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American Journal of Physical... Feb 2015The discovery that metabolically active brown fat is present in humans throughout ontogeny raises new questions about the interactions between thermoregulatory,... (Review)
Review
The discovery that metabolically active brown fat is present in humans throughout ontogeny raises new questions about the interactions between thermoregulatory, metabolic, and skeletal homeostasis. Brown adipose tissue (BAT) is distinct from white adipose tissue (WAT) for its ability to burn, rather than store, energy. BAT uniquely expresses uncoupling protein-1 (abbreviated as UCP1), which diverts the energy produced by cellular respiration to generate heat. While BAT is found in small mammals, hibernators, and newborns, this depot was thought to regress in humans during early postnatal life. Recent studies revealed that human BAT remains metabolically active throughout childhood and even in adulthood, particularly in response to cold exposure. In addition to the constitutive BAT depots present at birth, BAT cells can be induced within WAT depots under specific metabolic and climatic conditions. These cells, called inducible brown fat, "brite," or beige fat, are currently the focus of intense investigation as a possible treatment for obesity. Inducible brown fat is associated with higher bone mineral density, suggesting that brown fat interacts with bone growth in previously unrecognized ways. Finally, BAT may have contributed to climatic adaptation in hominins. Here, I review current findings on the role of BAT in thermoregulation, bone growth, and metabolism, describe the potential role of BAT in moderating the obesity epidemic, and outline possible functions of BAT across hominin evolutionary history.
Topics: Adipose Tissue, Brown; Adipose Tissue, White; Adolescent; Adult; Animals; Anthropology, Physical; Bone and Bones; Child; Female; Humans; Infant, Newborn; Male; Obesity; Primates
PubMed: 25388370
DOI: 10.1002/ajpa.22661 -
Comprehensive Physiology Sep 2017Brown and beige adipocytes arise from distinct developmental origins. Brown adipose tissue (BAT) develops embryonically from precursors that also give to skeletal... (Review)
Review
Brown and beige adipocytes arise from distinct developmental origins. Brown adipose tissue (BAT) develops embryonically from precursors that also give to skeletal muscle. Beige fat develops postnatally and is highly inducible. Beige fat recruitment is mediated by multiple mechanisms, including de novo beige adipogenesis and white-to-brown adipocyte transdifferentiaiton. Beige precursors reside around vasculatures, and proliferate and differentiate into beige adipocytes. PDGFRα+Ebf2+ precursors are restricted to beige lineage cells, while another PDGFRα+ subset gives rise to beige adipocytes, white adipocytes, or fibrogenic cells. White adipocytes can be reprogramed and transdifferentiated into beige adipocytes. Brown and beige adipocytes display many similar properties, including multilocular lipid droplets, dense mitochondria, and expression of UCP1. UCP1-mediated thermogenesis is a hallmark of brown/beige adipocytes, albeit UCP1-independent thermogenesis also occurs. Development, maintenance, and activation of BAT/beige fat are guided by genetic and epigenetic programs. Numerous transcriptional factors and coactivators act coordinately to promote BAT/beige fat thermogenesis. Epigenetic reprograming influences expression of brown/beige adipocyte-selective genes. BAT/beige fat is regulated by neuronal, hormonal, and immune mechanisms. Hypothalamic thermal circuits define the temperature setpoint that guides BAT/beige fat activity. Metabolic hormones, paracrine/autocrine factors, and various immune cells also play a critical role in regulating BAT/beige fat functions. BAT and beige fat defend temperature homeostasis, and regulate body weight and glucose and lipid metabolism. Obesity is associated with brown/beige fat deficiency, and reactivation of brown/beige fat provides metabolic health benefits in some patients. Pharmacological activation of BAT/beige fat may hold promise for combating metabolic diseases. © 2017 American Physiological Society. Compr Physiol 7:1281-1306, 2017.
Topics: Adipose Tissue, Beige; Adipose Tissue, Brown; Animals; Humans; Metabolic Diseases; Thermogenesis; Uncoupling Protein 1
PubMed: 28915325
DOI: 10.1002/cphy.c170001 -
Journal of Applied Physiology... Feb 2018With the recent rediscovery of brown fat in adult humans, our outlook on adipose tissue biology has undergone a paradigm shift. While we attempt to identify, recruit,... (Review)
Review
With the recent rediscovery of brown fat in adult humans, our outlook on adipose tissue biology has undergone a paradigm shift. While we attempt to identify, recruit, and activate classic brown fat stores in humans, identification of beige fat has also raised the possibility of browning our white fat stores. Whether such transformation of human white fat depots can be achieved to enhance the whole body oxidative potential remains to be seen. Evidence to date, however, largely points toward a major oxidative role only for classic brown fat depots, at least in rodents. White fat stores seem to provide the main fuel for sustaining thermogenesis via lipolysis. Interestingly, molecular markers consistent with both classic brown and beige fat identity can be observed in human supraclavicular depot, thereby complicating the discussion on beige fat in humans. Here, we review the recent advances made in our understanding of brown and beige fat in humans and mice. We further provide an overview of their plausible physiological relevance to whole body energy metabolism.
Topics: Adipose Tissue, Beige; Adipose Tissue, Brown; Animals; Bodily Secretions; Energy Metabolism; Humans; Phenotype; Thermogenesis
PubMed: 28302705
DOI: 10.1152/japplphysiol.00021.2017 -
Redox Biology Aug 2017Activation of brown adipose tissue (BAT) in adult humans increase glucose and fatty acid clearance as well as resting metabolic rate, whereas a prolonged elevation of... (Review)
Review
Activation of brown adipose tissue (BAT) in adult humans increase glucose and fatty acid clearance as well as resting metabolic rate, whereas a prolonged elevation of BAT activity improves insulin sensitivity. However, substantial reductions in body weight following BAT activation has not yet been shown in humans. This observation raise the possibility for feedback mechanisms in adult humans in terms of a brown fat-brain crosstalk, possibly mediated by batokines, factors produced by and secreted from brown fat. Batokines also seems to be involved in BAT recruitment by stimulating proliferation and differentiation of brown fat progenitors. Increasing human BAT capacity could thus include inducing brown fat biogenesis as well as identifying novel batokines. Another attractive approach would be to induce a brown fat phenotype, the so-called brite or beige fat, within the white fat depots. In adult humans, white fat tissue transformation into beige has been observed in patients with pheochromocytoma, a norepinephrine-producing tumor. Interestingly, human beige fat is predominantly induced in regions that were BAT during early childhood, possibly reflecting that a presence of human beige progenitors is depot specific and originating from BAT. In conclusion, to utilize the anti-obesity potential of human BAT focus should be directed towards identifying novel regulators of brown and beige fat progenitor cells, as well as feedback mechanisms of BAT activation. This would allow for identification of novel anti-obesity targets.
Topics: Adipose Tissue, Beige; Adipose Tissue, Brown; Energy Metabolism; Feedback, Physiological; Humans; Obesity
PubMed: 28431377
DOI: 10.1016/j.redox.2017.04.011 -
Diabetes Jul 2015The epidemic of obesity and type 2 diabetes has increased interest in pathways that affect energy balance in mammalian systems. Brown fat, in all of its dimensions, can... (Review)
Review
The epidemic of obesity and type 2 diabetes has increased interest in pathways that affect energy balance in mammalian systems. Brown fat, in all of its dimensions, can increase energy expenditure through the dissipation of chemical energy in the form of heat, using mitochondrial uncoupling and perhaps other pathways. We discuss here some of the thermodynamic and cellular aspects of recent progress in brown fat research. This includes studies of developmental lineages of UCP1(+) adipocytes, including the discovery of beige fat cells, a new thermogenic cell type. We also discuss the physiology and transcriptional control of brown and beige cells in rodents and the state of current knowledge about human brown fat.
Topics: Adipocytes; Adipose Tissue, Brown; Animals; Cold Temperature; DNA-Binding Proteins; Energy Metabolism; Humans; Ion Channels; Mitochondrial Proteins; Thermodynamics; Thermogenesis; Transcription Factors; Transcription, Genetic; Uncoupling Protein 1
PubMed: 26050670
DOI: 10.2337/db15-0318 -
Trends in Endocrinology and Metabolism:... Apr 2014Brown adipose tissue (BAT) dissipates energy as heat to maintain optimal thermogenesis and to contribute to energy expenditure in rodents and possibly humans. The... (Review)
Review
Brown adipose tissue (BAT) dissipates energy as heat to maintain optimal thermogenesis and to contribute to energy expenditure in rodents and possibly humans. The energetic processes executed by BAT require a readily-available fuel supply, which includes glucose and fatty acids (FAs). FAs become available by cellular uptake, de novo lipogenesis, and multilocular lipid droplets in brown adipocytes. BAT also possesses a great capacity for glucose uptake and metabolism, and an ability to regulate insulin sensitivity. These properties make BAT an appealing target for the treatment of obesity, diabetes, and other metabolic disorders. Recent research has provided a better understanding of the processes of fuel utilization carried out by brown adipocytes, which is the focus of the current review.
Topics: Adipose Tissue, Brown; Animals; Energy Metabolism; Glucose; Humans; Lipid Metabolism; Thermogenesis
PubMed: 24389130
DOI: 10.1016/j.tem.2013.12.004 -
Cell Metabolism Nov 2017We thought we knew how the heat-producing uncoupling protein 1 in brown adipose tissue was activated: by fatty acids released upon lipid droplet breakdown in the brown...
We thought we knew how the heat-producing uncoupling protein 1 in brown adipose tissue was activated: by fatty acids released upon lipid droplet breakdown in the brown adipocytes. However, two studies in this issue (Schreiber et al., 2017; Shin et al., 2017) imply that this classical model may not be valid: heat can be produced in brown fat without intracellular lipolysis.
Topics: Adipose Tissue, Brown; Ion Channels; Lipolysis; Mitochondrial Proteins; Myocardium; Thermogenesis; Uncoupling Protein 1
PubMed: 29117542
DOI: 10.1016/j.cmet.2017.10.012 -
International Journal of Molecular... Feb 2022Mitochondrial uncoupling protein 1 (UCP1) is the crucial mechanistic component of heat production in classical brown fat and the newly identified beige or brite fat.... (Review)
Review
Mitochondrial uncoupling protein 1 (UCP1) is the crucial mechanistic component of heat production in classical brown fat and the newly identified beige or brite fat. Thermogenesis inevitably comes at a high energetic cost and brown fat, ultimately, is an energy-wasting organ. A constrained strategy that minimizes brown fat activity unless obligate will have been favored during natural selection to safeguard metabolic thriftiness. Accordingly, UCP1 is constitutively inhibited and is inherently not leaky without activation. It follows that increasing brown adipocyte number or UCP1 abundance genetically or pharmacologically does not lead to an automatic increase in thermogenesis or subsequent metabolic consequences in the absence of a plausible route of concomitant activation. Despite its apparent obviousness, this tenet is frequently ignored. Consequently, incorrect conclusions are often drawn from increased BAT or brite/beige depot mass, e.g., predicting or causally linking beneficial metabolic effects. Here, we highlight the inherently inactive nature of UCP1, with a particular emphasis on the molecular brakes and releases of UCP1 activation under physiological conditions. These controls of UCP1 activity represent potential targets of therapeutic interventions to unlock constraints and efficiently harness the energy-expending potential of brown fat to prevent and treat obesity and associated metabolic disorders.
Topics: Adipose Tissue, Beige; Adipose Tissue, Brown; Animals; Energy Metabolism; Humans; Lipolysis; Thermogenesis; Uncoupling Protein 1
PubMed: 35269549
DOI: 10.3390/ijms23052406 -
Autophagy Mar 2023Brown adipose tissue (BAT) thermogenesis affects energy balance, and thereby it has the potential to induce weight loss and to prevent obesity. Here, we document a...
Brown adipose tissue (BAT) thermogenesis affects energy balance, and thereby it has the potential to induce weight loss and to prevent obesity. Here, we document a macroautophagic/autophagic-dependent mechanism of peroxisome proliferator-activated receptor gamma (PPARG) activity regulation that induces brown adipose differentiation and thermogenesis and that is mediated by TP53INP2. Disruption of TP53INP2-dependent autophagy reduced brown adipogenesis in cultured cells. specific- ablation in brown precursor cells or in adult mice decreased the expression of thermogenic and mature adipocyte genes in BAT. As a result, TP53INP2-deficient mice had reduced UCP1 content in BAT and impaired maximal thermogenic capacity, leading to lipid accumulation and to positive energy balance. Mechanistically, TP53INP2 stimulates PPARG activity and adipogenesis in brown adipose cells by promoting the autophagic degradation of NCOR1, a PPARG co-repressor. Moreover, the modulation of TP53INP2 expression in BAT and in human brown adipocytes suggests that this protein increases PPARG activity during metabolic activation of brown fat. In all, we have identified a novel molecular explanation for the contribution of autophagy to BAT energy metabolism that could facilitate the design of therapeutic strategies against obesity and its metabolic complications.
Topics: Mice; Humans; Animals; Adipose Tissue, Brown; PPAR gamma; Autophagy; Obesity; Thermogenesis; Nuclear Proteins; Nuclear Receptor Co-Repressor 1
PubMed: 35947488
DOI: 10.1080/15548627.2022.2111081 -
Discovery Medicine Mar 2011Caloric restriction is associated with a reduction in body weight and temperature, as well as a reduction in trabecular bone volume and paradoxically an increase in... (Review)
Review
Caloric restriction is associated with a reduction in body weight and temperature, as well as a reduction in trabecular bone volume and paradoxically an increase in adipocytes within the bone marrow. The nature of these adipocytes is uncertain, although there is emerging evidence of a direct relationship between bone remodeling and brown adipocytes. For example, in heterotrophic ossification, brown adipocytes set up a hypoxic gradient that leads to vascular invasion, chondrocyte differentiation, and subsequent bone formation. Additionally, deletion of retinoblastoma protein in an osteosarcoma model leads to increased hibernoma (brown fat tumor). Brown adipose tissue (BAT) becomes senescent with age at a time when thermoregulation is altered, bone loss becomes apparent, and sympathetic activity increases. Interestingly, heart rate is an unexpected but good predictor of fracture risk in elderly individuals, pointing to a key role for the sympathetic nervous system in senile osteoporosis. Hence the possibility exists that BAT could play an indirect role in age-related bone loss. However, evidence of an indirect effect from thermogenic dysfunction on bone loss is currently limited. Here, we present current evidence for a relationship between brown adipose tissue and bone as well as provide novel insights into the effects of thermoregulation on bone mineral density.
Topics: Adipose Tissue, Brown; Animals; Body Temperature Regulation; Bone and Bones; Homeostasis; Humans
PubMed: 21447277
DOI: No ID Found