Recent identification of active brown fat in adult humans has stimulated research into the role of brown adipocytes in energy homeostasis. Brown fat exists in hibernating animals, rodents and human infants; however, until recently, it was considered irrelevant in adult humans. Recent findings that metabolically active brown fat exists in humans (1 – 4) have stimulated research into the therapeutic potential of brown fat to combat metabolic diseases (5, 6). Brown fat shares its developmental origin with muscle (7, 8), and the transcription factor PRDM16 determines the fate of Myf5+-precursor cells toward brown fat lineage (9, 10). As reviewed recently (11), brown adipocytes are also found interspersed within the white adipose tissue in response to chemical or hormonal stimulation, environmental changes, cold exposure and various genetic manipulations (12 – 14). Transdifferentiation is considered a potential mechanism that leads to brown fat induction (14) along with the possibility that multilocular fat cells may derive from a precursor cell that gives rise to more typical brown adipocytes (15). Recently, a muscle-derived hormone, irisin (16), brain-derived neurotrophic factor (17) and neuropeptide Y (18) have been implicated in promoting brown fat features in white fat.
We recently elucidated the importance of TGF-β signaling in the appearance of brown adipocytes within the white adipose tissue and its implication in glucose and energy homeostasis (19, 20). White fat from Smad3−∕− mice showed enrichment of genes that represent brown fat and mitochondrial and skeletal muscle biology (20). Our results using the anti-TGF-β antibody, combined with the findings of elevated TGF-β levels in obese subjects, strongly suggest that targeting the TGF-β pathway has potential utility in treatment of human obesity and diabetes. Elevated TGF-β levels are common in many disease conditions, and there is a push to develop TGF-β antagonist therapies (21). Anti-TGF-β regimens are being clinically evaluated for human diseases, such as cancer, fibrosis, scarring and diabetic nephropathy, in which elevated TGF-β levels are implicated (22 – 24). However, the TGF-β family proteins engage specific receptors in virtually every cell type, making neutralization of the pathway a challenging proposition (25). In addition to the canonical TGF-β/Smad signaling node, cross-talk with other signaling networks is a common feature of TGF-β signals (26), and inhibiting the TGF-β pathway at the ligand-receptor level may damage essential signaling networks that cross-talk with TGF-β.
Although we propose that modulation of TGF-β/Smad3 signaling activates a brown adipocyte-like phenotype in rodent white fat, its implication in similarly browning human white fat is unclear. Further understanding of the mechanistic details of TGF-β/Smad3 signaling as it pertains to brown adipocyte induction in white fat is needed to translate the research observations to therapeutic benefit. Several questions remain to be answered. Does TGF-β signaling affect the transdifferentiation potential of white fat to brown fat or the precursor cell dynamics during brown fat induction? Which white fat depots are the primary targets of TGF-β signals? How do the TGF-β signals harmonize with other signaling pathways that also induce browning of white fat? Answers to these questions will allow greater mechanistic insights into TGF-β’s role in browning of white fat while potentially yielding novel targets for the development of therapeutics to counter obesity and diabetes.
We apologize to authors whose contribution to this field of research have not been cited or have been cited only indirectly due to space limitations. Support for this work came from funds from the National Institute of Diabetes and Digestive and Kidney Diseases at the National Institutes of Health intramural program.
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