White adipocytes serve as lipid reservoirs, whereas brown adipocytes are rich in mitochondria and catabolize lipids through a process involving the mitochondrial protein UCP-1, which uncouples fatty acid oxidation from ATP production to generate heat. White adipocytes can be induced in vitro to express a subset of brown fat–specific genes, an effect that could prove therapeutically useful in treating metabolic diseases such as obesity and diabetes. Yadav et al. examined the role of transforming growth factor–β (TGF-β) and its transcriptional effector Smad3 in metabolic regulation. Compared with wild-type mice, Smad3–/– mice showed enhanced basal insulin sensitivity and increased insulin signaling and glucose uptake in white adipose tissue. They also gained less weight, showed better glucose tolerance and insulin sensitivity, and were protected from hepatic steatosis when fed a high-fat diet. Furthermore, Smad3–/– mice had reduced fat mass; smaller adipocytes; and lower circulating concentrations of triglyceride, white adipose tissue-derived hormones (leptin and resistin), and inflammatory cytokines. Smad3–/– white adipocytes had features reminiscent of brown adipocytes, such as the presence of UCP-1 and mRNAs encoding markers of brown adipogenesis. The production of heat by brown fat is important in thermoregulation, and Smad3–/– mice had higher basal body temperatures, could maintain a higher body temperature in the cold, and showed increased fatty acid oxidation. White adipocytes from Smad3–/– mice had higher numbers of mitochondria and, accordingly, showed higher mitochondrial activity, basal respiration rates, and oxygen consumption. In 3T3-L1 preadipocytes, Smad3 occupied the promoter of the gene encoding PGC-1α (a transcriptional coactivator that promotes mitochondrial biogenesis), and TGF-β treatment reduced the activity of a PGC-1α luciferase reporter in a Smad3-dependent fashion. Higher circulating TGF-β concentrations in humans correlated with greater adiposity, fasting insulin concentrations, and insulin resistance. TGF-β concentrations and phosphorylation of Smad3 in white adipose tissue were higher in two mouse models of obesity and diabetes, Lepob/ob mice and mice fed a high-fat diet. Treatment of Lepob/ob mice and mice on a high-fat diet with an antibody directed against TGF-β (1D11) reduced phosphorylation of Smad3 in white adipose tissue, decreased weight gain, improved glucose and insulin tolerance, and improved hepatic steatosis. Thus, suppression of TGF-β and Smad3 signaling causes white fat to adopt properties characteristic of brown fat and may be a viable strategy for treating metabolic diseases such as obesity and diabetes. The authors note that a related version of the TGF-β antibody 1D11 is under evaluation in clinical trials.
H. Yadav, C. Quijano, A. K. Kamaraju, O. Gavrilova, R. Malek, W. Chen, P. Zerfas, D. Zhigang, E. C. Wright, C. Stuelten, P. Sun, S. Lonning, M. Skarulis, A. E. Sumner, T. Finkel, S. G. Rane, Protection from obesity and diabetes by blockade of TGF-β/Smad3 signaling. Cell Metab. 14, 67–79 (2011). [PubMed]