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      Nature's fat-burning machine: brown adipose tissue in a hibernating mammal

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      The Journal of Experimental Biology
      The Company of Biologists

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          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. Summary: 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.

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          Transcriptional control of brown fat determination by PRDM16.

          Brown fat cells are specialized to dissipate energy and can counteract obesity; however, the transcriptional basis of their determination is largely unknown. We show here that the zinc-finger protein PRDM16 is highly enriched in brown fat cells compared to white fat cells. When expressed in white fat cell progenitors, PRDM16 activates a robust brown fat phenotype including induction of PGC-1alpha, UCP1, and type 2 deiodinase (Dio2) expression and a remarkable increase in uncoupled respiration. Transgenic expression of PRDM16 at physiological levels in white fat depots stimulates the formation of brown fat cells. Depletion of PRDM16 through shRNA expression in brown fat cells causes a near total loss of the brown characteristics. PRDM16 activates brown fat cell identity at least in part by simultaneously activating PGC-1alpha and PGC-1beta through direct protein binding. These data indicate that PRDM16 can control the determination of brown fat fate.
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            New role of bone morphogenetic protein 7 in brown adipogenesis and energy expenditure.

            Adipose tissue is central to the regulation of energy balance. Two functionally different types of fat are present in mammals: white adipose tissue, the primary site of triglyceride storage, and brown adipose tissue, which is specialized in energy expenditure and can counteract obesity. Factors that specify the developmental fate and function of white and brown adipose tissue remain poorly understood. Here we demonstrate that whereas some members of the family of bone morphogenetic proteins (BMPs) support white adipocyte differentiation, BMP7 singularly promotes differentiation of brown preadipocytes even in the absence of the normally required hormonal induction cocktail. BMP7 activates a full program of brown adipogenesis including induction of early regulators of brown fat fate PRDM16 (PR-domain-containing 16; ref. 4) and PGC-1alpha (peroxisome proliferator-activated receptor-gamma (PPARgamma) coactivator-1alpha; ref. 5), increased expression of the brown-fat-defining marker uncoupling protein 1 (UCP1) and adipogenic transcription factors PPARgamma and CCAAT/enhancer-binding proteins (C/EBPs), and induction of mitochondrial biogenesis via p38 mitogen-activated protein (MAP) kinase-(also known as Mapk14) and PGC-1-dependent pathways. Moreover, BMP7 triggers commitment of mesenchymal progenitor cells to a brown adipocyte lineage, and implantation of these cells into nude mice results in development of adipose tissue containing mostly brown adipocytes. Bmp7 knockout embryos show a marked paucity of brown fat and an almost complete absence of UCP1. Adenoviral-mediated expression of BMP7 in mice results in a significant increase in brown, but not white, fat mass and leads to an increase in energy expenditure and a reduction in weight gain. These data reveal an important role of BMP7 in promoting brown adipocyte differentiation and thermogenesis in vivo and in vitro, and provide a potential new therapeutic approach for the treatment of obesity.
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              Comparative studies of gene expression and the evolution of gene regulation.

              The hypothesis that differences in gene regulation have an important role in speciation and adaptation is more than 40 years old. With the advent of new sequencing technologies, we are able to characterize and study gene expression levels and associated regulatory mechanisms in a large number of individuals and species at an unprecedented resolution and scale. We have thus gained new insights into the evolutionary pressures that shape gene expression levels and have developed an appreciation for the relative importance of evolutionary changes in different regulatory genetic and epigenetic mechanisms. The current challenge is to link gene regulatory changes to adaptive evolution of complex phenotypes. Here we mainly focus on comparative studies in primates and how they are complemented by studies in model organisms.
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                Author and article information

                Journal
                The Journal of Experimental Biology
                J Exp Biol
                The Company of Biologists
                0022-0949
                1477-9145
                March 07 2018
                March 07 2018
                March 07 2018
                March 07 2018
                : 221
                : Suppl 1
                : jeb162586
                Article
                10.1242/jeb.162586
                6919643
                29514878
                e50812dd-2b2e-452b-a58b-53628c286164
                © 2018

                http://www.biologists.com/user-licence-1-1

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