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Czamara K, Majka Z, Stanek E, Hachlica N, Kaczor A. Raman studies of the adipose tissue: Current state-of-art and future perspectives in diagnostics. Prog Lipid Res 2022; 87:101183. [PMID: 35961483 DOI: 10.1016/j.plipres.2022.101183] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2022] [Revised: 08/05/2022] [Accepted: 08/05/2022] [Indexed: 10/15/2022]
Abstract
The last decades revealed that the adipose tissue shows an unexplored therapeutic potential. In particular, targeting the perivascular adipose tissue (PVAT), that surrounds blood vessels, can prevent cardiovascular pathologies and browning of the adipose tissue can become an effective strategy against obesity. Therefore, new analytical tools are necessary to analyze this tissue. This review reports on the recent developments of various Raman-based techniques for the identification and quantification of the adipose tissue compared to conventional analytical methods. In particular, the emphasis is on analysis of PVAT, investigation of pathological changes of the adipose tissue in model systems and possibilities for its characterization in the clinical context. Overall, the review critically discusses the potential and limitations of Raman techniques in adipose tissue-targeted diagnostics and possible future anti-obesity therapies.
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Affiliation(s)
- Krzysztof Czamara
- Jagiellonian Centre of Experimental Therapeutics (JCET), Jagiellonian University, 14 Bobrzynskiego Str., 30-348 Krakow, Poland.
| | - Zuzanna Majka
- Jagiellonian Centre of Experimental Therapeutics (JCET), Jagiellonian University, 14 Bobrzynskiego Str., 30-348 Krakow, Poland
| | - Ewa Stanek
- Jagiellonian Centre of Experimental Therapeutics (JCET), Jagiellonian University, 14 Bobrzynskiego Str., 30-348 Krakow, Poland
| | - Natalia Hachlica
- Jagiellonian Centre of Experimental Therapeutics (JCET), Jagiellonian University, 14 Bobrzynskiego Str., 30-348 Krakow, Poland; Faculty of Chemistry, Jagiellonian University, 2 Gronostajowa Str., 30-387 Krakow, Poland
| | - Agnieszka Kaczor
- Jagiellonian Centre of Experimental Therapeutics (JCET), Jagiellonian University, 14 Bobrzynskiego Str., 30-348 Krakow, Poland; Faculty of Chemistry, Jagiellonian University, 2 Gronostajowa Str., 30-387 Krakow, Poland.
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Van Schaik L, Kettle C, Green R, Irving HR, Rathner JA. Effects of Caffeine on Brown Adipose Tissue Thermogenesis and Metabolic Homeostasis: A Review. Front Neurosci 2021; 15:621356. [PMID: 33613184 PMCID: PMC7889509 DOI: 10.3389/fnins.2021.621356] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2020] [Accepted: 01/11/2021] [Indexed: 12/11/2022] Open
Abstract
The impact of brown adipose tissue (BAT) metabolism on understanding energy balance in humans is a relatively new and exciting field of research. The pathogenesis of obesity can be largely explained by an imbalance between caloric intake and energy expenditure, but the underlying mechanisms are far more complex. Traditional non-selective sympathetic activators have been used to artificially elevate energy utilization, or suppress appetite, however undesirable side effects are apparent with the use of these pharmacological interventions. Understanding the role of BAT, in relation to human energy homeostasis has the potential to dramatically offset the energy imbalance associated with obesity. This review discusses paradoxical effects of caffeine on peripheral adenosine receptors and the possible role of adenosine in increasing metabolism is highlighted, with consideration to the potential of central rather than peripheral mechanisms for caffeine mediated BAT thermogenesis and energy expenditure. Research on the complex physiology of adipose tissue, the embryonic lineage and function of the different types of adipocytes is summarized. In addition, the effect of BAT on overall human metabolism and the extent of the associated increase in energy expenditure are discussed. The controversy surrounding the primary β-adrenoceptor involved in human BAT activation is examined, and suggestions as to the lack of translational findings from animal to human physiology and human in vitro to in vivo models are provided. This review compares and distinguishes human and rodent BAT effects, thus developing an understanding of human BAT thermogenesis to aid lifestyle interventions targeting obesity and metabolic syndrome. The focus of this review is on the effect of BAT thermogenesis on overall metabolism, and the potential therapeutic effects of caffeine in increasing metabolism via its effects on BAT.
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Affiliation(s)
- Lachlan Van Schaik
- Department of Pharmacy and Biomedical Sciences, La Trobe Institute for Molecular Science, La Trobe University, Bendigo, VIC, Australia
| | - Christine Kettle
- Department of Pharmacy and Biomedical Sciences, La Trobe Institute for Molecular Science, La Trobe University, Bendigo, VIC, Australia
| | - Rodney Green
- Department of Pharmacy and Biomedical Sciences, La Trobe Institute for Molecular Science, La Trobe University, Bendigo, VIC, Australia
| | - Helen R. Irving
- Department of Pharmacy and Biomedical Sciences, La Trobe Institute for Molecular Science, La Trobe University, Bendigo, VIC, Australia
| | - Joseph A. Rathner
- Department of Pharmacy and Biomedical Sciences, La Trobe Institute for Molecular Science, La Trobe University, Bendigo, VIC, Australia
- Department of Physiology, School of Biomedical Sciences, The University of Melbourne, Melbourne, VIC, Australia
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Pravednikova AE, Shevchenko SY, Kerchev VV, Skhirtladze MR, Larina SN, Kachaev ZM, Egorov AD, Shidlovskii YV. Association of uncoupling protein (Ucp) gene polymorphisms with cardiometabolic diseases. Mol Med 2020; 26:51. [PMID: 32450815 PMCID: PMC7249395 DOI: 10.1186/s10020-020-00180-4] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2020] [Accepted: 05/11/2020] [Indexed: 12/23/2022] Open
Abstract
The hereditary aspect of obesity is a major focus of modern medical genetics. The genetic background is known to determine a higher-than-average prevalence of obesity in certain regions, like Oceania. There is evidence that dysfunction of brown adipose tissue (BAT) may be a risk factor for obesity and type 2 diabetes (T2D). A significant number of studies in the field focus on the UCP family. The Ucp genes code for electron transport carriers. UCP1 (thermogenin) is the most abundant protein of the UCP superfamily and is expressed in BAT, contributing to its capability of generating heat. Single nucleotide polymorphisms (SNPs) of Ucp1-Ucp3 were recently associated with risk of cardiometabolic diseases. This review covers the main Ucp SNPs A-3826G, A-1766G, A-112C, Met229Leu, Ala64Thr (Ucp1), Ala55Val, G-866A (Ucp2), and C-55 T (Ucp3), which may be associated with the development of obesity, disturbance in lipid metabolism, T2D, and cardiovascular diseases.
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Affiliation(s)
- Anna E. Pravednikova
- Laboratory of Gene Expression Regulation in Development, Institute of Gene Biology, Russian Academy of Sciences, Moscow, Russia
- I.M. Sechenov First Moscow State Medical University, Ministry of Health of the Russian Federation, Moscow, Russia
| | - Sergey Y. Shevchenko
- Laboratory of Gene Expression Regulation in Development, Institute of Gene Biology, Russian Academy of Sciences, Moscow, Russia
| | - Victor V. Kerchev
- I.M. Sechenov First Moscow State Medical University, Ministry of Health of the Russian Federation, Moscow, Russia
| | - Manana R. Skhirtladze
- I.M. Sechenov First Moscow State Medical University, Ministry of Health of the Russian Federation, Moscow, Russia
| | - Svetlana N. Larina
- I.M. Sechenov First Moscow State Medical University, Ministry of Health of the Russian Federation, Moscow, Russia
| | - Zaur M. Kachaev
- Laboratory of Gene Expression Regulation in Development, Institute of Gene Biology, Russian Academy of Sciences, Moscow, Russia
| | - Alexander D. Egorov
- Laboratory of Gene Expression Regulation in Development, Institute of Gene Biology, Russian Academy of Sciences, Moscow, Russia
| | - Yulii V. Shidlovskii
- Laboratory of Gene Expression Regulation in Development, Institute of Gene Biology, Russian Academy of Sciences, Moscow, Russia
- I.M. Sechenov First Moscow State Medical University, Ministry of Health of the Russian Federation, Moscow, Russia
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Liu J, Zhang C, Zhang B, Sheng Y, Xu W, Luo Y, He X, Huang K. Comprehensive Analysis of the Characteristics and Differences in Adult and Newborn Brown Adipose Tissue (BAT): Newborn BAT Is a More Active/Dynamic BAT. Cells 2020; 9:cells9010201. [PMID: 31947603 PMCID: PMC7017059 DOI: 10.3390/cells9010201] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2019] [Revised: 12/13/2019] [Accepted: 01/07/2020] [Indexed: 02/08/2023] Open
Abstract
Brown adipose tissue (BAT) plays an essential role in maintaining body temperature and in treating obesity and diabetes. The adult BAT (aBAT) and neonatal BAT (neBAT) vary greatly in capacity, but the characteristics and differences between them on the molecular level, as well as the related features of BAT as it develops post-delivery, have not yet been fully determined. In this study, we examined the morphological features of aBAT and neBAT of mice by using hematoxylin-eosin (H&E) staining, transmission electron microscopy (TEM), and scanning electron microscopy (SEM). We found that neBAT contains a smaller number and size of lipid droplets, as well as more abundant mitochondria, compared with aBAT. The dynamic morphological changes revealed that the number and size of lipid droplets increase, but the number of mitochondria gradually decrease during the post-delivery development, which consisted of some differences in RNA or protein expression levels, such as gradually decreased uncoupling protein 1 (UCP1) expression levels and mitochondrial genes, such as mitochondrial transcription factor A (Tfam). The adipocyte differentiation-related genes, such as transcription factor CCAAT enhancer-binding protein β (CEBPβ), were also continuously upregulated. Additionally, the different features of aBAT and neBAT were analyzed from the global transcription (RNA-Seq) level, which included messenger RNA (mRNA), microRNA, long non-coding RNA (lncRNA), circRNA, and DNA methylation, as well as proteins (proteomics). Differentially methylated region (DMR) analysis identified 383 hyper- and 503 hypo-methylated genes, as well as 1221 new circRNA in ne-BAT and 1991 new circRNA in a-BAT, with significantly higher expression of circRNA in aBAT compared with neBAT. Gene ontology (GO) enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis indicated that mitochondrial activity, protein synthesis, and cell life activity levels were higher in neBAT, and pathways related to ribosomes, spliceosomes, and metabolism were significantly activated in neBAT compared to aBAT. Collectively, this study describes the dynamic changes occurring throughout post-delivery development from the morphological, molecular and omics perspectives. Our study provides information that may be utilized in improving BAT functional activity through gene regulation and/or epigenetic regulation.
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Affiliation(s)
- Junyu Liu
- Beijing Advanced Innovation Center for Food Nutrition and Human Health, College of Food Science and Nutritional Engineering, China Agricultural University, Beijing 100083, China; (J.L.); (C.Z.); (B.Z.); (Y.S.); (W.X.); (Y.L.)
- Key Laboratory of Safety Assessment of Genetically Modifed Organism (Food Safety), Ministry of Agriculture, Beijing 100083, China
| | - Chuanhai Zhang
- Beijing Advanced Innovation Center for Food Nutrition and Human Health, College of Food Science and Nutritional Engineering, China Agricultural University, Beijing 100083, China; (J.L.); (C.Z.); (B.Z.); (Y.S.); (W.X.); (Y.L.)
- Key Laboratory of Safety Assessment of Genetically Modifed Organism (Food Safety), Ministry of Agriculture, Beijing 100083, China
| | - Boyang Zhang
- Beijing Advanced Innovation Center for Food Nutrition and Human Health, College of Food Science and Nutritional Engineering, China Agricultural University, Beijing 100083, China; (J.L.); (C.Z.); (B.Z.); (Y.S.); (W.X.); (Y.L.)
- Key Laboratory of Safety Assessment of Genetically Modifed Organism (Food Safety), Ministry of Agriculture, Beijing 100083, China
| | - Yao Sheng
- Beijing Advanced Innovation Center for Food Nutrition and Human Health, College of Food Science and Nutritional Engineering, China Agricultural University, Beijing 100083, China; (J.L.); (C.Z.); (B.Z.); (Y.S.); (W.X.); (Y.L.)
- Key Laboratory of Safety Assessment of Genetically Modifed Organism (Food Safety), Ministry of Agriculture, Beijing 100083, China
| | - Wentao Xu
- Beijing Advanced Innovation Center for Food Nutrition and Human Health, College of Food Science and Nutritional Engineering, China Agricultural University, Beijing 100083, China; (J.L.); (C.Z.); (B.Z.); (Y.S.); (W.X.); (Y.L.)
- Key Laboratory of Safety Assessment of Genetically Modifed Organism (Food Safety), Ministry of Agriculture, Beijing 100083, China
| | - Yunbo Luo
- Beijing Advanced Innovation Center for Food Nutrition and Human Health, College of Food Science and Nutritional Engineering, China Agricultural University, Beijing 100083, China; (J.L.); (C.Z.); (B.Z.); (Y.S.); (W.X.); (Y.L.)
- Key Laboratory of Safety Assessment of Genetically Modifed Organism (Food Safety), Ministry of Agriculture, Beijing 100083, China
| | - Xiaoyun He
- Beijing Advanced Innovation Center for Food Nutrition and Human Health, College of Food Science and Nutritional Engineering, China Agricultural University, Beijing 100083, China; (J.L.); (C.Z.); (B.Z.); (Y.S.); (W.X.); (Y.L.)
- Key Laboratory of Safety Assessment of Genetically Modifed Organism (Food Safety), Ministry of Agriculture, Beijing 100083, China
- Correspondence: (X.H.); (K.H.)
| | - Kunlun Huang
- Beijing Advanced Innovation Center for Food Nutrition and Human Health, College of Food Science and Nutritional Engineering, China Agricultural University, Beijing 100083, China; (J.L.); (C.Z.); (B.Z.); (Y.S.); (W.X.); (Y.L.)
- Key Laboratory of Safety Assessment of Genetically Modifed Organism (Food Safety), Ministry of Agriculture, Beijing 100083, China
- Correspondence: (X.H.); (K.H.)
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Conditionally immortalized brown preadipocytes can switch between proliferative and differentiated states. Biochim Biophys Acta Mol Cell Biol Lipids 2019; 1864:158511. [DOI: 10.1016/j.bbalip.2019.08.007] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2019] [Revised: 08/19/2019] [Accepted: 08/20/2019] [Indexed: 11/21/2022]
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Zheng S, Guo S, Sun G, Shi Y, Wei Z, Tang Y, He F, Shi C, Dai P, Chong H, Samuelson I, Zen K, Zhang CY, Zhang Y, Li J, Jiang X. Gain of Metabolic Benefit with Ablation of miR-149-3p from Subcutaneous Adipose Tissue in Diet-Induced Obese Mice. MOLECULAR THERAPY. NUCLEIC ACIDS 2019; 18:194-203. [PMID: 31561124 PMCID: PMC6796689 DOI: 10.1016/j.omtn.2019.07.024] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/16/2019] [Revised: 07/17/2019] [Accepted: 07/24/2019] [Indexed: 12/31/2022]
Abstract
The global rise in obesity has become a public health crisis. During the onset of obesity, disrupted catecholamine signals have been described to contribute to excess fat accumulation, however, the molecular and metabolic change of subcutaneous adipose tissue (SAT) upon chronic high-fat feeding has rarely been investigated. Here, we show that chronic high-fat feeding caused a significant decrease in the expression of thermogenic genes and acquisition of partial deleterious features of visceral fat in SAT. Upregulated miR-149-3p was involved in this obesity-induced "visceralization" of SAT via inhibiting PRDM16, a master regulator that promoted SAT thermogenesis. Reduction of miR-149-3p significantly increased PRDM16 expression in SAT, with improved whole-body insulin sensitivity, decreased SAT inflammation, and liver steatosis in high-fat fed mice. These findings provided direct evidence of the anti-obese and anti-diabetic effect of PRDM16 in the obese background for the first time and identified that miR-149-3p could serve as a therapeutic target to protect against diet-induced obesity and metabolic dysfunctions.
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Affiliation(s)
- Shasha Zheng
- State Key Laboratory of Pharmaceutical Biotechnology, NJU Advanced Institute for Life Sciences (NAILS), School of Life Sciences, Nanjing University, Nanjing, Jiangsu 210093, China
| | - Shanjun Guo
- State Key Laboratory of Pharmaceutical Biotechnology, NJU Advanced Institute for Life Sciences (NAILS), School of Life Sciences, Nanjing University, Nanjing, Jiangsu 210093, China
| | - Gongrui Sun
- State Key Laboratory of Pharmaceutical Biotechnology, NJU Advanced Institute for Life Sciences (NAILS), School of Life Sciences, Nanjing University, Nanjing, Jiangsu 210093, China
| | - Yanteng Shi
- State Key Laboratory of Pharmaceutical Biotechnology, NJU Advanced Institute for Life Sciences (NAILS), School of Life Sciences, Nanjing University, Nanjing, Jiangsu 210093, China
| | - Zhe Wei
- State Key Laboratory of Pharmaceutical Biotechnology, NJU Advanced Institute for Life Sciences (NAILS), School of Life Sciences, Nanjing University, Nanjing, Jiangsu 210093, China
| | - Yuhang Tang
- State Key Laboratory of Pharmaceutical Biotechnology, NJU Advanced Institute for Life Sciences (NAILS), School of Life Sciences, Nanjing University, Nanjing, Jiangsu 210093, China
| | - Fangfang He
- State Key Laboratory of Pharmaceutical Biotechnology, NJU Advanced Institute for Life Sciences (NAILS), School of Life Sciences, Nanjing University, Nanjing, Jiangsu 210093, China
| | - Chenke Shi
- State Key Laboratory of Pharmaceutical Biotechnology, NJU Advanced Institute for Life Sciences (NAILS), School of Life Sciences, Nanjing University, Nanjing, Jiangsu 210093, China
| | - Peng Dai
- State Key Laboratory of Pharmaceutical Biotechnology, NJU Advanced Institute for Life Sciences (NAILS), School of Life Sciences, Nanjing University, Nanjing, Jiangsu 210093, China
| | - Hoshun Chong
- Department of Thoracic and Cardiovascular Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
| | - Isabella Samuelson
- University of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK
| | - Ke Zen
- State Key Laboratory of Pharmaceutical Biotechnology, NJU Advanced Institute for Life Sciences (NAILS), School of Life Sciences, Nanjing University, Nanjing, Jiangsu 210093, China
| | - Chen-Yu Zhang
- State Key Laboratory of Pharmaceutical Biotechnology, NJU Advanced Institute for Life Sciences (NAILS), School of Life Sciences, Nanjing University, Nanjing, Jiangsu 210093, China
| | - Yujing Zhang
- State Key Laboratory of Pharmaceutical Biotechnology, NJU Advanced Institute for Life Sciences (NAILS), School of Life Sciences, Nanjing University, Nanjing, Jiangsu 210093, China.
| | - Jing Li
- State Key Laboratory of Pharmaceutical Biotechnology, NJU Advanced Institute for Life Sciences (NAILS), School of Life Sciences, Nanjing University, Nanjing, Jiangsu 210093, China.
| | - Xiaohong Jiang
- State Key Laboratory of Pharmaceutical Biotechnology, NJU Advanced Institute for Life Sciences (NAILS), School of Life Sciences, Nanjing University, Nanjing, Jiangsu 210093, China.
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PRDM16 Represses the Pig White Lipogenesis through Promoting Lipolysis Activity. BIOMED RESEARCH INTERNATIONAL 2019; 2019:1969413. [PMID: 31312653 PMCID: PMC6595380 DOI: 10.1155/2019/1969413] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/08/2019] [Accepted: 05/27/2019] [Indexed: 12/12/2022]
Abstract
The positive regulatory domain containing 16 (PRDM16) gene is a dominant transcriptional regulator that favors the “browning” of white adipocytes in rodents. Since the “browning” of white fat is important in pig in terms of producing heat fighting against cold environment, avoiding obesity, and improving meat quality, understanding the critical role that PRDM16 gene played in pig adipose “browning” and energy metabolism is of great significance. However, the constitution of pig fat differs a lot from rodents and human as they do not have brown adipose tissue (BAT) even in the newborn piglets. In this study, we isolated porcine primary preadipocytes and investigated the function of PRDM16 during preadipocytes differentiation. Our results showed that overexpression of the PR domain of PRDM16 repressed the differentiation of porcine preadipocytes, indicated by oil red O staining and the deposition of the triglyceride. Overexpression of the PR domain significantly increased the level of lipolysis and mitochondrial oxidative capacity detected by Western blotting during differentiation. Furthermore, we purified the protein coded by the PR domain and demonstrated that this protein has the H3K9me1 methyltransferase activity. In conclusion, the PR domain of the porcine PRDM16 gene repressed the mature of the porcine preadipocytes by promoting its oxidative activity.
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8
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Levy SB. Field and laboratory methods for quantifying brown adipose tissue thermogenesis. Am J Hum Biol 2019; 31:e23261. [DOI: 10.1002/ajhb.23261] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2019] [Revised: 05/07/2019] [Accepted: 05/11/2019] [Indexed: 12/11/2022] Open
Affiliation(s)
- Stephanie B. Levy
- Department of Anthropology CUNY Hunter College New York, New York
- Department of Anthropology Yale University New Haven Connecticut
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9
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The contribution of Swiss scientists to the assessment of energy metabolism. Eur J Clin Nutr 2018; 72:665-679. [PMID: 29748652 PMCID: PMC5945584 DOI: 10.1038/s41430-018-0139-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2018] [Accepted: 02/12/2018] [Indexed: 11/24/2022]
Abstract
Although Switzerland is considered a small country, it has its share in discoveries, inventions and developments for the assessment of energy metabolism. This includes seminal contributions to respiratory and metabolic physiology and to devices for measuring energy expenditure by direct and indirect calorimetry in vivo in humans and small animals (as well as in vitro in organs/tissues), for the purpose of evaluating the basic nutritional requirements. A strong momentum came during World War II when it was necessary to evaluate the energy requirements of soldiers protecting the country by assessing their energy expenditure, as well as to determine the nutritional needs of the Swiss civil population in time of war when food rationing was necessary to ensure national neutrality and independence. A further impetus came in the 1970s at the start of the obesity epidemics, toward a better understanding of the metabolic basis of obesity, ranging from the development of whole-body concepts to molecular mechanisms. In a trip down memory lane, this review focuses on some of the earlier leading Swiss scientists who have contributed to a better understanding of the field.
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Ballinger MA, Andrews MT. Nature's fat-burning machine: brown adipose tissue in a hibernating mammal. ACTA ACUST UNITED AC 2018. [PMID: 29514878 DOI: 10.1242/jeb.162586] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
Brown adipose tissue (BAT) is a unique thermogenic tissue in mammals that rapidly produces heat via nonshivering thermogenesis. Small mammalian hibernators have evolved the greatest capacity for BAT because they use it to rewarm from hypothermic torpor numerous times throughout the hibernation season. Although hibernator BAT physiology has been investigated for decades, recent efforts have been directed toward understanding the molecular underpinnings of BAT regulation and function using a variety of methods, from mitochondrial functional assays to 'omics' approaches. As a result, the inner-workings of hibernator BAT are now being illuminated. In this Review, we discuss recent research progress that has identified players and pathways involved in brown adipocyte differentiation and maturation, as well as those involved in metabolic regulation. The unique phenotype of hibernation, and its reliance on BAT to generate heat to arouse mammals from torpor, has uncovered new molecular mechanisms and potential strategies for biomedical applications.
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Affiliation(s)
- Mallory A Ballinger
- Department of Integrative Biology and Museum of Vertebrate Zoology, University of California, Berkeley, CA 94720, USA
| | - Matthew T Andrews
- Department of Biochemistry and Biophysics, Oregon State University, Corvallis, OR 97331, USA
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11
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Connexin 43 is required for the maintenance of mitochondrial integrity in brown adipose tissue. Sci Rep 2017; 7:7159. [PMID: 28769076 PMCID: PMC5540980 DOI: 10.1038/s41598-017-07658-y] [Citation(s) in RCA: 42] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2017] [Accepted: 06/30/2017] [Indexed: 11/09/2022] Open
Abstract
We investigated the role of connexin 43 (Cx43) in maintaining the integrity of mitochondria in brown adipose tissue (BAT). The functional effects of Cx43 were evaluated using inducible, adipocyte-specific Cx43 knockout in mice (Gja1adipoqKO) and by overexpression and knockdown of Cx43 in cultured adipocytes. Mitochondrial morphology was evaluated by electron microscopy and mitochondrial function and autophagy were assessed by immunoblotting, immunohistochemistry, and qPCR. The metabolic effects of adipocyte-specific knockout of Cx43 were assessed during cold stress and following high fat diet feeding. Cx43 expression was higher in BAT compared to white adipose tissue. Treatment with the β3-adrenergic receptor agonist CL316,243 increased Cx43 expression and mitochondrial localization. Gja1adipoqKO mice reduced mitochondrial density and increased the presence of damaged mitochondria in BAT. Moreover, metabolic activation with CL316,243 further reduced mitochondrial integrity and upregulated autophagy in the BAT of Gja1adipoqKO mice. Inhibition of Cx43 in cultured adipocytes increased the generation of reactive oxygen species and induction of autophagy during β-adrenergic stimulation. Gja1adipoqKO mice were cold intolerant, expended less energy in response to β3-adrenergic receptor activation, and were more insulin resistant after a high-fat diet challenge. Collectively, our data demonstrate that Cx43 is required for maintaining the mitochondrial integrity and metabolic activity of BAT.
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12
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Jiang Y, Liu Z, Holenz J, Yang H. Competitive Intelligence–based Lead Generation and Fast Follower Approaches. ACTA ACUST UNITED AC 2016. [DOI: 10.1002/9783527677047.ch08] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
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Unser AM, Mooney B, Corr DT, Tseng YH, Xie Y. 3D brown adipogenesis to create "Brown-Fat-in-Microstrands". Biomaterials 2015; 75:123-134. [PMID: 26496384 DOI: 10.1016/j.biomaterials.2015.10.017] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2015] [Revised: 10/05/2015] [Accepted: 10/06/2015] [Indexed: 01/19/2023]
Abstract
The ability of brown adipocytes (fat cells) to dissipate energy as heat shows great promise for the treatment of obesity and other metabolic disorders. Employing pluripotent stem cells, with an emphasis on directed differentiation, may overcome many issues currently associated with primary fat cell cultures. In addition, three-dimensional (3D) cell culture systems are needed to better understand the role of brown adipocytes in energy balance and treating obesity. To address this need, we created 3D "Brown-Fat-in-Microstrands" by microfluidic synthesis of alginate hydrogel microstrands that encapsulated cells and directly induced cell differentiation into brown adipocytes, using mouse embryonic stem cells (ESCs) as a model of pluripotent stem cells, and brown preadipocytes as a positive control. Brown adipocyte differentiation within microstrands was confirmed by immunocytochemistry and qPCR analysis of the expression of the brown adipocyte-defining marker uncoupling protein 1 (UCP1), as well as other general adipocyte markers. Cells within microstrands were responsive to a β-adrenergic agonist with an increase in gene expression of thermogenic UCP1, indicating that these "Brown-Fat-in-Microstrands" are functional. The ability to create "Brown-Fat-in-Microstrands" from pluripotent stem cells opens up a new arena to understanding brown adipogenesis and its implications in obesity and metabolic disorders.
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Affiliation(s)
- Andrea M Unser
- Colleges of Nanoscale Science and Engineering, SUNY Polytechnic Institute, 257 Fuller Road, Albany, NY 12203, USA
| | - Bridget Mooney
- Colleges of Nanoscale Science and Engineering, SUNY Polytechnic Institute, 257 Fuller Road, Albany, NY 12203, USA
| | - David T Corr
- Department of Biomedical Engineering, Rensselaer Polytechnic Institute, 110 8th Street, Troy, NY 12180, USA
| | - Yu-Hua Tseng
- Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, MA 02215, USA
| | - Yubing Xie
- Colleges of Nanoscale Science and Engineering, SUNY Polytechnic Institute, 257 Fuller Road, Albany, NY 12203, USA.
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Kocazeybek B, Saribas S, Ergin S. The role of Ad-36 as a risk factor in males with gynecomastia. Med Hypotheses 2015; 85:992-6. [PMID: 26394544 DOI: 10.1016/j.mehy.2015.08.020] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2014] [Revised: 08/25/2015] [Accepted: 08/30/2015] [Indexed: 12/13/2022]
Abstract
Gynecomastia is highly prevalent worldwide and Adenovirus-36 (Ad-36), recently implicated in increased adipose tissue deposition due to its affinity for adipose tissue, is a potential etiological agent in the development of obesity and therefore we hypothesized that Ad-36 may also play a role in the development of gynecomastia by possibly accompanying increased regional adiposity. To support our hypothesis, we conducted a study that included 33 adult males with gynecomastia (PG) and 15 adult males as the patient control group (HCG). Leptin and adiponectin levels were monitored using ELISA. A significant difference in Ad-36 antibody positivity was found between the groups (p<0.05). Average leptin levels were found to be higher, but average adiponectin levels were found to be lower in Ad-36 Ab(+) patient group. No Ad-36 DNA was detected in any tissue samples. In conclusion, we hypothesize that low-grade chronic inflammation, which was caused by Ad-36 infection, possibly caused an increase in circulating leptin. This in turn may have caused an increase in local or circulating estrogens and/or the estrogen/androgen ratio by stimulating the aromatase enzyme activity in adipose stromal cells and breast tissues. We suggest that gynecomastia may develop following an increase in aromatase enzyme activity, by which more oestrogen is produced and the estrogen-androgen balance disrupted. Also, regional adipose tissue enlargements may cause the excessive production of estrogens leading to gynecomastia. Adipose tissue has been recognized as a major endocrine organ in recent years. Another plausible explanation is excessive aromatization of androgens to estrogens by peripheral adipose tissue may promote gynecomastia in males. Moreover, our results suggest that there might be a relationship between Ad-36 and gynecomastia.
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Affiliation(s)
- Bekir Kocazeybek
- Istanbul University, Cerrahpasa Medical Faculty, Department of Medical Microbiology, Istanbul, Turkey
| | - Suat Saribas
- Istanbul University, Cerrahpasa Medical Faculty, Department of Medical Microbiology, Istanbul, Turkey
| | - Sevgi Ergin
- Istanbul University, Cerrahpasa Medical Faculty, Department of Medical Microbiology, Istanbul, Turkey.
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15
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Unser AM, Tian Y, Xie Y. Opportunities and challenges in three-dimensional brown adipogenesis of stem cells. Biotechnol Adv 2015; 33:962-79. [PMID: 26231586 DOI: 10.1016/j.biotechadv.2015.07.005] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2015] [Revised: 07/07/2015] [Accepted: 07/23/2015] [Indexed: 12/21/2022]
Abstract
The formation of brown adipose tissue (BAT) via brown adipogenesis has become a notable process due to its ability to expend energy as heat with implications in the treatment of metabolic disorders and obesity. With the advent of complexity within white adipose tissue (WAT) along with inducible brown adipocytes (also known as brite and beige), there has been a surge in deciphering adipocyte biology as well as in vivo adipogenic microenvironments. A therapeutic outcome would benefit from understanding early events in brown adipogenesis, which can be accomplished by studying cellular differentiation. Pluripotent stem cells are an efficient model for differentiation and have been directed towards both white adipogenic and brown adipogenic lineages. The stem cell microenvironment greatly contributes to terminal cell fate and as such, has been mimicked extensively by various polymers including those that can form 3D hydrogel constructs capable of biochemical and/or mechanical modifications and modulations. Using bioengineering approaches towards the creation of 3D cell culture arrangements is more beneficial than traditional 2D culture in that it better recapitulates the native tissue biochemically and biomechanically. In addition, such an approach could potentially protect the tissue formed from necrosis and allow for more efficient implantation. In this review, we highlight the promise of brown adipocytes with a focus on brown adipogenic differentiation of stem cells using bioengineering approaches, along with potential challenges and opportunities that arise when considering the energy expenditure of BAT for prospective therapeutics.
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Affiliation(s)
- Andrea M Unser
- Colleges of Nanoscale Science and Engineering, SUNY Polytechnic Institute, 257 Fuller Road Albany, NY 12203, USA
| | - Yangzi Tian
- Colleges of Nanoscale Science and Engineering, SUNY Polytechnic Institute, 257 Fuller Road Albany, NY 12203, USA
| | - Yubing Xie
- Colleges of Nanoscale Science and Engineering, SUNY Polytechnic Institute, 257 Fuller Road Albany, NY 12203, USA.
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16
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Hannoush H, Sachdev V, Brofferio A, Arai AE, LaRocca G, Sapp J, Sidenko S, Brenneman C, Biesecker LG, Keppler-Noreuil KM. Myocardial fat overgrowth in Proteus syndrome. Am J Med Genet A 2014; 167A:103-10. [PMID: 25377688 DOI: 10.1002/ajmg.a.36773] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2014] [Accepted: 08/20/2014] [Indexed: 12/31/2022]
Abstract
Proteus syndrome (PS) is a rare, mosaic disorder with asymmetric and distorting overgrowth of the skeletal system, skin, and adipose tissues. Cardiac abnormalities are rare in this syndrome and only two prior cases have been reported. Many patients with PS followed at our institution underwent transthoracic echocardiograms for preoperative evaluation or as work-up for associated pulmonary disease. Some were noted to have prominent, focal echodense areas in the myocardium. We further investigated cardiac findings in a cohort of children and adult patients with PS. Patients with abnormal echocardiograms were referred for cardiac magnetic resonance imaging, Holter monitoring, and exercise treadmill testing. Twenty children and adults with PS, age 24 months to 50 years old, underwent transthoracic echocardiograms. Seven patients (35%) had focal bright echodense areas within the myocardium suggesting fatty infiltration. The majority of patients had significant involvement of the interventricular septum. The cardiac characteristics of all patients with fatty infiltration on transthoracic echocardiograms were compared to Proteus patients without these findings. There were no significant differences in chamber sizes, mass, systolic or diastolic function. No increased risk of conduction defects or arrhythmias was found. This study shows that abnormal fat overgrowth is a common finding in the myocardium in patients with Proteus syndrome; however, it is not associated with functional derangements or arrhythmias. Further evaluation of a larger number of Proteus patients is needed in order to determine the frequency and prognosis of cardiac involvement. Published 2014. This article is a U.S. Government work and is in the public domain in the USA.
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Affiliation(s)
- H Hannoush
- Cardiovascular and Pulmonary Branch, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland
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17
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18
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Giby VG, Ajith TA. Role of adipokines and peroxisome proliferator-activated receptors in nonalcoholic fatty liver disease. World J Hepatol 2014; 6:570-579. [PMID: 25232450 PMCID: PMC4163740 DOI: 10.4254/wjh.v6.i8.570] [Citation(s) in RCA: 78] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/03/2014] [Revised: 04/29/2014] [Accepted: 05/28/2014] [Indexed: 02/06/2023] Open
Abstract
Intrahepatic fat deposition has been demonstrated in patients with nonalcoholic fatty liver disease (NAFLD). Genetic and environmental factors are important for the development of NAFLD. Diseases such as obesity, diabetes, and hypertension have been found to be closely associated with the incidence of NAFLD. Evidence suggests that obesity and insulin resistance are the major factors that contribute to the development of NAFLD. In comparing the factors that contribute to the buildup of excess calories in obesity, an imbalance of energy homeostasis can be considered as the basis. Among the peripheral signals that are generated to regulate the uptake of food, signals from adipose tissue are of major relevance and involve the maintenance of energy homeostasis through processes such as lipogenesis, lipolysis, and oxidation of fatty acids. Advances in research on adipose tissue suggest an integral role played by adipokines in NAFLD. Cytokines secreted by adipocytes, such as tumor necrosis factor-α, transforming growth factor-β, and interleukin-6, are implicated in NAFLD. Other adipokines, such as leptin and adiponectin and, to a lesser extent, resistin and retinol binding protein-4 are also involved. Leptin and adiponectin can augment the oxidation of fatty acid in liver by activating the nuclear receptor super-family of transcription factors, namely peroxisome proliferator-activated receptor (PPAR)-α. Recent studies have proposed downregulation of PPAR-α in cases of hepatic steatosis. This review discusses the role of adipokines and PPARs with regard to hepatic energy metabolism and progression of NAFLD.
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Affiliation(s)
- Vettickattuparambil George Giby
- Vettickattuparambil George Giby, Thekkuttuparambil Ananthanarayanan Ajith, Department of Biochemistry, Amala Institute of Medical Sciences, Thrissur-680 555, Kerala, India
| | - Thekkuttuparambil Ananthanarayanan Ajith
- Vettickattuparambil George Giby, Thekkuttuparambil Ananthanarayanan Ajith, Department of Biochemistry, Amala Institute of Medical Sciences, Thrissur-680 555, Kerala, India
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19
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Abarrategi A, Perez-Tavarez R, Rodriguez-Milla MA, Cubillo I, Mulero F, Alfranca A, Lopez-Lacomba JL, García-Castro J. In vivo ectopic implantation model to assess human mesenchymal progenitor cell potential. Stem Cell Rev Rep 2014; 9:833-46. [PMID: 23934266 PMCID: PMC3834175 DOI: 10.1007/s12015-013-9464-1] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Clinical interest on human mesenchymal progenitor cells (hMPC) relies on their potential applicability in cell-based therapies. An in vitro characterization is usually performed in order to define MPC potency. However, in vitro predictions not always correlate with in vivo results and thus there is no consensus in how to really assess cell potency. Our goal was to provide an in vivo testing method to define cell behavior before therapeutic usage, especially for bone tissue engineering applications. In this context, we wondered whether bone marrow stromal cells (hBMSC) would proceed in an osteogenic microenvironment. Based on previous approaches, we developed a fibrin/ceramic/BMP-2/hBMSCs compound. We implanted the compound during only 2 weeks in NOD-SCID mice, either orthotopically to assess its osteoinductive property or subcutaneously to analyze its adequacy as a cell potency testing method. Using fluorescent cell labeling and immunohistochemistry techniques, we could ascertain cell differentiation to bone, bone marrow, cartilage, adipocyte and fibrous tissue. We observed differences in cell potential among different batches of hBMSCs, which did not strictly correlate with in vitro analyses. Our data indicate that the method we have developed is reliable, rapid and reproducible to define cell potency, and may be useful for testing cells destined to bone tissue engineering purposes. Additionally, results obtained with hMPCs from other sources indicate that our method is suitable for testing any potentially implantable mesenchymal cell. Finally, we propose that this model could successfully be employed for bone marrow niche and bone tumor studies.
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Affiliation(s)
- Ander Abarrategi
- Unidad de Biotecnología Celular, Instituto de Investigación en Enfermedades Raras, Instituto de Salud Carlos III, Carretera Majadahonda-Pozuelo km. 2.200, Majadahonda, Madrid, Spain
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20
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Geer EB, Islam J, Buettner C. Mechanisms of glucocorticoid-induced insulin resistance: focus on adipose tissue function and lipid metabolism. Endocrinol Metab Clin North Am 2014; 43:75-102. [PMID: 24582093 PMCID: PMC3942672 DOI: 10.1016/j.ecl.2013.10.005] [Citation(s) in RCA: 257] [Impact Index Per Article: 23.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Glucocorticoids (GCs) are critical in the regulation of the stress response, inflammation and energy homeostasis. Excessive GC exposure results in whole-body insulin resistance, obesity, cardiovascular disease, and ultimately decreased survival, despite their potent anti-inflammatory effects. This apparent paradox may be explained by the complex actions of GCs on adipose tissue functionality. The wide prevalence of oral GC therapy makes their adverse systemic effects an important yet incompletely understood clinical problem. This article reviews the mechanisms by which supraphysiologic GC exposure promotes insulin resistance, focusing in particular on the effects on adipose tissue function and lipid metabolism.
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Affiliation(s)
- Eliza B Geer
- Division of Endocrinology, Mount Sinai Medical Center, One Gustave Levy Place, Box 1055, New York, NY 10029, USA.
| | - Julie Islam
- Division of Endocrinology and Metabolism, Beth Israel Medical Center, 317 East 17th Street, 8th Floor, New York, NY 10003, USA
| | - Christoph Buettner
- Division of Endocrinology, Mount Sinai Medical Center, One Gustave Levy Place, Box 1055, New York, NY 10029, USA
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21
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Tanzi MC, Farè S. Adipose tissue engineering: state of the art, recent advances and innovative approaches. Expert Rev Med Devices 2014; 6:533-51. [DOI: 10.1586/erd.09.37] [Citation(s) in RCA: 72] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
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22
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Zhang J, Cui X, Shen Y, Pang L, Zhang A, Fu Z, Chen J, Guo X, Gan W, Ji C. Distinct expression profiles of LncRNAs between brown adipose tissue and skeletal muscle. Biochem Biophys Res Commun 2013; 443:1028-34. [PMID: 24365148 DOI: 10.1016/j.bbrc.2013.12.092] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2013] [Accepted: 12/17/2013] [Indexed: 12/31/2022]
Abstract
Both brown adipose tissue and skeletalmuscle have abundant mitochondria and energy consumption capacity. They are similar in origin and gain different potential of energy metabolism after differentiation and maturation. The mechanism that cause the difference is not yet fully understood. Long non-coding RNAs (lncRNAs) which comprise the bulk of the human non-coding transcriptome have been proved to play key roles in various biological processes. Whether they will have a function on the differentiation and energy metabolism between BAT and skeletalmuscle is still unknown. To identify the cellular long noncoding RNAs (lncRNAs) involved in the progress, we used the next generation transcriptome sequencing and microarray techniques, and investigated 704 up-regulated and 896 down-regulated lncRNAs (fold-change >3.0) in BAT by comparing the expression profile. Furthermore, we reported AK003288 associated with junctophilin 2 (Jph2) gene which may affect energy metabolism. This study show distinct expression profiles of LncRNAs between brown adipose tissue and skeletal muscle which provide information for further research on differentiation of adipocyte and transdifferentiation between BAT and skeletalmuscle that will be helpful to find a new therapeutic target for combatting obesity.
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Affiliation(s)
- Jun Zhang
- Nanjing Maternal and Child Health Care Institute, Nanjing Maternal and Child Health Care Hospital Affiliated to Nanjing Medical University, Nanjing 210029, China; Department of Pediatric Center, The Second Affiliated Hospital of Nanjing Medical University, Nanjing 210003, China
| | - Xianwei Cui
- Nanjing Maternal and Child Health Care Institute, Nanjing Maternal and Child Health Care Hospital Affiliated to Nanjing Medical University, Nanjing 210029, China
| | - Yahui Shen
- Nanjing Maternal and Child Health Care Institute, Nanjing Maternal and Child Health Care Hospital Affiliated to Nanjing Medical University, Nanjing 210029, China
| | - Lingxia Pang
- Nanjing Maternal and Child Health Care Institute, Nanjing Maternal and Child Health Care Hospital Affiliated to Nanjing Medical University, Nanjing 210029, China
| | - Aiqing Zhang
- Department of Pediatric Center, The Second Affiliated Hospital of Nanjing Medical University, Nanjing 210003, China
| | - Ziyi Fu
- Nanjing Maternal and Child Health Care Institute, Nanjing Maternal and Child Health Care Hospital Affiliated to Nanjing Medical University, Nanjing 210029, China
| | - Jiantao Chen
- The Third Affiliated Hospital of Xinxiang Medical University, Xinxiang 453003, China
| | - Xirong Guo
- Nanjing Maternal and Child Health Care Institute, Nanjing Maternal and Child Health Care Hospital Affiliated to Nanjing Medical University, Nanjing 210029, China
| | - Weihua Gan
- Department of Pediatric Center, The Second Affiliated Hospital of Nanjing Medical University, Nanjing 210003, China.
| | - Chenbo Ji
- Nanjing Maternal and Child Health Care Institute, Nanjing Maternal and Child Health Care Hospital Affiliated to Nanjing Medical University, Nanjing 210029, China.
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Abstract
Obesity represents a major risk factor for the development of several of our most common medical conditions, including Type 2 diabetes, dyslipidaemia, non-alcoholic fatty liver, cardiovascular disease and even some cancers. Although increased fat mass is the main feature of obesity, not all fat depots are created equal. Adipocytes found in white adipose tissue contain a single large lipid droplet and play well-known roles in energy storage. By contrast, brown adipose tissue is specialized for thermogenic energy expenditure. Owing to its significant capacity to dissipate energy and regulate triacylglycerol (triglyceride) and glucose metabolism, and its demonstrated presence in adult humans, brown fat could be a potential target for the treatment of obesity and metabolic syndrome. Undoubtedly, fundamental knowledge about the formation of brown fat and regulation of its activity is imperatively needed to make such therapeutics possible. In the present review, we integrate the recent advancements on the regulation of brown fat formation and activity by developmental and hormonal signals in relation to its metabolic function.
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24
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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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25
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Mavrogianni A, Johnson F, Ucci M, Marmot A, Wardle J, Oreszczyn T, Summerfield A. Historic Variations in Winter Indoor Domestic Temperatures and Potential Implications for Body Weight Gain. INDOOR + BUILT ENVIRONMENT : THE JOURNAL OF THE INTERNATIONAL SOCIETY OF THE BUILT ENVIRONMENT 2013; 22:360-375. [PMID: 26321874 PMCID: PMC4456148 DOI: 10.1177/1420326x11425966] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 08/11/2011] [Indexed: 06/02/2023]
Abstract
It has been argued that the amount of time spent by humans in thermoneutral environments has increased in recent decades. This paper examines evidence of historic changes in winter domestic temperatures in industrialised countries. Future trajectories for indoor thermal comfort are also explored. Whilst methodological differences across studies make it difficult to compare data and accurately estimate the absolute size of historic changes in indoor domestic temperatures, data analysis does suggest an upward trend, particularly in bedrooms. The variations in indoor winter residential temperatures might have been further exacerbated in some countries by a temporary drop in demand temperatures due to the 1970s energy crisis, as well as by recent changes in the building stock. In the United Kingdom, for example, spot measurement data indicate that an increase of up to 1.3°C per decade in mean dwelling winter indoor temperatures may have occurred from 1978 to 1996. The findings of this review paper are also discussed in the context of their significance for human health and well-being. In particular, historic indoor domestic temperature trends are discussed in conjunction with evidence on the links between low ambient temperatures, body energy expenditure and weight gain.
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Affiliation(s)
- A. Mavrogianni
- UCL Energy Institute, University College London, London, UK
| | - F. Johnson
- Department of Epidemiology and Public Health, University College London,
London, UK
| | - M. Ucci
- The Bartlett School of Graduate Studies, University College London, London,
UK
| | - A. Marmot
- The Bartlett School of Graduate Studies, University College London, London,
UK
| | - J. Wardle
- Department of Epidemiology and Public Health, University College London,
London, UK
| | - T. Oreszczyn
- UCL Energy Institute, University College London, London, UK
| | - A. Summerfield
- UCL Energy Institute, University College London, London, UK
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26
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Liu J, Kong X, Wang L, Qi H, Di W, Zhang X, Wu L, Chen X, Yu J, Zha J, Lv S, Zhang A, Cheng P, Hu M, Li Y, Bi J, Li Y, Hu F, Zhong Y, Xu Y, Ding G. Essential roles of 11β-HSD1 in regulating brown adipocyte function. J Mol Endocrinol 2013. [PMID: 23197361 DOI: 10.1530/jme-12-0099] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
Brown adipose tissue (BAT) increases energy expenditure and is an attractive therapeutic target for obesity. 11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1), an amplifier of local glucocorticoid activity, has been shown to modulate white adipose tissue (WAT) metabolism and function. In this study, we investigated the roles of 11β-HSD1 in regulating BAT function. We observed a significant increase in the expression of BAT-specific genes, including UCP1, Cidea, Cox7a1, and Cox8b, in BVT.2733 (a selective inhibitor of 11β-HSD1)-treated and 11β-HSD1-deficient primary brown adipocytes of mice. By contrast, a remarkable decrease in BAT-specific gene expression was detected in brown adipocytes when 11β-HSD1 was overexpressed, which effect was reversed by BVT.2733 treatment. Consistent with the in vitro results, expression of a range of genes related to brown fat function in high-fat diet-fed mice treated with BVT.2733. Our results indicate that 11β-HSD1 acts as a vital regulator that controls the expression of genes related to brown fat function and as such may become a potential target in preventing obesity.
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Affiliation(s)
- Juan Liu
- Department of Gerontology, First Hospital Affiliated to Nanjing Medical University, Nanjing 210029, People's Republic of China
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27
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28
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Billon N, Dani C. Developmental origins of the adipocyte lineage: new insights from genetics and genomics studies. Stem Cell Rev Rep 2012; 8:55-66. [PMID: 21365256 DOI: 10.1007/s12015-011-9242-x] [Citation(s) in RCA: 95] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
The current epidemic of obesity and overweight has caused a surge of interest in the study of adipose tissue formation. Much progress has been made in defining the transcriptional networks controlling the terminal differentiation of adipocyte progenitors into mature adipocytes. However, the early steps of adipocyte development and the embryonic origin of this lineage have been largely disregarded until recently. In mammals, two functionally different types of adipose tissues coexist, which are both involved in energy balance but assume opposite functions. White adipose tissue (WAT) stores energy, while brown adipose tissue (BAT) is specialized in energy expenditure. WAT and BAT can be found as several depots located in various sites of the body. Individual fat depots exhibit different timing of appearance during development, as well as distinct functional properties, suggesting possible differences in their developmental origin. This hypothesis has recently been revisited through large-scale genomics studies and in vivo lineage tracing approaches, which are reviewed in this report. These studies have provided novel fundamental insights into adipocyte biology, pointing out distinct developmental origins for WAT and BAT, as well as for individual WAT depots. They suggest that the adipose tissue is composed of distinct mini-organs, exhibiting developmental and functional differences, as well as variable contribution to obesity-related metabolic diseases.
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Affiliation(s)
- Nathalie Billon
- Institut Biologie du Développement et Cancer, CNRS UMR 6543, Faculté de Médecine Pasteur, Université de Nice Sophia-Antipolis, 28 avenue de Valombrose, 06108, Nice Cedex 2, France.
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29
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A pleiotropic role for the orphan nuclear receptor small heterodimer partner in lipid homeostasis and metabolic pathways. J Lipids 2012; 2012:304292. [PMID: 22577560 PMCID: PMC3346990 DOI: 10.1155/2012/304292] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2011] [Accepted: 12/05/2011] [Indexed: 12/29/2022] Open
Abstract
Nuclear receptors (NRs) comprise one of the most abundant classes of transcriptional regulators of metabolic diseases and have emerged as promising pharmaceutical targets. Small heterodimer partner (SHP; NR0B2) is a unique orphan NR lacking a DNA-binding domain but contains a putative ligand-binding domain. SHP is a transcriptional regulator affecting multiple key biological functions and metabolic processes including cholesterol, bile acid, and fatty acid metabolism, as well as reproductive biology and glucose-energy homeostasis. About half of all mammalian NRs and several transcriptional coregulators can interact with SHP. The SHP-mediated repression of target transcription factors includes at least three mechanisms including direct interference with the C-terminal activation function 2 (AF2) coactivator domains of NRs, recruitment of corepressors, or direct interaction with the surface of NR/transcription factors. Future research must focus on synthetic ligands acting on SHP as a potential therapeutic target in a series of metabolic abnormalities. Current understanding about the pleiotropic role of SHP is examined in this paper, and principal metabolic aspects connected with SHP function will be also discussed.
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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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31
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High-fat diet induces emergence of brown-like adipocytes in white adipose tissue of spontaneously hypertensive rats. Hypertens Res 2011; 35:279-86. [DOI: 10.1038/hr.2011.188] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
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Symonds ME, Budge H, Perkins AC, Lomax MA. Adipose tissue development – Impact of the early life environment. PROGRESS IN BIOPHYSICS AND MOLECULAR BIOLOGY 2011; 106:300-6. [DOI: 10.1016/j.pbiomolbio.2010.11.008] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/30/2010] [Revised: 11/18/2010] [Accepted: 11/26/2010] [Indexed: 12/21/2022]
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Johnson F, Mavrogianni A, Ucci M, Vidal-Puig A, Wardle J. Could increased time spent in a thermal comfort zone contribute to population increases in obesity? Obes Rev 2011; 12:543-51. [PMID: 21261804 DOI: 10.1111/j.1467-789x.2010.00851.x] [Citation(s) in RCA: 67] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
Domestic winter indoor temperatures in the USA, UK and other developed countries appear to be following an upwards trend. This review examines evidence of a causal link between thermal exposures and increases in obesity prevalence, focusing on acute and longer-term biological effects of time spent in thermal comfort compared with mild cold. Reduced exposure to seasonal cold may have a dual effect on energy expenditure, both minimizing the need for physiological thermogenesis and reducing thermogenic capacity. Experimental studies show a graded association between acute mild cold and human energy expenditure over the range of temperatures relevant to indoor heating trends. Meanwhile, recent studies of the role of brown adipose tissue (BAT) in human thermogenesis suggest that increased time spent in conditions of thermal comfort can lead to a loss of BAT and reduced thermogenic capacity. Pathways linking cold exposure and adiposity have not been directly tested in humans. Research in naturalistic and experimental settings is needed to establish effects of changes in thermal exposures on weight, which may raise possibilities for novel public health strategies to address obesity.
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Affiliation(s)
- F Johnson
- Cancer Research UK Health Behaviour Research Centre, Department of Epidemiology and Public Health, University College London, London, UK.
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Symonds ME, Sebert S, Budge H. The obesity epidemic: from the environment to epigenetics - not simply a response to dietary manipulation in a thermoneutral environment. Front Genet 2011; 2:24. [PMID: 22303320 PMCID: PMC3268579 DOI: 10.3389/fgene.2011.00024] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2011] [Accepted: 05/12/2011] [Indexed: 12/22/2022] Open
Abstract
The prevalence of obesity continues to increase particularly in developed countries. To establish the primary mechanisms involved, relevant animal models which track the developmental pathway to obesity are required. This need is emphasized by the substantial rise in the number of overweight and obese children, of which a majority will remain obese through adulthood. The past half century has been accompanied with unprecedented transitions in our lifestyle. Each of these changes substantially contributes to enhancing our capacity to store energy into adipose tissues. The complex etiology of adiposity is critical as a majority of models investigating obesity utilize a simplistic high-fat/low-carbohydrate diet, fed over a short time period to comparatively young inbred animals maintained in fixed environment. The natural history of obesity is much more complex involving many other mechanisms and this type of challenge may not be the optimal experimental intervention. Such processes include changes in adipose tissue composition with time and the transition from brown to white adipose tissue. Brown adipose tissue, due its unique ability to rapidly produce large amounts of heat could have a pivotal role in energy balance and is under epigenetic regulation mediated by the histone H3k9-specific demethylase Jhdma2a. Furthermore, day length has a potential role in determining endocrine and metabolic responses in brown fat. The potential to utilize novel models and interventions across a range of animal species in adipose tissue development may finally start to yield sustainable strategies by which excess fat mass can, at last, be avoided in humans.
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Affiliation(s)
- Michael E Symonds
- Early Life Nutrition Research Unit, Academic Division of Child Health, Nottingham Respiratory Medicine Biomedical Research Unit, School of Clinical Sciences, University Hospital Nottingham, UK
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35
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Pfannenberg C, Werner MK, Ripkens S, Stef I, Deckert A, Schmadl M, Reimold M, Häring HU, Claussen CD, Stefan N. Impact of age on the relationships of brown adipose tissue with sex and adiposity in humans. Diabetes 2010; 59:1789-93. [PMID: 20357363 PMCID: PMC2889780 DOI: 10.2337/db10-0004] [Citation(s) in RCA: 321] [Impact Index Per Article: 21.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/01/2022]
Abstract
OBJECTIVE Brown adipose tissue (BAT) regulates energy homeostasis and fat mass in mammals and newborns and, most likely, in adult humans. Because BAT activity and BAT mass decline with age in humans, the impact of BAT on adiposity may decrease with aging. In the present study we addressed this hypothesis and further investigated the effect of age on the sex differences in BAT activity and BAT mass. RESEARCH DESIGN AND METHODS Data from 260 subjects (98 with BAT and 162 study date-matched control subjects) who underwent (18)F-fluorodeoxyglucose positron emission tomography/computed tomography ((18)F-FDG PET/CT) under thermoneutral conditions were analyzed. BAT activity and BAT mass were determined in the upper body. RESULTS BAT activity and BAT mass were higher in female (1.59 +/- 0.10 and 32 +/- 5 g vs. 1.02 +/- 0.10 and 18 +/- 4 g, both P < or = 0.0006) than in male subjects. In multivariate analyses, sex (P < 0.0001), age (P < 0.0001), and BMI (P = 0.0018) were associated independently with BAT activity. Interestingly, only in male subjects was there an interaction between BMI and age in determining BAT activity (P = 0.008) and BAT mass (P = 0.0002); BMI decreased with increasing BAT activity and BAT mass in the lowest age tertile (Spearman rank correlation coefficient r(s) = -0.38, P = 0.015 and r(s) = -0.37, P = 0.017, respectively), not in the higher age tertiles. Furthermore, BAT activity and mass differed between female and male subjects only in the upper two age tertiles (all P < or = 0.09). CONCLUSIONS Our data corroborate that, in general, BAT activity and BAT mass are elevated in female subjects and in younger people. Importantly, we provide novel evidence that the impact of BAT activity and BAT mass on adiposity appears to decline with aging only in male subjects. Furthermore, while BAT activity and BAT mass only moderately decline with increasing age in female subjects, a much stronger effect is found in male subjects.
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Affiliation(s)
- Christina Pfannenberg
- Department of Diagnostic and Interventional Radiology, University of Tübingen, Tübingen, Germany
| | - Matthias K. Werner
- Department of Diagnostic and Interventional Radiology, University of Tübingen, Tübingen, Germany
| | - Sabine Ripkens
- Department of Diagnostic and Interventional Radiology, University of Tübingen, Tübingen, Germany
| | - Irina Stef
- Department of Diagnostic and Interventional Radiology, University of Tübingen, Tübingen, Germany
| | - Annette Deckert
- Department of Diagnostic and Interventional Radiology, University of Tübingen, Tübingen, Germany
| | - Maria Schmadl
- Department of Diagnostic and Interventional Radiology, University of Tübingen, Tübingen, Germany
| | | | - Hans-Ulrich Häring
- Department of Internal Medicine, Division of Endocrinology, Diabetology, Vascular Medicine, Nephrology and Clinical Chemistry, University of Tübingen, Tübingen, Germany
| | - Claus D. Claussen
- Department of Diagnostic and Interventional Radiology, University of Tübingen, Tübingen, Germany
| | - Norbert Stefan
- Department of Internal Medicine, Division of Endocrinology, Diabetology, Vascular Medicine, Nephrology and Clinical Chemistry, University of Tübingen, Tübingen, Germany
- Corresponding author: Norbert Stefan,
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Zukotynski KA, Fahey FH, Laffin S, Davis R, Treves ST, Grant FD, Drubach LA. Seasonal variation in the effect of constant ambient temperature of 24 degrees C in reducing FDG uptake by brown adipose tissue in children. Eur J Nucl Med Mol Imaging 2010; 37:1854-60. [PMID: 20505932 DOI: 10.1007/s00259-010-1485-2] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2010] [Accepted: 04/18/2010] [Indexed: 11/28/2022]
Abstract
PURPOSE It has been shown that warming patients prior to and during (18)F-FDG uptake by controlling the room temperature can decrease uptake by brown adipose tissue (BAT). The aim of this study is to determine if this effect is subject to seasonal variation. METHODS A retrospective review was conducted of all patients referred for whole-body (18)F-FDG PET between December 2006 and December 2008. After December 2007, all patients were kept in the PET injection room at a constant 24 degrees C for 30 min before and until 1 h following FDG administration. Patients over 22 years of age and those who received pre-medication known to reduce FDG uptake by BAT were excluded. One hundred and three patients were warmed to 24 degrees C prior to scanning. The number of patients showing uptake by BAT in this group was compared to a control group of 99 patients who underwent PET prior to December 2007 when the injection room temperature was 21 degrees C. RESULTS Uptake by BAT occurred in 9% of studies performed after patient warming (24 degrees C), compared to 27% of studies performed on the control group (21 degrees C) (p < 0.00001). The effect of warming on decreasing FDG accumulation in BAT was statistically significant in the winter (p < 0.005) and summer (p < 0.001). However, in the spring and autumn, though the effect of warming on decreasing FDG accumulation in BAT was evident, it was not statistically significant (p > 0.05). CONCLUSION Maintaining room temperature at a constant 24 degrees C for 30 min prior to and 1 h after IV tracer administration significantly decreases FDG uptake by BAT in children. This effect is greatest in the summer and winter.
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Affiliation(s)
- Katherine A Zukotynski
- Department of Imaging, Division of Nuclear Medicine, Dana-Farber Cancer Institute, Harvard Medical School, 44 Binney Street, Boston, MA 02115, USA.
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Giacobino JP, Casteilla L. Thermogenic brown adipocytes as new targets for the treatment of obesity in humans. ACTA ACUST UNITED AC 2010. [DOI: 10.2217/clp.10.5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
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Petrovic N, Walden TB, Shabalina IG, Timmons JA, Cannon B, Nedergaard J. Chronic peroxisome proliferator-activated receptor gamma (PPARgamma) activation of epididymally derived white adipocyte cultures reveals a population of thermogenically competent, UCP1-containing adipocytes molecularly distinct from classic brown adipocytes. J Biol Chem 2009; 285:7153-64. [PMID: 20028987 DOI: 10.1074/jbc.m109.053942] [Citation(s) in RCA: 1039] [Impact Index Per Article: 64.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023] Open
Abstract
The recent insight that brown adipocytes and muscle cells share a common origin and in this respect are distinct from white adipocytes has spurred questions concerning the origin and molecular characteristics of the UCP1-expressing cells observed in classic white adipose tissue depots under certain physiological or pharmacological conditions. Examining precursors from the purest white adipose tissue depot (epididymal), we report here that chronic treatment with the peroxisome proliferator-activated receptor gamma agonist rosiglitazone promotes not only the expression of PGC-1alpha and mitochondriogenesis in these cells but also a norepinephrine-augmentable UCP1 gene expression in a significant subset of the cells, providing these cells with a genuine thermogenic capacity. However, although functional thermogenic genes are expressed, the cells are devoid of transcripts for the novel transcription factors now associated with classic brown adipocytes (Zic1, Lhx8, Meox2, and characteristically PRDM16) or for myocyte-associated genes (myogenin and myomirs (muscle-specific microRNAs)) and retain white fat characteristics such as Hoxc9 expression. Co-culture experiments verify that the UCP1-expressing cells are not proliferating classic brown adipocytes (adipomyocytes), and these cells therefore constitute a subset of adipocytes ("brite" adipocytes) with a developmental origin and molecular characteristics distinguishing them as a separate class of cells.
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Affiliation(s)
- Natasa Petrovic
- Wenner-Gren Institute, The Arrhenius Laboratories, Stockholm University, SE-106 91 Stockholm, Sweden.
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40
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van Marken Lichtenbelt WD, Vanhommerig JW, Smulders NM, Drossaerts JMAFL, Kemerink GJ, Bouvy ND, Schrauwen P, Teule GJJ. Cold-activated brown adipose tissue in healthy men. N Engl J Med 2009; 360:1500-8. [PMID: 19357405 DOI: 10.1056/nejmoa0808718] [Citation(s) in RCA: 2623] [Impact Index Per Article: 163.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
BACKGROUND Studies in animals indicate that brown adipose tissue is important in the regulation of body weight, and it is possible that individual variation in adaptive thermogenesis can be attributed to variations in the amount or activity of brown adipose tissue. Until recently, the presence of brown adipose tissue was thought to be relevant only in small mammals and infants, with negligible physiologic relevance in adult humans. We performed a systematic examination of the presence, distribution, and activity of brown adipose tissue in lean and obese men during exposure to cold temperature. Brown-adipose-tissue activity was studied in relation to body composition and energy metabolism. METHODS We studied 24 healthy men--10 who were lean (body-mass index [BMI] [the weight in kilograms divided by the square of the height in meters], < 25) and 14 who were overweight or obese (BMI, > or = 25)--under thermoneutral conditions (22 degrees C) and during mild cold exposure (16 degrees C). Putative brown-adipose-tissue activity was determined with the use of integrated (18)F-fluorodeoxyglucose positron-emission tomography and computed tomography. Body composition and energy expenditure were measured with the use of dual-energy x-ray absorptiometry and indirect calorimetry. RESULTS Brown-adipose-tissue activity was observed in 23 of the 24 subjects (96%) during cold exposure but not under thermoneutral conditions. The activity was significantly lower in the overweight or obese subjects than in the lean subjects (P=0.007). BMI and percentage of body fat both had significant negative correlations with brown adipose tissue, whereas resting metabolic rate had a significant positive correlation. CONCLUSIONS The percentage of young men with brown adipose tissue is high, but its activity is reduced in men who are overweight or obese. Brown adipose tissue may be metabolically important in men, and the fact that it is reduced yet present in most overweight or obese subjects may make it a target for the treatment of obesity.
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Frühbeck G, Sesma P, Burrell MA. PRDM16: the interconvertible adipo-myocyte switch. Trends Cell Biol 2009; 19:141-6. [PMID: 19285866 DOI: 10.1016/j.tcb.2009.01.007] [Citation(s) in RCA: 52] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2008] [Revised: 01/12/2009] [Accepted: 01/13/2009] [Indexed: 12/16/2022]
Abstract
Both brown and white adipocytes were previously considered to be derived from the same precursor cell, despite being histologically and functionally different. However, a recent study shows that overexpression of the transcriptional regulator positive regulatory domain containing 16 (PRDM16) determines the development of brown adipocytes from a progenitor that expresses myoblast markers. Surprisingly, loss of PRDM16 from these precursors does not lead to white adipocyte differentiation. Thus, PRDM16 controls a bidirectional cell fate switch between skeletal myoblasts and brown adipocytes.
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Affiliation(s)
- Gema Frühbeck
- Department of Endocrinology and Metabolic Research Laboratory, Clínica Universitaria, University of Navarra, Pamplona, Spain.
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42
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Wijers SLJ, Saris WHM, van Marken Lichtenbelt WD. Recent advances in adaptive thermogenesis: potential implications for the treatment of obesity. Obes Rev 2009; 10:218-26. [PMID: 19021870 DOI: 10.1111/j.1467-789x.2008.00538.x] [Citation(s) in RCA: 78] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Large inter-individual differences in cold-induced (non-shivering) and diet-induced adaptive thermogenesis exist in animals and humans. These differences in energy expenditure can have a large impact on long-term energy balance and thus body weight (when other factors remain stable). Therefore, the level of adaptive thermogenesis might relate to the susceptibility to obesity; efforts to increase adaptive thermogenesis might be used to treat obesity. In small mammals, the main process involved is mitochondrial uncoupling in brown adipose tissue (BAT), which is regulated by the sympathetic nervous system. For a long time, it was assumed that mitochondrial uncoupling is not a major physiological contributor to adaptive thermogenesis in adult humans. However, several studies conducted in recent years suggest that mitochondrial uncoupling in BAT and skeletal muscle tissue in adult humans can be physiologically significant. Other mechanisms besides mitochondrial uncoupling that might be involved are futile calcium cycling, protein turnover and substrate cycling. In conjunction with recent advances on signal transduction studies, this knowledge makes manipulation of adaptive thermogenesis a more realistic option and thus a pharmacologically interesting target to treat obesity.
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Affiliation(s)
- S L J Wijers
- Department of Human Biology, Nutrition and Toxicology Research Institute Maastricht, Maastricht University, Maastricht, The Netherlands.
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Zukotynski KA, Fahey FH, Laffin S, Davis R, Treves ST, Grant FD, Drubach LA. Constant ambient temperature of 24 degrees C significantly reduces FDG uptake by brown adipose tissue in children scanned during the winter. Eur J Nucl Med Mol Imaging 2008; 36:602-6. [PMID: 19037639 DOI: 10.1007/s00259-008-0983-y] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2008] [Accepted: 10/03/2008] [Indexed: 11/25/2022]
Abstract
PURPOSE The aim of this study was to determine if warming patients prior to and during (18)F-FDG uptake by controlling the room temperature could decrease uptake by brown adipose tissue (BAT). METHODS A group of 40 children underwent (18)F-FDG PET after being kept in the injection room at a constant temperature of 24 degrees C for half an hour before and 1 hour after intravenous tracer administration. The rate of uptake by BAT in this group was compared to the uptake in a control group of 45 patients who underwent PET when the injection room temperature was 21 degrees C. RESULTS Uptake by BAT occurred in 5% of studies in the temperature-controlled room compared to 31% of studies performed when the injection room temperature was 21 degrees C (p<0.002). CONCLUSION Maintaining room temperature at a constant 24 degrees C, half an hour prior to and during the period of FDG uptake significantly decreases accumulation of FDG in BAT in children.
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Affiliation(s)
- Katherine A Zukotynski
- Department of Radiology, Division of Nuclear Medicine/PET, Children's Hospital Boston, Harvard Medical School, Boston, MA 02115, USA
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