproductive Medicine, Beijing Obstetrics and Gynecology Hospital, Beijing Maternal and Child Health Care Hospital, Capital Medical University, Beijing, China
- *Correspondence: Suwen Chen, ; Xiaowei Liu, ; Shuyu Wang,
| | - Suwen Chen
- Department of Reproductive Regulation (Family Planning), Beijing Obstetrics and Gynecology Hospital, Beijing Maternal and Child Health Care Hospital, Capital Medical University, Beijing, China
- *Correspondence: Suwen Chen, ; Xiaowei Liu, ; Shuyu Wang,
| | - Xiaowei Liu
- Department of Obstetrics, Beijing Obstetrics and Gynecology Hospital, Beijing Maternal and Child Health Care Hospital, Capital Medical University, Beijing, China
- *Correspondence: Suwen Chen, ; Xiaowei Liu, ; Shuyu Wang,
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Tournissac M, Leclerc M, Valentin-Escalera J, Vandal M, Bosoi CR, Planel E, Calon F. Metabolic determinants of Alzheimer's disease: A focus on thermoregulation. Ageing Res Rev 2021; 72:101462. [PMID: 34534683 DOI: 10.1016/j.arr.2021.101462] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2021] [Revised: 08/09/2021] [Accepted: 09/11/2021] [Indexed: 12/12/2022]
Abstract
Alzheimer's disease (AD) is a complex age-related neurodegenerative disease, associated with central and peripheral metabolic anomalies, such as impaired glucose utilization and insulin resistance. These observations led to a considerable interest not only in lifestyle-related interventions, but also in repurposing insulin and other anti-diabetic drugs to prevent or treat dementia. Body temperature is the oldest known metabolic readout and mechanisms underlying its maintenance fail in the elderly, when the incidence of AD rises. This raises the possibility that an age-associated thermoregulatory deficit contributes to energy failure underlying AD pathogenesis. Brown adipose tissue (BAT) plays a central role in thermogenesis and maintenance of body temperature. In recent years, the modulation of BAT activity has been increasingly demonstrated to regulate energy expenditure, insulin sensitivity and glucose utilization, which could also provide benefits for AD. Here, we review the evidence linking thermoregulation, BAT and insulin-related metabolic defects with AD, and we propose mechanisms through which correcting thermoregulatory impairments could slow the progression and delay the onset of AD.
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Couvineau A, Voisin T, Nicole P, Gratio V, Blais A. Orexins: A promising target to digestive cancers, inflammation, obesity and metabolism dysfunctions. World J Gastroenterol 2021; 27:7582-7596. [PMID: 34908800 PMCID: PMC8641057 DOI: 10.3748/wjg.v27.i44.7582] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/20/2021] [Revised: 06/22/2021] [Accepted: 11/18/2021] [Indexed: 02/06/2023] Open
Abstract
Hypothalamic neuropeptides named hypocretin/orexins which were identified in 1998 regulate critical functions such as wakefulness in the central nervous system. These past 20 years had revealed that orexins/receptors system was also present in the peripheral nervous system where they participated to the regulation of multiple functions including blood pressure regulation, intestinal motility, hormone secretion, lipolyze and reproduction functions. Associated to these peripheral functions, it was found that orexins and their receptors were involved in various diseases such as acute/chronic inflammation, metabolic syndrome and cancers. The present review suggests that orexins or the orexin neural circuitry represent potential therapeutic targets for the treatment of multiple pathologies related to inflammation including intestinal bowel disease, multiple sclerosis and septic shock, obesity and digestive cancers.
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Affiliation(s)
- Alain Couvineau
- INSERM UMR1149/Inflammation Research Center, Team “From inflammation to cancer in digestive diseases” labeled by “la Ligue Nationale contre le Cancer”, University of Paris, DHU UNITY, Paris 75018, France
| | - Thierry Voisin
- INSERM UMR1149/Inflammation Research Center, Team “From inflammation to cancer in digestive diseases” labeled by “la Ligue Nationale contre le Cancer”, University of Paris, DHU UNITY, Paris 75018, France
| | - Pascal Nicole
- INSERM UMR1149/Inflammation Research Center, Team “From inflammation to cancer in digestive diseases” labeled by “la Ligue Nationale contre le Cancer”, University of Paris, DHU UNITY, Paris 75018, France
| | - Valerie Gratio
- INSERM UMR1149/Inflammation Research Center, Team “From inflammation to cancer in digestive diseases” labeled by “la Ligue Nationale contre le Cancer”, University of Paris, DHU UNITY, Paris 75018, France
| | - Anne Blais
- UMR PNCA, AgroParisTech, INRA, Université Paris-Saclay, Paris 75005, France
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Xiang-Li, Bo-Xing, Xin-Liu, Jiang XW, Lu HY, Xu ZH, Yue-Yang, Qiong-Wu, Dong-Yao, Zhang YS, Zhao QC. Network pharmacology-based research uncovers cold resistance and thermogenesis mechanism of Cinnamomum cassia. Fitoterapia 2021; 149:104824. [PMID: 33388379 DOI: 10.1016/j.fitote.2020.104824] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2020] [Revised: 12/25/2020] [Accepted: 12/26/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND Cinnamomum cassia (L.) J.Presl (Cinnamon) was known as a kind of hot herb, improved circulation and warmed the body. However, the active components and mechanisms of dispelling cold remain unknown. METHODS The effects of several Chinses herbs on thermogenesis were evaluated on body temperature and activation of brown adipose tissue. After confirming the effect, the components of cinnamon were identified using HPLC-Q-TOF/MS and screened with databases. The targets of components were obtained with TCMSP, SymMap, Swiss and STITCH databases. Thermogenesis genes were predicted with DisGeNET and GeneCards databases. The protein-protein interaction network was constructed with Cytoscape 3.7.1 software. GO enrichment analysis was accomplished with STRING databases. KEGG pathway analysis was established with Omicshare tools. The top 20 targets for four compounds were obtained according to the number of edges of PPI network. In addition, the network results were verified with experimental research for the effects of extracts and major compounds. RESULTS Cinnamon extract significantly upregulated the body temperature during cold exposure.121 components were identified in HPLC-Q-TOF/MS. Among them, 60 compounds were included in the databases. 116 targets were obtained for the compounds, and 41 genes were related to thermogenesis. The network results revealed that 27 active ingredients and 39 target genes. Through the KEGG analysis, the top 3 pathways were PPAR signaling pathway, AMPK signaling pathway, thermogenesis pathway. The thermogenic protein PPARγ, UCP1 and PGC1-α was included in the critical targets of four major compounds. The three major compounds increased the lipid consumption and activated the brown adipocyte. They also upregulated the expression of UCP1, PGC1-α and pHSL, especially 2-methoxycinnamaldehyde was confirmed the effect for the first time. Furthermore, cinnamaldehyde and cinnamon extract activated the expression of TRPA1 on DRG cells. CONCLUSION The mechanisms of cinnamon on cold resistance were investigated with network pharmacology and experiment validation. This work provided research direction to support the traditional applications of thermogenesis.
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Affiliation(s)
- Xiang-Li
- Department of Life Science and Biochemistry, Shenyang Pharmaceutical University, Shenyang 110016, China; Department of Pharmacy, General Hospital of Northern Theater Command, Shenyang 110840, China
| | - Bo-Xing
- Department of Life Science and Biochemistry, Shenyang Pharmaceutical University, Shenyang 110016, China
| | - Xin-Liu
- Department of Life Science and Biochemistry, Shenyang Pharmaceutical University, Shenyang 110016, China
| | - Xiao-Wen Jiang
- Department of Life Science and Biochemistry, Shenyang Pharmaceutical University, Shenyang 110016, China
| | - Hong-Yuan Lu
- Department of Life Science and Biochemistry, Shenyang Pharmaceutical University, Shenyang 110016, China
| | - Zi-Hua Xu
- Department of Life Science and Biochemistry, Shenyang Pharmaceutical University, Shenyang 110016, China
| | - Yue-Yang
- Department of Life Science and Biochemistry, Shenyang Pharmaceutical University, Shenyang 110016, China
| | - Qiong-Wu
- Department of Life Science and Biochemistry, Shenyang Pharmaceutical University, Shenyang 110016, China
| | - Dong-Yao
- Department of Pharmacy, General Hospital of Northern Theater Command, Shenyang 110840, China
| | - Ying-Shi Zhang
- Department of Life Science and Biochemistry, Shenyang Pharmaceutical University, Shenyang 110016, China
| | - Qing-Chun Zhao
- Department of Life Science and Biochemistry, Shenyang Pharmaceutical University, Shenyang 110016, China; Department of Pharmacy, General Hospital of Northern Theater Command, Shenyang 110840, China.
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Ghadge AA, Khaire AA. Leptin as a predictive marker for metabolic syndrome. Cytokine 2019; 121:154735. [DOI: 10.1016/j.cyto.2019.154735] [Citation(s) in RCA: 44] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2018] [Revised: 03/16/2019] [Accepted: 05/24/2019] [Indexed: 02/07/2023]
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Introducing a mammalian nerve-muscle preparation ideal for physiology and microscopy, the transverse auricular muscle in the ear of the mouse. Neuroscience 2019; 439:80-105. [PMID: 31351140 DOI: 10.1016/j.neuroscience.2019.07.028] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2019] [Revised: 07/10/2019] [Accepted: 07/15/2019] [Indexed: 11/23/2022]
Abstract
A new mammalian neuromuscular preparation is introduced for physiology and microscopy of all sorts: the intrinsic muscle of the mouse ear. The great utility of this preparation is demonstrated by illustrating how it has permitted us to develop a wholly new technique for staining muscle T-tubules, the critical conductive-elements in muscle. This involves sequential immersion in dilute solutions of osmium and ferrocyanide, then tannic acid, and then uranyl acetate, all of which totally blackens the T-tubules but leaves the muscle pale, thereby revealing that the T-tubules in mouse ear-muscles become severely distorted in several pathological conditions. These include certain mouse-models of muscular dystrophy (specifically, dysferlin-mutations), certain mutations of muscle cytoskeletal proteins (specifically, beta-tubulin mutations), and also in denervation-fibrillation, as observed in mouse ears maintained with in vitro tissue-culture conditions. These observations permit us to generate the hypothesis that T-tubules are the "Achilles' heel" in several adult-onset muscular dystrophies, due to their unique susceptibility to damage via muscle lattice-dislocations. These new observations strongly encourage further in-depth studies of ear-muscle architecture, in the many available mouse-models of various devastating human muscle-diseases. Finally, we demonstrate that the delicate and defined physical characteristics of this 'new' mammalian muscle are ideal for ultrastructural study, and thereby facilitate the imaging of synaptic vesicle membrane recycling in mammalian neuromuscular junctions, a topic that is critical to myasthenia gravis and related diseases, but which has, until now, completely eluded electron microscopic analysis. This article is part of a Special Issue entitled: Honoring Ricardo Miledi - outstanding neuroscientist of XX-XXI centuries.
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Chen Y, Zhao M, Zheng T, Adlat S, Jin H, Wang C, Li D, Zaw Myint MZ, Yao Y, Xu L, San M, Wen H, Zhang Y, Lu X, Yang L, Zhang L, Feng X, Zheng Y. Repression of adipose vascular endothelial growth factor reduces obesity through adipose browning. Am J Physiol Endocrinol Metab 2019; 316:E145-E155. [PMID: 30398903 DOI: 10.1152/ajpendo.00196.2018] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Obesity is the result of excessive energy accumulation and is associated with many diseases. We previously reported that universal repression of vascular endothelial growth factor (VEGF) leads to brown-like adipocyte development in white adipose tissues, and that these mice are resistant to obesity (Lu X et al. Endocrinology 153: 3123-3132, 2012). Using an adipose-specific VEGF repression mouse model (aP2-rtTR-krabtg/+/VEGFtetO/tetO), we show that adipose-specific VEGF repression can repeat the previous phenotypes, including adipose browning, increased energy consumption, and reduction in body weight. Expression of brown adipose-associated genes is increased, and white adipose-associated genes are downregulated under VEGF repression. Our study demonstrates that adipose-specific VEGF repression can lead to antiobesity activity through adipose browning and has potential clinical value.
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Affiliation(s)
- Yang Chen
- Transgenic Research Center, Northeast Normal University, Changchun, China
| | - Mingyue Zhao
- Transgenic Research Center, Northeast Normal University, Changchun, China
| | - Tingting Zheng
- Transgenic Research Center, Northeast Normal University, Changchun, China
| | - Salah Adlat
- Transgenic Research Center, Northeast Normal University, Changchun, China
| | - Honghong Jin
- Transgenic Research Center, Northeast Normal University, Changchun, China
| | - Chenhao Wang
- Transgenic Research Center, Northeast Normal University, Changchun, China
| | - Dan Li
- Transgenic Research Center, Northeast Normal University, Changchun, China
| | - May Zun Zaw Myint
- Transgenic Research Center, Northeast Normal University, Changchun, China
| | - Yapeng Yao
- Transgenic Research Center, Northeast Normal University, Changchun, China
| | - Liu Xu
- Transgenic Research Center, Northeast Normal University, Changchun, China
| | - Mingjun San
- Transgenic Research Center, Northeast Normal University, Changchun, China
| | - Huaizhen Wen
- Transgenic Research Center, Northeast Normal University, Changchun, China
| | - Yuntao Zhang
- Transgenic Research Center, Northeast Normal University, Changchun, China
| | - Xiaodan Lu
- Transgenic Research Center, Northeast Normal University, Changchun, China
| | - Ling Yang
- Shanxi Medical University , Taiyuan , China
| | - Luqing Zhang
- Transgenic Research Center, Northeast Normal University, Changchun, China
- Key Laboratory of Molecular Epigenetics of Ministry of Education, Northeast Normal University , Changchun , China
| | - Xuechao Feng
- Transgenic Research Center, Northeast Normal University, Changchun, China
- Key Laboratory of Molecular Epigenetics of Ministry of Education, Northeast Normal University , Changchun , China
| | - Yaowu Zheng
- Transgenic Research Center, Northeast Normal University, Changchun, China
- Key Laboratory of Molecular Epigenetics of Ministry of Education, Northeast Normal University , Changchun , China
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Zhou J, Mao L, Xu P, Wang Y. Effects of (-)-Epigallocatechin Gallate (EGCG) on Energy Expenditure and Microglia-Mediated Hypothalamic Inflammation in Mice Fed a High-Fat Diet. Nutrients 2018; 10:nu10111681. [PMID: 30400620 PMCID: PMC6266769 DOI: 10.3390/nu10111681] [Citation(s) in RCA: 58] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2018] [Revised: 10/30/2018] [Accepted: 11/02/2018] [Indexed: 12/28/2022] Open
Abstract
Obesity is an escalating global epidemic caused by an imbalance between energy intake and expenditure. (−)-Epigallocatechin-3-gallate (EGCG), the major polyphenol in green tea, has been reported to be conducive to preventing obesity and alleviating obesity-related chronic diseases. However, the role of EGCG in energy metabolism disorders and central nervous system dysfunction induced by a high-fat diet (HFD) remains to be elucidated. The aim of this study was to evaluate the effects of EGCG on brown adipose tissue (BAT) thermogenesis and neuroinflammation in HFD-induced obese C57BL/6J mice. Mice were randomly divided into four groups with different diets: normal chow diet (NCD), normal chow diet supplemented with 1% EGCG (NCD + EGCG), high-fat diet (HFD), and high-fat diet supplemented with 1% EGCG (HFD + EGCG). Investigations based on a four-week experiment were carried out including the BAT activity, energy consumption, mRNA expression of major inflammatory cytokines in the hypothalamus, nuclear factor-kappa B (NF-κB) and signal transducer and activator of transcription 3 (STAT3) phosphorylation, and immunofluorescence staining of microglial marker Iba1 in hypothalamic arcuate nucleus (ARC). Experimental results demonstrated that dietary supplementation of EGCG significantly inhibited HFD-induced obesity by enhancing BAT thermogenesis, and attenuated the hypothalamic inflammation and microglia overactivation by regulating the NF-κB and STAT3 signaling pathways.
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Affiliation(s)
- Jihong Zhou
- Tea Research Institute, Zhejiang University, Hangzhou 310058, China.
| | - Limin Mao
- Tea Research Institute, Zhejiang University, Hangzhou 310058, China.
| | - Ping Xu
- Tea Research Institute, Zhejiang University, Hangzhou 310058, China.
| | - Yuefei Wang
- Tea Research Institute, Zhejiang University, Hangzhou 310058, China.
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14
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Skrzypski M, Billert M, Nowak KW, Strowski MZ. The role of orexin in controlling the activity of the adipo-pancreatic axis. J Endocrinol 2018; 238:R95-R108. [PMID: 29848609 DOI: 10.1530/joe-18-0122] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/17/2018] [Accepted: 05/30/2018] [Indexed: 12/29/2022]
Abstract
Orexin A and B are two neuropeptides, which regulate a variety of physiological functions by interacting with central nervous system and peripheral tissues. Biological effects of orexins are mediated through two G-protein-coupled receptors (OXR1 and OXR2). In addition to their strong influence on the sleep-wake cycle, there is growing evidence that orexins regulate body weight, glucose homeostasis and insulin sensitivity. Furthermore, orexins promote energy expenditure and protect against obesity by interacting with brown adipocytes. Fat tissue and the endocrine pancreas play pivotal roles in maintaining energy homeostasis. Since both organs are crucially important in the context of pathophysiology of obesity and diabetes, we summarize the current knowledge regarding the role of orexins and their receptors in controlling adipocytes as well as the endocrine pancreatic functions. Particularly, we discuss studies evaluating the effects of orexins in controlling brown and white adipocytes as well as pancreatic alpha and beta cell functions.
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Affiliation(s)
- M Skrzypski
- Department of Animal Physiology and BiochemistryPoznań University of Life Sciences, Poznań, Poland
| | - M Billert
- Department of Animal Physiology and BiochemistryPoznań University of Life Sciences, Poznań, Poland
| | - K W Nowak
- Department of Animal Physiology and BiochemistryPoznań University of Life Sciences, Poznań, Poland
| | - M Z Strowski
- Department of Hepatology and Gastroenterology & The Interdisciplinary Centre of Metabolism: EndocrinologyDiabetes and Metabolism, Charité-University Medicine Berlin, Berlin, Germany
- Park-Klinik WeissenseeInternal Medicine - Gastroenterology, Berlin, Germany
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15
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Grigoraş A, Amalinei C, Balan RA, Giuşcă SE, Avădănei ER, Lozneanu L, Căruntu ID. Adipocytes spectrum - From homeostasia to obesity and its associated pathology. Ann Anat 2018; 219:102-120. [PMID: 30049662 DOI: 10.1016/j.aanat.2018.06.004] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2018] [Accepted: 06/17/2018] [Indexed: 02/07/2023]
Abstract
Firstly identified by anatomists, the fat tissue is nowadays an area of intense research due to increased global prevalence of obesity and its associated diseases. Histologically, there are four types of fat tissue cells which are currently recognized (white, brown, beige, and perivascular adipocytes). Therefore, in this study we are reviewing the most recent data regarding the origin, structure, and molecular mechanisms involved in the development of adipocytes. White adipocytes can store triglycerides as a consequence of lipogenesis, under the regulation of growth hormone or leptin and adiponectin, and release fatty acids resulted from lipolysis, under the regulation of the sympathetic nervous system, glucocorticoids, TNF-α, insulin, and natriuretic peptides. Brown adipocytes possess a mitochondrial transmembrane protein thermogenin or UCP1 which allows heat generation. Recently, thermogenic, UCP positive adipocytes have been identified in the subcutaneous white adipose tissue and have been named beige adipocytes. The nature of these cells is still controversial, as current theories are suggesting their origin either by transdifferentiation of white adipocytes, or by differentiation from an own precursor cell. Perivascular adipocytes surround most of the arteries, exhibiting a supportive role and being involved in the maintenance of intravascular temperature. Thoracic perivascular adipocytes resemble brown adipocytes, while abdominal ones are more similar to white adipocytes and, consequently, are involved in obesity-induced inflammatory reactions. The factors involved in the regulation of adipose stem cells differentiation may represent potential pathways to inhibit or to divert adipogenesis. Several molecules, such as pro-adipogenic factors (FGF21, BMP7, BMP8b, and Cox-2), cell surface proteins or receptors (Asc-1, PAT2, P2RX5), and hypothalamic receptors (MC4R) have been identified as the most promising targets for the development of future therapies. Further investigations are necessary to complete the knowledge about adipose tissue and the development of a new generation of therapeutic tools based on molecular targets.
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Affiliation(s)
- Adriana Grigoraş
- Department of Morphofunctional Sciences I, "Grigore T. Popa" University of Medicine and Pharmacy, Iasi, Romania; Department of Histopathology, Institute of Legal Medicine, Iasi, Romania.
| | - Cornelia Amalinei
- Department of Morphofunctional Sciences I, "Grigore T. Popa" University of Medicine and Pharmacy, Iasi, Romania; Department of Histopathology, Institute of Legal Medicine, Iasi, Romania.
| | - Raluca Anca Balan
- Department of Morphofunctional Sciences I, "Grigore T. Popa" University of Medicine and Pharmacy, Iasi, Romania.
| | - Simona Eliza Giuşcă
- Department of Morphofunctional Sciences I, "Grigore T. Popa" University of Medicine and Pharmacy, Iasi, Romania.
| | - Elena Roxana Avădănei
- Department of Morphofunctional Sciences I, "Grigore T. Popa" University of Medicine and Pharmacy, Iasi, Romania.
| | - Ludmila Lozneanu
- Department of Morphofunctional Sciences I, "Grigore T. Popa" University of Medicine and Pharmacy, Iasi, Romania.
| | - Irina-Draga Căruntu
- Department of Morphofunctional Sciences I, "Grigore T. Popa" University of Medicine and Pharmacy, Iasi, Romania.
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16
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Recent advances in the detection of brown adipose tissue in adult humans: a review. Clin Sci (Lond) 2018; 132:1039-1054. [PMID: 29802209 DOI: 10.1042/cs20170276] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2017] [Revised: 03/23/2018] [Accepted: 03/23/2018] [Indexed: 02/07/2023]
Abstract
The activation of brown adipose tissue (BAT) is associated with reductions in circulating lipids and glucose in rodents and contributes to energy expenditure in humans indicating the potential therapeutic importance of targetting this tissue for the treatment of a variety of metabolic disorders. In order to evaluate the therapeutic potential of human BAT, a variety of methodologies for assessing the volume and metabolic activity of BAT are utilized. Cold exposure is often utilized to increase BAT activity but inconsistencies in the characteristics of the exposure protocols make it challenging to compare findings. The metabolic activity of BAT in response to cold exposure has most commonly been measured by static positron emission tomography of 18F-fluorodeoxyglucose in combination with computed tomography (18F-FDG PET-CT) imaging, but recent studies suggest that under some conditions this may not always reflect BAT thermogenic activity. Therefore, recent studies have used alternative positron emission tomography and computed tomography (PET-CT) imaging strategies and radiotracers that may offer important insights. In addition to PET-CT, there are numerous emerging techniques that may have utility for assessing BAT metabolic activity including magnetic resonance imaging (MRI), skin temperature measurements, near-infrared spectroscopy (NIRS) and contrast ultrasound (CU). In this review, we discuss and critically evaluate the various methodologies used to measure BAT metabolic activity in humans and provide a contemporary assessment of protocols which may be useful in interpreting research findings and guiding the development of future studies.
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17
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Nakamura K, Kishida T, Ejima A, Tateyama R, Morishita S, Ono T, Murakoshi M, Sugiyama K, Nishino H, Mazda O. Bovine lactoferrin promotes energy expenditure via the cAMP-PKA signaling pathway in human reprogrammed brown adipocytes. Biometals 2018; 31:415-424. [PMID: 29744695 DOI: 10.1007/s10534-018-0103-9] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2017] [Accepted: 04/05/2018] [Indexed: 11/26/2022]
Abstract
Lactoferrin (LF) is a multifunctional protein in mammalian milk. We previously reported that enteric-coated bovine LF reduced the visceral fat in a double-blind clinical study. We further demonstrated that bovine LF (bLF) inhibited adipogenesis and promoted lipolysis in white adipocytes, but the effect of bLF on brown adipocytes has not been clarified. In this study, we investigated the effects of bLF on energy expenditure and cyclic adenosine monophosphate (cAMP)-protein kinase A (PKA) signaling pathway using human reprogrammed brown adipocytes generated by gene transduction. bLF at concentrations of ≥ 100 μg/mL significantly increased uncoupling protein 1 (UCP1) mRNA levels, with the maximum value observed 4 h after bLF addition. At the same time point, bLF stimulation also significantly increased oxygen consumption. Signaling pathway analysis revealed rapid increases of intracellular cAMP and cAMP response element-binding protein (CREB) phosphorylation levels beginning 5 min after bLF addition. The mRNA levels of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) were also significantly increased after 1 h of bLF stimulation. H-89, a specific PKA inhibitor, abrogated bLF-induced UCP1 gene expression. Moreover, receptor-associated protein (Rap), an antagonist of low-density lipoprotein receptor-related protein 1 (LRP1), significantly reduced bLF-induced UCP1 gene expression in a dose-dependent manner. These results suggest that bLF promotes UCP1 gene expression in brown adipocytes through the cAMP-PKA signaling pathway via the LRP1 receptor, leading to increased energy expenditure.
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Affiliation(s)
- Kanae Nakamura
- Research and Development Headquarters, Lion Corporation, 100 Tajima, Odawara, Kanagawa, 256-0811, Japan
| | - Tsunao Kishida
- Department of Immunology, Kyoto Prefectural University of Medicine, Kamikyo, Kyoto, 602-8566, Japan
| | - Akika Ejima
- Division of Applied Biosciences, Graduate School of Agriculture, Kyoto University, Kitashirakawa Oiwake-cho, Sakyo-ku, Kyoto, 606-8502, Japan
| | - Riho Tateyama
- Research and Development Headquarters, Lion Corporation, 100 Tajima, Odawara, Kanagawa, 256-0811, Japan
| | - Satoru Morishita
- Research and Development Headquarters, Lion Corporation, 100 Tajima, Odawara, Kanagawa, 256-0811, Japan
- "Food for Life", Organization for Interdisciplinary Research Projects, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo, 113-8657, Japan
| | - Tomoji Ono
- Research and Development Headquarters, Lion Corporation, 100 Tajima, Odawara, Kanagawa, 256-0811, Japan
- Advanced Medical Research Center, Yokohama City University, 3-9 Fukuura, Kanazawa-ku, Yokohama, Kanagawa, 236-0004, Japan
| | - Michiaki Murakoshi
- Research and Development Headquarters, Lion Corporation, 100 Tajima, Odawara, Kanagawa, 256-0811, Japan
- Advanced Medical Research Center, Yokohama City University, 3-9 Fukuura, Kanazawa-ku, Yokohama, Kanagawa, 236-0004, Japan
- Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kamigyou-ku, Kyoto, 602-0841, Japan
| | - Keikichi Sugiyama
- Research Organization of Science and Engineering, Ritsumeikan University, 1-1-1 Nojihigashi, Kusatsu, Shiga, 525-8577, Japan
| | - Hoyoku Nishino
- Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kamigyou-ku, Kyoto, 602-0841, Japan
| | - Osam Mazda
- Department of Immunology, Kyoto Prefectural University of Medicine, Kamikyo, Kyoto, 602-8566, Japan.
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18
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Haq T, Crane JD, Kanji S, Gunn E, Tarnopolsky MA, Gerstein HC, Steinberg GR, Morrison KM. Optimizing the methodology for measuring supraclavicular skin temperature using infrared thermography; implications for measuring brown adipose tissue activity in humans. Sci Rep 2017; 7:11934. [PMID: 28931855 PMCID: PMC5607277 DOI: 10.1038/s41598-017-11537-x] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2017] [Accepted: 08/21/2017] [Indexed: 12/21/2022] Open
Abstract
The discovery of brown adipose tissue (BAT) in adults has sparked interest in its role as a therapeutic target in metabolic disorders. Infrared thermography is a promising way to quantify BAT; however, a standardized methodology has not been established. This study aims to establish a standardized and reproducible protocol to measure thermal response to cold in the supraclavicular area using thermographic imaging. In Phase 1, we compared the thermal response to 12 °C cold after acclimation at either 32 °C or room temperature using thermographic imaging. Repeatability of the 32 °C acclimation trial was studied in a second group in Phase 2. Phase 1 included 28 men (mean age 23.9 ± 5.9 y; mean BMI 25.2 ± 3.9 kg/m2) and Phase 2 included 14 men (mean age 20.9 ± 2.4 y; mean BMI 23.6 ± 3.1 kg/m2). The thermal response was greater after 32 °C than after room temperature acclimation (0.22 ± 0.19 vs 0.13 ± 0.17 °C, p = 0.05), was not related to outdoor temperature (r = −0.35, p = 0.07), did not correlate with supraclavicular fat (r = −0.26, p = 0.21) measured with dual-energy x-ray absorptiometry and was repeatable [ICC 0.69 (0.14–0.72)]. Acclimation at 32 °C followed by cold generates a reproducible change in supraclavicular skin temperature measurable by thermal imaging that may be indicative of BAT metabolic activity.
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Affiliation(s)
- Tahniyah Haq
- Department of Pediatrics, McMaster University, Hamilton, L8S 4K1, Canada
| | - Justin D Crane
- Department of Pediatrics, McMaster University, Hamilton, L8S 4K1, Canada
| | - Sarah Kanji
- Department of Pediatrics, McMaster University, Hamilton, L8S 4K1, Canada
| | - Elizabeth Gunn
- Department of Pediatrics, McMaster University, Hamilton, L8S 4K1, Canada
| | - Mark A Tarnopolsky
- Department of Pediatrics, McMaster University, Hamilton, L8S 4K1, Canada.,Department of Medicine, McMaster University, Hamilton, L8S 4K1, Canada
| | | | - Gregory R Steinberg
- Department of Medicine, McMaster University, Hamilton, L8S 4K1, Canada. .,Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, L8S 4K1, Canada.
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19
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Brandão BB, Guerra BA, Mori MA. Shortcuts to a functional adipose tissue: The role of small non-coding RNAs. Redox Biol 2017; 12:82-102. [PMID: 28214707 PMCID: PMC5312655 DOI: 10.1016/j.redox.2017.01.020] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2017] [Accepted: 01/30/2017] [Indexed: 12/20/2022] Open
Abstract
Metabolic diseases such as type 2 diabetes are a major public health issue worldwide. These diseases are often linked to a dysfunctional adipose tissue. Fat is a large, heterogenic, pleiotropic and rather complex tissue. It is found in virtually all cavities of the human body, shows unique plasticity among tissues, and harbors many cell types in addition to its main functional unit - the adipocyte. Adipose tissue function varies depending on the localization of the fat depot, the cell composition of the tissue and the energy status of the organism. While the white adipose tissue (WAT) serves as the main site for triglyceride storage and acts as an important endocrine organ, the brown adipose tissue (BAT) is responsible for thermogenesis. Beige adipocytes can also appear in WAT depots to sustain heat production upon certain conditions, and it is becoming clear that adipose tissue depots can switch phenotypes depending on cell autonomous and non-autonomous stimuli. To maintain such degree of plasticity and respond adequately to changes in the energy balance, three basic processes need to be properly functioning in the adipose tissue: i) adipogenesis and adipocyte turnover, ii) metabolism, and iii) signaling. Here we review the fundamental role of small non-coding RNAs (sncRNAs) in these processes, with focus on microRNAs, and demonstrate their importance in adipose tissue function and whole body metabolic control in mammals.
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Affiliation(s)
- Bruna B Brandão
- Program in Molecular Biology, Universidade Federal de São Paulo, São Paulo, Brazil; Department of Biochemistry and Tissue Biology, Universidade Estadual de Campinas, Campinas, Brazil
| | - Beatriz A Guerra
- Program in Molecular Biology, Universidade Federal de São Paulo, São Paulo, Brazil; Department of Biochemistry and Tissue Biology, Universidade Estadual de Campinas, Campinas, Brazil
| | - Marcelo A Mori
- Program in Molecular Biology, Universidade Federal de São Paulo, São Paulo, Brazil; Department of Biochemistry and Tissue Biology, Universidade Estadual de Campinas, Campinas, Brazil; Program in Genetics and Molecular Biology, Universidade Estadual de Campinas, Campinas, Brazil.
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20
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Tham SW, Li L, Effraim P, Waxman S. Between fire and ice: refractory hypothermia and warmth-induced pain in inherited erythromelalgia. BMJ Case Rep 2017; 2017:bcr-2017-219486. [PMID: 28751508 DOI: 10.1136/bcr-2017-219486] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Inherited erythromelalgia (IEM) is a well-described pain disorder caused by mutations of sodium channel Nav1.7, a peripheral channel expressed within dorsal root ganglion and the sympathetic ganglion neurons. Clinically, IEM is characterised by paroxysmal attacks of severe pain, usually in the distal extremities, triggered by warmth or exercise. Pain is not adequately treated by existing pharmacological agents. Individuals with IEM classically cool their limbs for relief, in some cases resulting in tissue injury. We describe a patient from a family with IEM due to the L858F mutation of Nav1.7 who presented with refractory hypothermia due to overcooling. This presentation of refractory hypothermia necessitating warming strategies, complicated by severe warmth-induced pain, posed a substantial therapeutic challenge. We report our experience in overcoming hypothermia lasting 3 weeks in a child with IEM, discuss possible pathophysiological mechanisms underlying this unusual complication and suggest potential therapeutic interventions.
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Affiliation(s)
- See Wan Tham
- Seattle Children's Research Institute, Seattle, Washington, USA.,Department of Anesthesia and Pain Medicine, University of Washington School of Medicine, Seattle, Washington, USA
| | - Li Li
- Department of Anesthesia and Pain Medicine, University of Washington School of Medicine, Seattle, Washington, USA
| | - Philip Effraim
- Department of Anesthesia, Yale University School of Medicine, New Haven, Connecticut, USA.,Center for Neuroscience and Regeneration Research, Yale University School of Medicine, Veteran Affairs Medical Center, West Haven, Connecticut, USA
| | - Stephen Waxman
- Center for Neuroscience and Regeneration Research, Yale University School of Medicine, Veteran Affairs Medical Center, West Haven, Connecticut, USA.,Department of Neurology, Yale University School of Medicine, West Haven, Connecticut, USA
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21
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Song NJ, Chang SH, Li DY, Villanueva CJ, Park KW. Induction of thermogenic adipocytes: molecular targets and thermogenic small molecules. Exp Mol Med 2017; 49:e353. [PMID: 28684864 PMCID: PMC5565954 DOI: 10.1038/emm.2017.70] [Citation(s) in RCA: 58] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2016] [Revised: 12/25/2016] [Accepted: 12/30/2016] [Indexed: 12/17/2022] Open
Abstract
Adipose tissue is a central metabolic organ that controls energy homeostasis of the whole body. White adipose tissue (WAT) stores excess energy in the form of triglycerides, whereas brown adipose tissue (BAT) dissipates energy in the form of heat through mitochondrial uncoupling protein 1 (Ucp1). A newly identified adipose tissue called 'beige fat' (BAT-like) is produced through a process called WAT browning. This tissue mainly resides in WAT depots and displays intermediate characteristics of both WAT and BAT. Since the recent discovery of BAT in the human body, along with the identification of molecular targets for BAT activation, stimulating energy expenditure has been considered as a great strategy to treat human obesity and metabolic diseases. Here we summarize recent findings regarding molecular targets and thermogenic small molecules that can stimulate BAT and increase energy expenditure, with an emphasis on possible therapeutic applications in humans.
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Affiliation(s)
- No-Joon Song
- Department of Food Science and Biotechnology, Sungkyunkwan University, Suwon, Korea
| | - Seo-Hyuk Chang
- Department of Food Science and Biotechnology, Sungkyunkwan University, Suwon, Korea
| | - Dean Y Li
- Department of Medicine, Program in Molecular Medicine, University of Utah, Salt Lake City, UT, USA
| | - Claudio J Villanueva
- Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, UT, USA
| | - Kye Won Park
- Department of Food Science and Biotechnology, Sungkyunkwan University, Suwon, Korea
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22
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Kohlie R, Perwitz N, Resch J, Schmid SM, Lehnert H, Klein J, Iwen KA. Dopamine directly increases mitochondrial mass and thermogenesis in brown adipocytes. J Mol Endocrinol 2017; 58:57-66. [PMID: 27923872 DOI: 10.1530/jme-16-0159] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/16/2016] [Accepted: 12/01/2016] [Indexed: 12/18/2022]
Abstract
Brown adipose tissue (BAT) is key to energy homeostasis. By virtue of its thermogenic potential, it may dissipate excessive energy, regulate body weight and increase insulin sensitivity. Catecholamines are critically involved in the regulation of BAT thermogenesis, yet research has focussed on the effects of noradrenaline and adrenaline. Some evidence suggests a role of dopamine (DA) in BAT thermogenesis, but the cellular mechanisms involved have not been addressed. We employed our extensively characterised murine brown adipocyte cells. D1-like and D2-like receptors were detectable at the protein level. Stimulation with DA caused an increase in cAMP concentrations. Oxygen consumption rates (OCR), mitochondrial membrane potential (Δψm) and uncoupling protein 1 (UCP1) levels increased after 24 h of treatment with either DA or a D1-like specific receptor agonist. A D1-like receptor antagonist abolished the DA-mediated effect on OCR, Δψm and UCP1. DA induced the release of fatty acids, which did not additionally alter DA-mediated increases of OCR. Mitochondrial mass (as determined by (i) CCCP- and oligomycin-mediated effects on OCR and (ii) immunoblot analysis of mitochondrial proteins) also increased within 24 h. This was accompanied by an increase in peroxisome proliferator-activated receptor gamma co-activator 1 alpha protein levels. Also, DA caused an increase in p38 MAPK phosphorylation and pharmacological inhibition of p38 MAPK abolished the DA-mediated effect on Δψm In summary, our study is the first to reveal direct D1-like receptor and p38 MAPK-mediated increases of thermogenesis and mitochondrial mass in brown adipocytes. These results expand our understanding of catecholaminergic effects on BAT thermogenesis.
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Affiliation(s)
- Rose Kohlie
- Universität zu LübeckUniversitätsklinikum Schleswig-Holstein, Campus Lübeck, Medizinische Klinik I, Lübeck, Germany
| | - Nina Perwitz
- Universität zu LübeckUniversitätsklinikum Schleswig-Holstein, Campus Lübeck, Medizinische Klinik I, Lübeck, Germany
| | - Julia Resch
- Universität zu LübeckUniversitätsklinikum Schleswig-Holstein, Campus Lübeck, Medizinische Klinik I, Lübeck, Germany
| | - Sebastian M Schmid
- Universität zu LübeckUniversitätsklinikum Schleswig-Holstein, Campus Lübeck, Medizinische Klinik I, Lübeck, Germany
| | - Hendrik Lehnert
- Universität zu LübeckUniversitätsklinikum Schleswig-Holstein, Campus Lübeck, Medizinische Klinik I, Lübeck, Germany
| | - Johannes Klein
- Universität zu LübeckUniversitätsklinikum Schleswig-Holstein, Campus Lübeck, Medizinische Klinik I, Lübeck, Germany
| | - K Alexander Iwen
- Universität zu LübeckUniversitätsklinikum Schleswig-Holstein, Campus Lübeck, Medizinische Klinik I, Lübeck, Germany
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23
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Bargut TCL, Souza-Mello V, Aguila MB, Mandarim-de-Lacerda CA. Browning of white adipose tissue: lessons from experimental models. Horm Mol Biol Clin Investig 2017; 31:hmbci-2016-0051. [PMID: 28099124 DOI: 10.1515/hmbci-2016-0051] [Citation(s) in RCA: 99] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2016] [Accepted: 12/01/2016] [Indexed: 04/25/2024]
Abstract
Beige or brite (brown-in-white) adipocytes are present in white adipose tissue (WAT) and have a white fat-like phenotype that when stimulated acquires a brown fat-like phenotype, leading to increased thermogenesis. This phenomenon is known as browning and is more likely to occur in subcutaneous fat depots. Browning involves the expression of many transcription factors, such as PR domain containing 16 (PRDM16) and peroxisome proliferator-activated receptor (PPAR)-γ, and of uncoupling protein (UCP)-1, which is the hallmark of thermogenesis. Recent papers pointed that browning can occur in the WAT of humans, with beneficial metabolic effects. This fact indicates that these cells can be targeted to treat a range of diseases, with both pharmacological and nutritional activators. Pharmacological approaches to induce browning include the use of PPAR-α agonist, adrenergic receptor stimulation, thyroid hormone administration, irisin and FGF21 induction. Most of them act through the induction of PPAR-γ coactivator (PGC) 1-α and the consequent mitochondrial biogenesis and UCP1 induction. About the nutritional inducers, several compounds have been described with multiple mechanisms of action. Some of these activators include specific amino acids restriction, capsaicin, bile acids, Resveratrol, and retinoic acid. Besides that, some classes of lipids, as well as many plant extracts, have also been implicated in the browning of WAT. In conclusion, the discovery of browning in human WAT opens the possibility to target the adipose tissue to fight a range of diseases. Studies have arisen showing promising results and bringing new opportunities in thermogenesis and obesity control.
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Affiliation(s)
- Thereza Cristina Lonzetti Bargut
- Laboratory of Morphometry, Metabolism and Cardiovascular Diseases, Biomedical Center, Institute of Biology, State University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Vanessa Souza-Mello
- Laboratory of Morphometry, Metabolism and Cardiovascular Diseases, Biomedical Center, Institute of Biology, State University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Marcia Barbosa Aguila
- Laboratory of Morphometry, Metabolism and Cardiovascular Diseases, Biomedical Center, Institute of Biology, State University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Carlos Alberto Mandarim-de-Lacerda
- Laboratorio de Morfometria, Metabolismo e Doença Cardiovascular, Instituto de Biologia, Universidade do Estado do Rio de Janeiro, 20551-030 Rio de Janeiro, Brazil, Phone (+55.21) 2868-8316, Fax: 2868-8033, E-mail:
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Ryu V, Watts AG, Xue B, Bartness TJ. Bidirectional crosstalk between the sensory and sympathetic motor systems innervating brown and white adipose tissue in male Siberian hamsters. Am J Physiol Regul Integr Comp Physiol 2017; 312:R324-R337. [PMID: 28077392 DOI: 10.1152/ajpregu.00456.2015] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2015] [Revised: 11/28/2016] [Accepted: 12/31/2016] [Indexed: 01/31/2023]
Abstract
The brain networks connected to the sympathetic motor and sensory innervations of brown (BAT) and white (WAT) adipose tissues were originally described using two transneuronally transported viruses: the retrogradely transported pseudorabies virus (PRV), and the anterogradely transported H129 strain of herpes simplex virus-1 (HSV-1 H129). Further complexity was added to this network organization when combined injections of PRV and HSV-1 H129 into either BAT or WAT of the same animal generated sets of coinfected neurons in the brain, spinal cord, and sympathetic and dorsal root ganglia. These neurons are well positioned to act as sensorimotor links in the feedback circuits that control each fat pad. We have now determined the extent of sensorimotor crosstalk between interscapular BAT (IBAT) and inguinal WAT (IWAT). PRV152 and HSV-1 H129 were each injected into IBAT or IWAT of the same animal: H129 into IBAT and PRV152 into IWAT. The reverse configuration was applied in a different set of animals. We found single-labeled neurons together with H129+PRV152 coinfected neurons in multiple brain sites, with lesser numbers in the sympathetic and dorsal root ganglia that innervate IBAT and IWAT. We propose that these coinfected neurons mediate sensory-sympathetic motor crosstalk between IBAT and IWAT. Comparing the relative numbers of coinfected neurons between the two injection configurations showed a bias toward IBAT-sensory and IWAT-sympathetic motor feedback loops. These coinfected neurons provide a neuroanatomical framework for functional interactions between IBAT thermogenesis and IWAT lipolysis that occurs with cold exposure, food restriction/deprivation, exercise, and more generally with alterations in adiposity.
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Affiliation(s)
- Vitaly Ryu
- Department of Biology, Obesity Reversal Center, Georgia State University, Atlanta, Georgia; and
| | - Alan G Watts
- Department of Biological Sciences, University of Southern California, Dornsife College of Letters, Arts, and Sciences, University of Southern California, Los Angeles, California
| | - Bingzhong Xue
- Department of Biology, Obesity Reversal Center, Georgia State University, Atlanta, Georgia; and
| | - Timothy J Bartness
- Department of Biology, Obesity Reversal Center, Georgia State University, Atlanta, Georgia; and
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Caron A, Richard D. Neuronal systems and circuits involved in the control of food intake and adaptive thermogenesis. Ann N Y Acad Sci 2016; 1391:35-53. [PMID: 27768821 DOI: 10.1111/nyas.13263] [Citation(s) in RCA: 48] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2016] [Revised: 08/18/2016] [Accepted: 08/24/2016] [Indexed: 12/27/2022]
Abstract
With the still-growing prevalence of obesity worldwide, major efforts are made to understand the various behavioral, environmental, and genetic factors that promote excess fat gain. Obesity results from an imbalance between energy intake and energy expenditure, which emphasizes the importance of deciphering the mechanisms behind energy balance regulation to understand its physiopathology. The control of energy balance is assured by brain systems/circuits capable of generating adequate ingestive and thermogenic responses to maintain the stability of energy reserves, which implies a proper integration of the homeostatic signals that inform about the status of the energy stores. In this article, we overview the organization and functionality of key neuronal circuits or pathways involved in the control of food intake and energy expenditure. We review the role of the corticolimbic (executive and reward) and autonomic systems that integrate their activities to regulate energy balance. We also describe the mechanisms and pathways whereby homeostatic sensing is achieved in response to variations of homeostatic hormones, such as leptin, insulin, and ghrelin, while putting some emphasis on the prominent importance of the mechanistic target of the rapamycin signaling pathway in coordinating the homeostatic sensing process.
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Affiliation(s)
- Alexandre Caron
- Institut Universitaire de Cardiologie et de Pneumologie de Quebec and Faculty of Medicine, Department of Medicine, Université Laval, Quebec City, Quebec, Canada
| | - Denis Richard
- Institut Universitaire de Cardiologie et de Pneumologie de Quebec and Faculty of Medicine, Department of Medicine, Université Laval, Quebec City, Quebec, Canada
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Zhao S, Mugabo Y, Ballentine G, Attane C, Iglesias J, Poursharifi P, Zhang D, Nguyen T, Erb H, Prentki R, Peyot ML, Joly E, Tobin S, Fulton S, Brown J, Madiraju S, Prentki M. α/β-Hydrolase Domain 6 Deletion Induces Adipose Browning and Prevents Obesity and Type 2 Diabetes. Cell Rep 2016; 14:2872-88. [DOI: 10.1016/j.celrep.2016.02.076] [Citation(s) in RCA: 49] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2015] [Revised: 12/21/2015] [Accepted: 02/18/2016] [Indexed: 01/22/2023] Open
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Ernande L, Stanford KI, Thoonen R, Zhang H, Clerte M, Hirshman MF, Goodyear LJ, Bloch KD, Buys ES, Scherrer-Crosbie M. Relationship of brown adipose tissue perfusion and function: a study through β2-adrenoreceptor stimulation. J Appl Physiol (1985) 2016; 120:825-32. [PMID: 26823340 DOI: 10.1152/japplphysiol.00634.2015] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2015] [Accepted: 01/27/2016] [Indexed: 12/16/2022] Open
Abstract
Brown adipose tissue (BAT) activation increases glucose and lipid consumption; as such, it is been considered as a potential therapy to decrease obesity. BAT is highly vascularized and its activation is associated with a necessary increase in blood flow. However, whether increasing BAT blood flow per se increases BAT activity is unknown. To examine this hypothesis, we investigated whether an isolated increase in BAT blood flow obtained by β2-adrenoreceptor (β2-AR) stimulation with salbutamol increased BAT activity. BAT blood flow was estimated in vivo in mice using contrast-enhanced ultrasound. The absence of direct effect of salbutamol on the function of isolated brown adipocytes was assessed by measuring oxygen consumption. The effect of salbutamol on BAT activity was investigated by measuring BAT glucose uptake in vivo. BAT blood flow increased by 2.3 ± 0.6-fold during β2-AR stimulation using salbutamol infusion in mice (P= 0.003). β2-AR gene expression was detectable in BAT but was extremely low in isolated brown adipocytes. Oxygen consumption of isolated brown adipocytes did not change with salbutamol exposure, confirming the absence of a direct effect of β2-AR agonist on brown adipocytes. Finally, β2-AR stimulation by salbutamol increased BAT glucose uptake in vivo (991 ± 358 vs. 135 ± 49 ng glucose/mg tissue/45 min in salbutamol vs. saline injected mice, respectively,P= 0.046). In conclusion, an increase in BAT blood flow without direct stimulation of the brown adipocytes is associated with increased BAT metabolic activity. Increasing BAT blood flow might represent a new therapeutic target in obesity.
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Affiliation(s)
- Laura Ernande
- Cardiac Ultrasound Laboratory and Cardiovascular Research Center, Cardiology Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; DHU Ageing-Thorax-Vessel-Blood, Hôpital Henri Mondor, Assistance Publique-Hôpitaux de Paris, Créteil, France
| | - Kristin I Stanford
- Research Division, Joslin Diabetes Center, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts
| | - Robrecht Thoonen
- Cardiac Ultrasound Laboratory and Cardiovascular Research Center, Cardiology Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
| | - Haihua Zhang
- Cardiac Ultrasound Laboratory and Cardiovascular Research Center, Cardiology Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
| | - Maëva Clerte
- Cardiac Ultrasound Laboratory and Cardiovascular Research Center, Cardiology Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
| | - Michael F Hirshman
- Research Division, Joslin Diabetes Center, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts
| | - Laurie J Goodyear
- Research Division, Joslin Diabetes Center, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts; Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts; and
| | - Kenneth D Bloch
- Anesthesia Center for Critical Care Research, Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
| | - Emmanuel S Buys
- Anesthesia Center for Critical Care Research, Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
| | - Marielle Scherrer-Crosbie
- Cardiac Ultrasound Laboratory and Cardiovascular Research Center, Cardiology Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts;
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Vila-Bedmar R, Cruces-Sande M, Lucas E, Willemen HLDM, Heijnen CJ, Kavelaars A, Mayor F, Murga C. Reversal of diet-induced obesity and insulin resistance by inducible genetic ablation of GRK2. Sci Signal 2015. [PMID: 26198359 DOI: 10.1126/scisignal.aaa4374] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Insulin resistance is a common feature of obesity and predisposes individuals to various prevalent pathological conditions. G protein (heterotrimeric guanine nucleotide-binding protein)-coupled receptor kinase 2 (GRK2) integrates several signal transduction pathways and is emerging as a physiologically relevant inhibitor of insulin signaling. GRK2 abundance is increased in humans with metabolic syndrome and in different murine models of insulin resistance. To support GRK2 as a potential drug target in type 2 diabetes and obesity, we investigated whether lowering GRK2 abundance reversed an ongoing systemic insulin-resistant phenotype, using a mouse model of tamoxifen-induced GRK2 ablation after high-fat diet-dependent obesity and insulin resistance. Tamoxifen-triggered GRK2 deletion impeded further body weight gain, normalized fasting glycemia, improved glucose tolerance, and was associated with preserved insulin sensitivity in skeletal muscle and liver, thereby maintaining whole-body glucose homeostasis. Moreover, when continued to be fed a high-fat diet, these animals displayed reduced fat mass and smaller adipocytes, were resistant to the development of liver steatosis, and showed reduced expression of proinflammatory markers in the liver. Our results indicate that GRK2 acts as a hub to control metabolic functions in different tissues, which is key to controlling insulin resistance development in vivo. These data suggest that inhibiting GRK2 could reverse an established insulin-resistant and obese phenotype, thereby putting forward this enzyme as a potential therapeutic target linking glucose homeostasis and regulation of adiposity.
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Affiliation(s)
- Rocio Vila-Bedmar
- Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Madrid 28049, Spain. Instituto de Investigación Sanitaria La Princesa, Madrid 28006, Spain
| | - Marta Cruces-Sande
- Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Madrid 28049, Spain. Instituto de Investigación Sanitaria La Princesa, Madrid 28006, Spain
| | - Elisa Lucas
- Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Madrid 28049, Spain. Instituto de Investigación Sanitaria La Princesa, Madrid 28006, Spain
| | - Hanneke L D M Willemen
- Laboratory of Neuroimmunology and Developmental Origins of Disease, University Medical Center Utrecht, Utrecht 3584 EA, Netherlands
| | - Cobi J Heijnen
- Laboratory of Neuroimmunology and Developmental Origins of Disease, University Medical Center Utrecht, Utrecht 3584 EA, Netherlands. Laboratory of Neuroimmunology, Division of Internal Medicine, Department of Symptom Research, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Annemieke Kavelaars
- Laboratory of Neuroimmunology and Developmental Origins of Disease, University Medical Center Utrecht, Utrecht 3584 EA, Netherlands. Laboratory of Neuroimmunology, Division of Internal Medicine, Department of Symptom Research, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Federico Mayor
- Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Madrid 28049, Spain. Instituto de Investigación Sanitaria La Princesa, Madrid 28006, Spain.
| | - Cristina Murga
- Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Madrid 28049, Spain. Instituto de Investigación Sanitaria La Princesa, Madrid 28006, Spain.
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Abstract
Brown adipose tissue (BAT) is an important source of thermogenesis which is nearly exclusively dependent on its sympathetic nervous system (SNS) innervation. We previously demonstrated the SNS outflow from brain to BAT using the retrograde SNS-specific transneuronal viral tract tracer, pseudorabies virus (PRV152) and demonstrated the sensory system (SS) inflow from BAT to brain using the anterograde SS-specific transneuronal viral tract tracer, H129 strain of herpes simplex virus-1. Several brain areas were part of both the SNS outflow to, and receive SS inflow from, interscapular BAT (IBAT) in these separate studies suggesting SNS-SS feedback loops. Therefore, we tested whether individual neurons participated in SNS-SS crosstalk by injecting both PRV152 and H129 into IBAT of Siberian hamsters. To define which dorsal root ganglia (DRG) are activated by BAT SNS stimulation, indicated by c-Fos immunoreactivity (IR), we prelabeled IBAT DRG innervating neurons by injecting the retrograde tracer Fast Blue (FB) followed 1 week later by intra-BAT injections of the specific β3-adrenoceptor agonist CL316,243 in one pad and the vehicle in the contralateral pad. There were PRV152+H129 dually infected neurons across the neuroaxis with highest densities in the raphe pallidus nucleus, nucleus of the solitary tract, periaqueductal gray, hypothalamic paraventricular nucleus, and medial preoptic area, sites strongly implicated in the control of BAT thermogenesis. CL316,243 significantly increased IBAT temperature, afferent nerve activity, and c-Fos-IR in C2-C4 DRG neurons ipsilateral to the CL316,243 injections versus the contralateral side. The neuroanatomical reality of the SNS-SS feedback loops suggests coordinated and/or multiple redundant control of BAT thermogenesis.
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30
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Saini S, Duraisamy AJ, Bayen S, Vats P, Singh SB. Role of BMP7 in appetite regulation, adipogenesis, and energy expenditure. Endocrine 2015; 48:405-9. [PMID: 25178649 DOI: 10.1007/s12020-014-0406-8] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/22/2014] [Accepted: 08/23/2014] [Indexed: 01/16/2023]
Abstract
Bone morphogenetic protein 7 (BMP7), also known as osteogenic protein-1 (OP-1) is a member of Transforming growth factor-β (TGF-β) family of proteins. Bone morphogenetic proteins were discovered in 1965 by Marshal Urist, of which BMP7 is of particular interest in this review being a leptin-independent anorexinogen and having role in energy expenditure in the brown adipose tissue, which makes it a potential target for preventing/treating obesity. As it has been established that Obesity displays a state of leptin-resistance, thus a protein-like BMP7 which acts through a leptin-independent pathway could give new therapeutic directions. This review will also discuss the synthesis and action of BMP7, along with its receptors and signal transduction. A brief note about BMP7-mediated brown fat development and energy balance is also discussed.
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Affiliation(s)
- Supriya Saini
- Endocrinology and Metabolism Division, Defence Institute of Physiology and Allied Sciences, Lucknow Road, Timarpur, Delhi, 110054, India
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Abstract
A 47-year-old woman with non small cell lung cancer underwent a F-FDG PET/CT scan to assess disease progression after she developed a second non small cell lung cancer. Seven years earlier, she had a left lower lobectomy adjuvant chemoradiation for stage IIIA disease with microscopic subcarinal nodal involvement. There was markedly increased FDG uptake into brown fat in the soft tissues of the posterior lateral head neck, both supra- and infra-clavicular fossae and the right costovertebral region. Brown fat FDG uptake in the left costovertebral region was absent below the left third rib, which corresponded to the radiation field.
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32
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Mice fed fish oil diet and upregulation of brown adipose tissue thermogenic markers. Eur J Nutr 2015; 55:159-69. [PMID: 25612928 DOI: 10.1007/s00394-015-0834-0] [Citation(s) in RCA: 78] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2014] [Accepted: 01/08/2015] [Indexed: 12/31/2022]
Abstract
PURPOSE Fish oil (FO) elicits diverse beneficial effects. Reduction in or prevention of body mass (BM) gain in animal models may be associated with modulation of brown adipose tissue (BAT). We aimed to evaluate the effects of different high-fat diets with FO on BAT metabolism and thermogenic markers. METHODS C57BL/6 male mice (3-month-old) were fed different diets during 8 weeks: standard-chow diet (SC 10% fat), high-fat lard diet (HF-L 50% fat), high-fat lard plus FO diet (HF-L+FO 50% fat), and high-fat FO diet (HF-FO 50% fat). We evaluated BM and performed an oral glucose tolerance test. At euthanasia, plasma was collected for leptin, and triacylglycerol measurement and interscapular BAT was dissected and stored for molecular analyses. RESULTS HF-L group showed elevated BM; glucose intolerance associated with diminished TC10 and GLUT4 expressions; hypertriglyceridemia associated with increased CD36 and diminished CPT1 expression; elevated expression of pro-inflammatory cytokines; and reduced PPAR expression. Furthermore, these animals showed hyperleptinemia with increased expression of thermogenic markers (beta3-AR, PGC1alpha, and UCP1). Conversely, HF-L+FO and HF-FO groups showed reduced BM gain with regularization of glucose tolerance and triglyceridemia, GLUT4, TC10, CD36, CPT1, and cytokines expressions. Both groups exhibited elevated PPAR and thermogenic markers expression in a dose-dependent way. CONCLUSIONS FO improves metabolic profile and upregulates thermogenic markers, suggesting an elevated thermogenesis that leads to reduced BM gain.
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Ghadge AA, Harke SM, Khadke SP, Diwan AG, Pankaj M, Kulkarni OP, Ranjekar PK, Kuvalekar AA. Circulatory adipocytokines and lipid profile variations in type-2 diabetic subjects: desirable side-effects of antidiabetic drugs. Diabetes Metab Syndr 2014; 8:230-232. [PMID: 25450822 DOI: 10.1016/j.dsx.2014.09.010] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
AIM Inspite of availability of a variety of drugs to treat type 2 diabetes, little is known about their effects on other systems. Normalization of glucose metabolism by these drugs may consequently affect the secretory function in adipocytes. Secretory adipocytokines like adiponectin and leptin are emerging as novel therapeutic targets for type 2 diabetes mellitus (T2DM). The present study was undertaken to analyze the effects of commonly used Oral Hypoglycemic Agents (OHAs) alone, or in combination with other drugs and/or insulin on circulatory adiponectin and leptin levels, lipid profile, and blood pressure in diabetic subjects. METHODS The study was undertaken at IRSHA and Bharati Vidyapeeth Medical College and Hospital, MS, India. Clinically diagnosed T2DM subjects and age, gender matched healthy controls were recruited. Fasting blood was collected from each subject and the blood samples were analyzed for circulatory adipocytokines and lipid parameters using commercial kits. RESULTS Serum adiponectin levels were significantly increased while leptin significantly decreased in diabetic men (p<0.05) and women (p<0.001) on OHA, as compared to healthy controls. Triglyceride levels significantly decreased (p<0.05) in diabetic men, however, they remained unchanged in women despite same drug treatment. Serum HDL and LDL levels (p<0.001) were significantly lower in diabetic women as compared to healthy women. Systolic (p<0.05) and diastolic (p<0.001) blood pressure was significantly high in diabetic men but remained unchanged in women. CONCLUSIONS Frequently used OHAs significantly improve circulatory levels of adipocytokines. Selecting best treatment option for each patient is a key, and 2012 European Association for the Study of Diabetes (EASD) and ADA guidelines recommend diabetes treatment to be individualized depending on various socioeconomic and lifestyle factors. We recommend regular analysis of circulatory adipocytokines in T2DM patients to help clinicians select the best treatment option to normalize levels of these important therapeutic targets.
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Affiliation(s)
- Abhijit A Ghadge
- Nutrigenomics and Functional Foods Laboratory, Interactive Research School for Health Affairs (IRSHA), Bharati Vidyapeeth Deemed University, Pune-Satara Road, Pune, Maharashtra 411043, India
| | - Shubhangi M Harke
- Nutrigenomics and Functional Foods Laboratory, Interactive Research School for Health Affairs (IRSHA), Bharati Vidyapeeth Deemed University, Pune-Satara Road, Pune, Maharashtra 411043, India
| | - Suresh P Khadke
- Nutrigenomics and Functional Foods Laboratory, Interactive Research School for Health Affairs (IRSHA), Bharati Vidyapeeth Deemed University, Pune-Satara Road, Pune, Maharashtra 411043, India
| | - Arundhati G Diwan
- Bharati Vidyapeeth Medical College and Hospital, Bharati Vidyapeeth Deemed University, Pune, Maharashtra 411043, India
| | - Madhu Pankaj
- Bharati Vidyapeeth Medical College and Hospital, Bharati Vidyapeeth Deemed University, Pune, Maharashtra 411043, India
| | - Omkar P Kulkarni
- Nutrigenomics and Functional Foods Laboratory, Interactive Research School for Health Affairs (IRSHA), Bharati Vidyapeeth Deemed University, Pune-Satara Road, Pune, Maharashtra 411043, India
| | - Prabhakar K Ranjekar
- Nutrigenomics and Functional Foods Laboratory, Interactive Research School for Health Affairs (IRSHA), Bharati Vidyapeeth Deemed University, Pune-Satara Road, Pune, Maharashtra 411043, India
| | - Aniket A Kuvalekar
- Nutrigenomics and Functional Foods Laboratory, Interactive Research School for Health Affairs (IRSHA), Bharati Vidyapeeth Deemed University, Pune-Satara Road, Pune, Maharashtra 411043, India.
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Chechi K, Nedergaard J, Richard D. Brown adipose tissue as an anti-obesity tissue in humans. Obes Rev 2014; 15:92-106. [PMID: 24165204 DOI: 10.1111/obr.12116] [Citation(s) in RCA: 67] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/08/2013] [Revised: 09/06/2013] [Accepted: 09/07/2013] [Indexed: 12/27/2022]
Abstract
During the 11th Stock Conference held in Montreal, Quebec, Canada, world-leading experts came together to present and discuss recent developments made in the field of brown adipose tissue biology. Owing to the vast capacity of brown adipose tissue for burning food energy in the process of thermogenesis, and due to demonstrations of its presence in adult humans, there is tremendous interest in targeting brown adipose tissue as an anti-obesity tissue in humans. However, the future of such therapeutic approaches relies on our understanding of the origin, development, recruitment, activation and regulation of brown adipose tissue in humans. As reviewed here, the 11th Stock Conference was organized around these themes to discuss the recent progress made in each aspect, to identify gaps in our current understanding and to further provide a common groundwork that could support collaborative efforts aimed at a future therapy for obesity, based on brown adipose tissue thermogenesis.
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Affiliation(s)
- K Chechi
- Centre de Recherche de l'Institut Universitaire de Cardiologie et de Pneumologie de Québec, Université Laval, Quebec, Canada
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35
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Guirguis E, Hockman S, Chung YW, Ahmad F, Gavrilova O, Raghavachari N, Yang Y, Niu G, Chen X, Yu ZX, Liu S, Degerman E, Manganiello V. A role for phosphodiesterase 3B in acquisition of brown fat characteristics by white adipose tissue in male mice. Endocrinology 2013; 154:3152-67. [PMID: 23766131 PMCID: PMC3749478 DOI: 10.1210/en.2012-2185] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Obesity is linked to various diseases, including insulin resistance, diabetes, and cardiovascular disorders. The idea of inducing white adipose tissue (WAT) to assume characteristics of brown adipose tissue (BAT), and thus gearing it to fat burning instead of storage, is receiving serious consideration as potential treatment for obesity and related disorders. Phosphodiesterase 3B (PDE3B) links insulin- and cAMP-signaling networks in tissues associated with energy metabolism, including WAT. We used C57BL/6 PDE3B knockout (KO) mice to elucidate mechanisms involved in the formation of BAT in epididymal WAT (EWAT) depots. Examination of gene expression profiles in PDE3B KO EWAT revealed increased expression of several genes that block white and promote brown adipogenesis, such as C-terminal binding protein, bone morphogenetic protein 7, and PR domain containing 16, but a clear BAT-like phenotype was not completely induced. However, acute treatment of PDE3B KO mice with the β3-adrenergic agonist, CL316243, markedly increased the expression of cyclooxygenase-2, which catalyzes prostaglandin synthesis and is thought to be important in the formation of BAT in WAT and the elongation of very long-chain fatty acids 3, which is linked to BAT recruitment upon cold exposure, causing a clear shift toward fat burning and the induction of BAT in KO EWAT. These data provide insight into the mechanisms of BAT formation in mouse EWAT, suggesting that, in a C57BL/6 background, an increase in cAMP, caused by ablation of PDE3B and administration of CL316243, may promote differentiation of prostaglandin-responsive progenitor cells in the EWAT stromal vascular fraction into functional brown adipocytes.
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MESH Headings
- Adipogenesis/drug effects
- Adipose Tissue, Brown/cytology
- Adipose Tissue, Brown/drug effects
- Adipose Tissue, Brown/metabolism
- Adipose Tissue, White/cytology
- Adipose Tissue, White/drug effects
- Adipose Tissue, White/metabolism
- Adrenergic beta-3 Receptor Agonists/pharmacology
- Adult Stem Cells/cytology
- Adult Stem Cells/drug effects
- Adult Stem Cells/metabolism
- Animals
- Biomarkers/metabolism
- Crosses, Genetic
- Cyclic AMP/metabolism
- Cyclic Nucleotide Phosphodiesterases, Type 3/chemistry
- Cyclic Nucleotide Phosphodiesterases, Type 3/genetics
- Cyclic Nucleotide Phosphodiesterases, Type 3/metabolism
- Cyclooxygenase 2/biosynthesis
- Cyclooxygenase 2/genetics
- Cyclooxygenase 2/metabolism
- Dioxoles/pharmacology
- Enzyme Induction/drug effects
- Epididymis
- Gene Expression Profiling
- Male
- Mice
- Mice, 129 Strain
- Mice, Inbred C57BL
- Mice, Knockout
- Phosphodiesterase Inhibitors/pharmacology
- Quinolones/pharmacology
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Affiliation(s)
- Emilia Guirguis
- Pulmonary Cardiovascular Branch, National Institutes of Health, Bethesda, Maryland 20892, USA.
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Chechi K, Carpentier AC, Richard D. Understanding the brown adipocyte as a contributor to energy homeostasis. Trends Endocrinol Metab 2013; 24:408-20. [PMID: 23711353 DOI: 10.1016/j.tem.2013.04.002] [Citation(s) in RCA: 74] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/20/2012] [Revised: 04/05/2013] [Accepted: 04/13/2013] [Indexed: 11/28/2022]
Abstract
Brown adipocytes are specialized cells capable of undergoing thermogenesis, a phenomenon regulated by the sympathetic nervous system, due to the presence of uncoupling protein 1 (UCP1). The recent demonstrations of their presence in adult humans, and the discovery that brown adipocytes can be derived from distinct precursors and express specific genes depending on their anatomic location, have sparked intense interest in enhancing the current understanding of their biology and relevance to human energy homeostasis. We provide an overview of the latest advances related to the developmental origins of brown adipocytes, discuss their regulation and function in both rodents and humans, and offer a critical perspective on the relevance of brown adipocyte-mediated thermogenesis in human physiology.
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Affiliation(s)
- Kanta Chechi
- Centre de Recherche de l'Institut Universitaire de Cardiologie et de Pneumologie de Québec, Université Laval, Quebec City, Quebec G1V 4G5, Canada
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Townsend KL, An D, Lynes MD, Huang TL, Zhang H, Goodyear LJ, Tseng YH. Increased mitochondrial activity in BMP7-treated brown adipocytes, due to increased CPT1- and CD36-mediated fatty acid uptake. Antioxid Redox Signal 2013; 19:243-57. [PMID: 22938691 PMCID: PMC3691916 DOI: 10.1089/ars.2012.4536] [Citation(s) in RCA: 76] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
AIMS Brown adipose tissue dissipates chemical energy in the form of heat and regulates triglyceride and glucose metabolism in the body. Factors that regulate fatty acid uptake and oxidation in brown adipocytes have not yet been fully elucidated. Bone morphogenetic protein 7 (BMP7) is a growth factor capable of inducing brown fat mitochondrial biogenesis during differentiation from adipocyte progenitors. Administration of BMP7 to mice also results in increased energy expenditure. To determine if BMP7 is able to affect the mitochondrial activity of mature brown adipocytes, independent of the differentiation process, we delivered BMP7 to mature brown adipocytes and measured mitochondrial activity. RESULTS We found that BMP7 increased mitochondrial activity, including fatty acid oxidation and citrate synthase activity, without increasing the mitochondrial number. This was accompanied by an increase in fatty acid uptake and increased protein expression of CPT1 and CD36, which import fatty acids into the mitochondria and the cell, respectively. Importantly, inhibition of either CPT1 or CD36 resulted in a blunting of the mitochondrial activity of BMP7-treated cells. INNOVATION These findings uncover a novel pathway regulating mitochondrial activities in mature brown adipocytes by BMP7-mediated fatty acid uptake and oxidation. CONCLUSION In conclusion, BMP7 increases mitochondrial activity in mature brown adipocytes via increased fatty acid uptake and oxidation, a process that requires the fatty acid transporters CPT1 and CD36.
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Affiliation(s)
- Kristy L Townsend
- Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts 02215, USA
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Carter S, Caron A, Richard D, Picard F. Role of leptin resistance in the development of obesity in older patients. Clin Interv Aging 2013; 8:829-44. [PMID: 23869170 PMCID: PMC3706252 DOI: 10.2147/cia.s36367] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
Obesity is a global epidemic associated with aging-like cellular processes; in both aging and obesity, resistance to hormones such as insulin and leptin can be observed. Leptin is a circulating hormone/cytokine with central and peripheral effects that is released mainly by subcutaneous white adipose tissue. Centrally, leptin controls food intake, energy expenditure, and fat distribution, whereas it controls (among several others) insulin sensitivity, free fatty acids (FFAs) oxidation, and lipolysis in the periphery. Aging is associated with important changes in both the distribution and the composition of adipose tissue. Fat is redistributed from the subcutaneous to the visceral depot and increased inflammation participates in adipocyte dysfunction. This redistribution of adipose tissue in favor of visceral fat influences negatively both longevity and healthy aging as shown in numerous animal models. These modifications observed during aging are also associated with leptin resistance. This resistance blunts normal central and peripheral functions of leptin, which leads to a decrease in neuroendocrine function and insulin sensitivity, an imbalance in energy regulation, and disturbances in lipid metabolism. Here, we review how age-related leptin resistance triggers metabolic disturbances and affects the longevity of obese patients. Furthermore, we discuss the potential impacts of leptin resistance on the decline of brown adipose tissue thermogenesis observed in elderly individuals.
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Affiliation(s)
- Sophie Carter
- Faculty of Pharmacy, Department of Anatomy and Physiology, Université Laval, Québec, QC, Canada
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Quarta C, Lodi F, Mazza R, Giannone F, Boschi L, Nanni C, Nisoli E, Boschi S, Pasquali R, Fanti S, Iozzo P, Pagotto U. (11)C-meta-hydroxyephedrine PET/CT imaging allows in vivo study of adaptive thermogenesis and white-to-brown fat conversion. Mol Metab 2013; 2:153-60. [PMID: 24049730 DOI: 10.1016/j.molmet.2013.04.002] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/21/2013] [Revised: 04/06/2013] [Accepted: 04/08/2013] [Indexed: 11/18/2022] Open
Abstract
Several lines of evidence suggest that novel pharmacological approaches aimed at converting white adipose tissue (WAT) into brown adipose tissue (BAT) may represent an effective therapeutic strategy for obesity and related disorders. ((18))F-fluorodeoxyglucose ((18)F-FDG) is the only positron emission tomography (PET) tracer commonly used to study BAT function, and so far no functional tools have been described to investigate in vivo white-to-brown fat conversion. In this report, we show that the PET tracer (11)C-meta-hydroxyephedrine ((11)C-MHED, a norepinephrine analogue) is a useful tool to investigate the sympathetic nervous system (SNS) activity in BAT of lean and dietary obese mice. Moreover, we demonstrate that (11)C-MHED is a specific marker of the SNS-mediated thermogenesis in typical BAT depots, and that this tracer can detect in vivo WAT to BAT conversion.
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Affiliation(s)
- Carmelo Quarta
- Endocrinology Unit and Center for Applied Biomedical Research, Department of Medical and Surgical Sciences, University of Bologna, Bologna 40138, Italy ; Department of Nuclear Medicine, S. Orsola-Malpighi Hospital, University of Bologna, Bologna 40138, Italy
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Shimizu I, Walsh K. Vascular remodeling mediated by Angptl2 produced from perivascular adipose tissue. J Mol Cell Cardiol 2013; 59:176-8. [PMID: 23528806 DOI: 10.1016/j.yjmcc.2013.03.009] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/11/2013] [Revised: 03/11/2013] [Accepted: 03/14/2013] [Indexed: 10/27/2022]
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Lenglos C, Mitra A, Guèvremont G, Timofeeva E. Sex differences in the effects of chronic stress and food restriction on body weight gain and brain expression of CRF and relaxin-3 in rats. GENES BRAIN AND BEHAVIOR 2013; 12:370-87. [PMID: 23425370 DOI: 10.1111/gbb.12028] [Citation(s) in RCA: 63] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Received: 06/05/2012] [Revised: 11/05/2012] [Accepted: 02/17/2013] [Indexed: 01/08/2023]
Abstract
This study investigated sex-specific effects of repeated stress and food restriction on food intake, body weight, corticosterone plasma levels and expression of corticotropin-releasing factor (CRF) in the hypothalamus and relaxin-3 in the nucleus incertus (NI). The CRF and relaxin-3 expression is affected by stress, and these neuropeptides produce opposite effects on feeding (anorexigenic and orexigenic, respectively), but sex-specific regulation of CRF and relaxin-3 by chronic stress is not fully understood. Male and female rats were fed ad libitum chow (AC) or ad libitum chow and intermittent palatable liquid Ensure without food restriction (ACE), or combined with repeated food restriction (60% chow, 2 days per week; RCE). Half of the rats were submitted to 1-h restraint stress once a week. In total, seven weekly cycles were applied. The body weight of the RCE stressed male rats significantly decreased, whereas the body weight of the RCE stressed female rats significantly increased compared with the respective control groups. The stressed female RCE rats considerably overate chow during recovery from stress and food restriction. The RCE female rats showed elevated plasma corticosterone levels and low expression of CRF mRNA in the paraventricular hypothalamic nucleus but not in the medial preoptic area. The NI expression of relaxin-3 mRNA was significantly higher in the stressed RCE female rats compared with other groups. An increase in the expression of orexigenic relaxin-3 and misbalanced hypothalamic-pituitary-adrenal axis activity may contribute to the overeating and increased body weight seen in chronically stressed and repeatedly food-restricted female rats.
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Affiliation(s)
- C Lenglos
- Département Psychiatrie et Neurosciences, Faculté de Médecine, Centre de Recherche de l'Institut Universitaire de Cardiologie et de Pneumologie de Québec, Université Laval, Québec, Canada
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Quarta C, Mazza R, Pasquali R, Pagotto U. Role of sex hormones in modulation of brown adipose tissue activity. J Mol Endocrinol 2012; 49:R1-7. [PMID: 22460126 DOI: 10.1530/jme-12-0043] [Citation(s) in RCA: 44] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
The recent demonstration that metabolically active brown adipose tissue (BAT) is present with a high prevalence in humans undoubtedly represents one of the major advancements in the field of metabolic research in the last few years. The increasing interest in BAT is justified by preclinical observations highlighting an important role of this tissue in energy dissipation and metabolic clearance of substrates from the blood. These findings imply that stimulation of BAT activity may represent a new therapeutic approach for obesity and associated comorbidities. However, before proposing BAT as a target organ for therapeutics in a clinical setting, many further notions about BAT function and modulation need to be explored. Keeping in mind the importance of sex dimorphism in energy metabolism control under physiological and pathological conditions, sex hormones may play a relevant role in the regulation of BAT activity in both males and females. Much of the evidence acquired in the past supports the concept of an important role for different sex hormones in BAT thermogenesis and indicates that this tissue mediates the ability of sex hormones to modulate energy balance. These findings make it plausible that a modified interaction between BAT and sex hormones may contribute to the development and the maintenance of obesity and associated metabolic complications.
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Affiliation(s)
- Carmelo Quarta
- Endocrinology Unit and Centro di Ricerca Biomedica Applicata, Department of Clinical Medicine, University of Bologna, Bologna, Italy
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Lu X, Ji Y, Zhang L, Zhang Y, Zhang S, An Y, Liu P, Zheng Y. Resistance to obesity by repression of VEGF gene expression through induction of brown-like adipocyte differentiation. Endocrinology 2012; 153:3123-32. [PMID: 22593269 DOI: 10.1210/en.2012-1151] [Citation(s) in RCA: 58] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
Adipose tissues are classified into white adipose tissue (WAT) and brown adipose tissue (BAT). WAT is responsible for energy storage, and malfunction is associated with obesity. BAT, on the contrary, consumes fat to generate heat through uncoupling mitochondrial respiration and is important in body weight control. Vascular endothelial growth factor (VEGF)-A is the founding member of the VEGF family and has been found highly expressed in adipose tissue. A genetic mouse model of an inducible VEGF (VEGF-A) repression system was used to study VEGF-regulated energy metabolism in WAT. VEGF-repressed mice demonstrated lower food efficiency, lower body weight, and resistance to high-fat diet-induced obesity. Repression of VEGF expression caused morphological and molecular changes in adipose tissues. VEGF repression induced brown-like adipocyte development in WAT, up-regulation of BAT-specific genes including PRDM16, GATA-1, BMP-7, CIDEA, and UCP-1 and down-regulation of leptin, a WAT-specific gene. VEGF repression up-regulated expression of VEGF-B and its downstream fatty acid transport proteins. Relative levels of VEGF/VEGF-B may be important switches in energy metabolism and of pharmaceutical significances.
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Affiliation(s)
- Xiaodan Lu
- Transgenic Animal Research Center, School of Life Science, Northeast Normal University, Changchun, Jilin 130024, China
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Abstract
Bone morphogenetic protein (BMP) signaling in diseases is the subject of an overwhelming array of studies. BMPs are excellent targets for treatment of various clinical disorders. Several BMPs have already been shown to be clinically beneficial in the treatment of a variety of conditions, including BMP-2 and BMP-7 that have been approved for clinical application in nonunion bone fractures and spinal fusions. With the use of BMPs increasingly accepted in spinal fusion surgeries, other therapeutic approaches targeting BMP signaling are emerging beyond applications to skeletal disorders. These approaches can further utilize next-generation therapeutic tools such as engineered BMPs and ex vivo- conditioned cell therapies. In this review, we focused to provide insights into such clinical potentials of BMPs in metabolic and vascular diseases, and in cancer. [BMB reports 2011; 44(10): 619-634].
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Affiliation(s)
- Meejung Kim
- Joint Center for Biosciences at Lee Gil Ya Cancer and Diabetes Research Institute, Gachon University of Medicine and Science, IncheonKorea
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Ouellet V, Labbé SM, Blondin DP, Phoenix S, Guérin B, Haman F, Turcotte EE, Richard D, Carpentier AC. Brown adipose tissue oxidative metabolism contributes to energy expenditure during acute cold exposure in humans. J Clin Invest 2012; 122:545-52. [PMID: 22269323 PMCID: PMC3266793 DOI: 10.1172/jci60433] [Citation(s) in RCA: 768] [Impact Index Per Article: 59.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2011] [Accepted: 11/16/2011] [Indexed: 11/17/2022] Open
Abstract
Brown adipose tissue (BAT) is vital for proper thermogenesis during cold exposure in rodents, but until recently its presence in adult humans and its contribution to human metabolism were thought to be minimal or insignificant. Recent studies using PET with 18F-fluorodeoxyglucose (18FDG) have shown the presence of BAT in adult humans. However, whether BAT contributes to cold-induced nonshivering thermogenesis in humans has not been proven. Using PET with 11C-acetate, 18FDG, and 18F-fluoro-thiaheptadecanoic acid (18FTHA), a fatty acid tracer, we have quantified BAT oxidative metabolism and glucose and nonesterified fatty acid (NEFA) turnover in 6 healthy men under controlled cold exposure conditions. All subjects displayed substantial NEFA and glucose uptake upon cold exposure. Furthermore, we demonstrated cold-induced activation of oxidative metabolism in BAT, but not in adjoining skeletal muscles and subcutaneous adipose tissue. This activation was associated with an increase in total energy expenditure. We found an inverse relationship between BAT activity and shivering. We also observed an increase in BAT radio density upon cold exposure, indicating reduced BAT triglyceride content. In sum, our study provides evidence that BAT acts as a nonshivering thermogenesis effector in humans.
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Affiliation(s)
- Véronique Ouellet
- Centre de recherche de l’Institut universitaire de cardiologie et de pneumologie de Québec, Université Laval, Quebec City, Quebec, Canada.
Department of Medicine, Centre de recherche clinique Etienne-Le Bel, Université de Sherbrooke, Sherbrooke, Quebec, Canada.
Unité de recherche sur la nutrition et le métabolisme, Montfort Hospital, University of Ottawa, Ottawa, Ontario, Canada.
Department of Nuclear Medicine and Radiobiology, Université de Sherbrooke, Sherbrooke, Quebec, Canada
| | - Sébastien M. Labbé
- Centre de recherche de l’Institut universitaire de cardiologie et de pneumologie de Québec, Université Laval, Quebec City, Quebec, Canada.
Department of Medicine, Centre de recherche clinique Etienne-Le Bel, Université de Sherbrooke, Sherbrooke, Quebec, Canada.
Unité de recherche sur la nutrition et le métabolisme, Montfort Hospital, University of Ottawa, Ottawa, Ontario, Canada.
Department of Nuclear Medicine and Radiobiology, Université de Sherbrooke, Sherbrooke, Quebec, Canada
| | - Denis P. Blondin
- Centre de recherche de l’Institut universitaire de cardiologie et de pneumologie de Québec, Université Laval, Quebec City, Quebec, Canada.
Department of Medicine, Centre de recherche clinique Etienne-Le Bel, Université de Sherbrooke, Sherbrooke, Quebec, Canada.
Unité de recherche sur la nutrition et le métabolisme, Montfort Hospital, University of Ottawa, Ottawa, Ontario, Canada.
Department of Nuclear Medicine and Radiobiology, Université de Sherbrooke, Sherbrooke, Quebec, Canada
| | - Serge Phoenix
- Centre de recherche de l’Institut universitaire de cardiologie et de pneumologie de Québec, Université Laval, Quebec City, Quebec, Canada.
Department of Medicine, Centre de recherche clinique Etienne-Le Bel, Université de Sherbrooke, Sherbrooke, Quebec, Canada.
Unité de recherche sur la nutrition et le métabolisme, Montfort Hospital, University of Ottawa, Ottawa, Ontario, Canada.
Department of Nuclear Medicine and Radiobiology, Université de Sherbrooke, Sherbrooke, Quebec, Canada
| | - Brigitte Guérin
- Centre de recherche de l’Institut universitaire de cardiologie et de pneumologie de Québec, Université Laval, Quebec City, Quebec, Canada.
Department of Medicine, Centre de recherche clinique Etienne-Le Bel, Université de Sherbrooke, Sherbrooke, Quebec, Canada.
Unité de recherche sur la nutrition et le métabolisme, Montfort Hospital, University of Ottawa, Ottawa, Ontario, Canada.
Department of Nuclear Medicine and Radiobiology, Université de Sherbrooke, Sherbrooke, Quebec, Canada
| | - François Haman
- Centre de recherche de l’Institut universitaire de cardiologie et de pneumologie de Québec, Université Laval, Quebec City, Quebec, Canada.
Department of Medicine, Centre de recherche clinique Etienne-Le Bel, Université de Sherbrooke, Sherbrooke, Quebec, Canada.
Unité de recherche sur la nutrition et le métabolisme, Montfort Hospital, University of Ottawa, Ottawa, Ontario, Canada.
Department of Nuclear Medicine and Radiobiology, Université de Sherbrooke, Sherbrooke, Quebec, Canada
| | - Eric E. Turcotte
- Centre de recherche de l’Institut universitaire de cardiologie et de pneumologie de Québec, Université Laval, Quebec City, Quebec, Canada.
Department of Medicine, Centre de recherche clinique Etienne-Le Bel, Université de Sherbrooke, Sherbrooke, Quebec, Canada.
Unité de recherche sur la nutrition et le métabolisme, Montfort Hospital, University of Ottawa, Ottawa, Ontario, Canada.
Department of Nuclear Medicine and Radiobiology, Université de Sherbrooke, Sherbrooke, Quebec, Canada
| | - Denis Richard
- Centre de recherche de l’Institut universitaire de cardiologie et de pneumologie de Québec, Université Laval, Quebec City, Quebec, Canada.
Department of Medicine, Centre de recherche clinique Etienne-Le Bel, Université de Sherbrooke, Sherbrooke, Quebec, Canada.
Unité de recherche sur la nutrition et le métabolisme, Montfort Hospital, University of Ottawa, Ottawa, Ontario, Canada.
Department of Nuclear Medicine and Radiobiology, Université de Sherbrooke, Sherbrooke, Quebec, Canada
| | - André C. Carpentier
- Centre de recherche de l’Institut universitaire de cardiologie et de pneumologie de Québec, Université Laval, Quebec City, Quebec, Canada.
Department of Medicine, Centre de recherche clinique Etienne-Le Bel, Université de Sherbrooke, Sherbrooke, Quebec, Canada.
Unité de recherche sur la nutrition et le métabolisme, Montfort Hospital, University of Ottawa, Ottawa, Ontario, Canada.
Department of Nuclear Medicine and Radiobiology, Université de Sherbrooke, Sherbrooke, Quebec, Canada
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Souza TL, Coelho CT, Guimarães PB, Goto EM, Silva SMA, Silva JA, Nunes MT, Ihara SS, Luz J. Intrauterine food restriction alters the expression of uncoupling proteins in brown adipose tissue of rat newborns. J Therm Biol 2012. [DOI: 10.1016/j.jtherbio.2011.12.002] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
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Abstract
PVAT (perivascular adipose tissue) has recently been recognized as a novel factor in vascular biology, with implications in the pathophysiology of cardiovascular disease. Composed mainly of adipocytes, PVAT releases a wide range of biologically active molecules that modulate vascular smooth muscle cell contraction, proliferation and migration. PVAT exerts an anti-contractile effect in various vascular beds which seems to be mediated by an as yet elusive PVRF [PVAT-derived relaxing factor(s)]. Considerable progress has been made on deciphering the nature and mechanisms of action of PVRF, and the PVRFs proposed until now are reviewed here. However, complex pathways seem to regulate PVAT function and more than one mechanism is probably responsible for PVAT actions in vascular biology. The present review describes our current knowledge on the structure and function of PVAT, with a focus on its role in modulating vascular tone. Potential involvements of PVAT dysfunction in obesity, hypertension and atherosclerosis will be highlighted.
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Affiliation(s)
- Theodora Szasz
- Department of Physiology, Georgia Health Sciences University, Augusta, GA 30912, USA.
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Richard D, Monge-Roffarello B, Chechi K, Labbé SM, Turcotte EE. Control and physiological determinants of sympathetically mediated brown adipose tissue thermogenesis. Front Endocrinol (Lausanne) 2012; 3:36. [PMID: 22654862 PMCID: PMC3356074 DOI: 10.3389/fendo.2012.00036] [Citation(s) in RCA: 35] [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] [Received: 10/25/2011] [Accepted: 02/13/2012] [Indexed: 02/05/2023] Open
Abstract
Brown adipose tissue (BAT) represents a remarkable heat-producing tissue. The thermogenic potential of BAT is conferred by uncoupling protein 1, a protein found uniquely in brown adipocytes. BAT activity and capacity is controlled by the sympathetic nervous system (SNS), which densely innervates brown fat depots. SNS-mediated BAT thermogenesis is essentially governed by hypothalamic and brainstem neurons. BAT activity is also modulated by brain energy balance pathways including the very significant brain melanocortin system, suggesting a genuine involvement of SNS-mediated BAT thermogenesis in energy homeostasis. The use of positron emission tomography/computed tomography scanning has revealed the presence of well-defined BAT depots in the cervical, clavicular, and paraspinal areas in adult humans. The prevalence of these depots is higher in subjects exposed to low temperature and is also higher in women compared to men. Moreover, the prevalence of BAT decreases with age and body fat mass, suggesting that BAT could be involved in energy balance regulation and obesity in humans. This short review summarizes recent progress made in our understanding of the control of SNS-mediated BAT thermogenesis and of the determinants of BAT prevalence or detection in humans.
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Affiliation(s)
- Denis Richard
- Centre de recherche de l’Institut universitaire de cardiologie et de pneumologie de Québec et Groupe interdisciplinaire de Recherche sur l’Obésité de l’Université LavalQuébec, QC, Canada
- *Correspondence: Denis Richard, Centre de recherche de l’Institut universitaire de cardiologie et de pneumologie de Québec, 2725 Chemin Sainte-Foy, Québec, QC, Canada G1V 4G5. e-mail:
| | - Boris Monge-Roffarello
- Centre de recherche de l’Institut universitaire de cardiologie et de pneumologie de Québec et Groupe interdisciplinaire de Recherche sur l’Obésité de l’Université LavalQuébec, QC, Canada
| | - Kanta Chechi
- Centre de recherche de l’Institut universitaire de cardiologie et de pneumologie de Québec et Groupe interdisciplinaire de Recherche sur l’Obésité de l’Université LavalQuébec, QC, Canada
| | - Sébastien M. Labbé
- Centre de recherche de l’Institut universitaire de cardiologie et de pneumologie de Québec et Groupe interdisciplinaire de Recherche sur l’Obésité de l’Université LavalQuébec, QC, Canada
| | - Eric E. Turcotte
- Centre de recherche de l’Institut universitaire de cardiologie et de pneumologie de Québec et Groupe interdisciplinaire de Recherche sur l’Obésité de l’Université LavalQuébec, QC, Canada
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Townsend K, Tseng YH. Brown adipose tissue: Recent insights into development, metabolic function and therapeutic potential. Adipocyte 2012; 1:13-24. [PMID: 23700507 PMCID: PMC3661118 DOI: 10.4161/adip.18951] [Citation(s) in RCA: 123] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
Abstract
Obesity is currently a global pandemic, and is associated with increased mortality and co-morbidities including many metabolic diseases. Obesity is characterized by an increase in adipose mass due to increased energy intake, decreased energy expenditure, or both. While white adipose tissue is specialized for energy storage, brown adipose tissue has a high concentration of mitochondria and uniquely expresses uncoupling protein 1, enabling it to be specialized for energy expenditure and thermogenesis. Although brown fat was once considered only necessary in babies, recent morphological and imaging studies have provided evidence that, contrary to prior belief, this tissue is present and active in adult humans. In recent years, the topic of brown adipose tissue has been reinvigorated with many new studies regarding brown adipose tissue differentiation, function and therapeutic promise. This review summarizes the recent advances, discusses the emerging questions and offers perspective on the potential therapeutic applications targeting this tissue.
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Affiliation(s)
- Kristy Townsend
- Joslin Diabetes Center and Harvard Medical School; Boston, MA USA
| | - Yu-Hua Tseng
- Joslin Diabetes Center and Harvard Medical School; Boston, MA USA
- Harvard Stem Cell Institute; Harvard University; Cambridge, MA USA
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Clemmensen C, Madsen AN, Smajilovic S, Holst B, Bräuner-Osborne H. L-Arginine improves multiple physiological parameters in mice exposed to diet-induced metabolic disturbances. Amino Acids 2011; 43:1265-75. [PMID: 22200933 DOI: 10.1007/s00726-011-1199-1] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2011] [Accepted: 12/06/2011] [Indexed: 12/16/2022]
Abstract
L-Arginine (L-Arg) is a conditionally essential amino acid and a natural constituent of dietary proteins. Studies in obese rats and type 2 diabetic humans have indicated that dietary supplementation with L-Arg can diminish gain in white adipose tissue (WAT) and improve insulin sensitivity. However, the effects of L-Arg on glucose homeostasis, body composition and energy metabolism remain unclear. In addition, no studies have, to our knowledge, examined whether L-Arg has beneficial effects as a dietary supplement in the mouse model. In the present study, we investigated the effects of L-Arg supplementation to male C57BL/6 mice on an array of physiological parameters. L-Arg supplemented mice were maintained on a low-protein diet and body composition, appetite regulation, glucose tolerance, insulin sensitivity and energy expenditure were evaluated. A significant reduction in epididymal WAT was observed in L-Arg supplemented mice compared with mice fed an isocaloric control diet. Surprisingly, the L-Arg supplemented animals were hyperphagic corresponding to a highly significant decrease in feed efficiency, as body weight developed in a similar pattern in both experimental groups. Glucose homeostasis experiments revealed a major effect of L-Arg supplementation on glucose tolerance and insulin sensitivity, interestingly, independent of a parallel regulation in whole-body adiposity. Increased L-Arg ingestion also raised energy expenditure; however, no concurrent effect on locomotor activity, substrate metabolism or expression of uncoupling proteins (UCP1 and UCP2) in adipose tissues was displayed. In conclusion, dietary L-Arg supplementation substantially affects an array of metabolic-associated parameters including a reduction in WAT, hyperphagia, improved insulin sensitivity and increased energy expenditure in mice fed a low-protein diet.
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Affiliation(s)
- Christoffer Clemmensen
- Department of Medicinal Chemistry, Faculty of Pharmaceutical Sciences, University of Copenhagen, Universitetsparken 2, Copenhagen, Denmark
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