TGF‐β/Smad3 signaling inhibition protects from obesity and diabetes through modulation of adipocyte biology

Abstract

Epidemic increase of obesity and diabetes drives to develop better understanding of pathways that promote obesity and diabetes and that might unravel novel therapeutic targets against obesity and diabetes. Transforming Growth Factor beta (TGFβ) signals regulate diverse cellular processes including proliferation, differentiation and apoptosis. Surprisingly, to‐date the role of TGFβ signaling in diabetes and obesity is obscure. We found that the TGFβ/Smad3 signaling pathway plays an important role in regulating glucose and energy homeostasis. Smad3 deletion in mice protects from diet‐induced obesity and diabetes. Interestingly, these effects were associated with increased brown like phenotype in Smad3−/− white adipose tissue (WAT) that is characterized by UCP1 positive cells and acquiring brown fat/skeletal muscle gene expression profile. In addition, Smad3−/− adipocytes demonstrated increased energy metabolic function and mitochondrial biogenesis. TGFβ has shown Smad3 dependent effects on PGC1α promoter activity and Smad3 acts as a repressor of PGC‐1α expression. Circulating TGFβ1 levels significantly correlated with adiposity in rodents and humans. Further, injecting anti‐TGFβ antibody protected mice from obesity, diabetes and hepatic steatosis. These results strongly suggest that blockade of TGFβ/Smad3 signaling strategy can be an effective therapy against obesity and diabetes.