Protection from Obesity and Diabetes by Blockade of TGF-beta/Smad3 Signaling. Imbalances in glucose and energy homeostasis are at the core of the worldwide epidemic of obesity and diabetes. We uncovered an important role of the TGF-beta/Smad3 signaling pathway in regulating glucose and energy homeostasis. Smad3-deficient mice are protected from diet-induced obesity and diabetes. Interestingly, the metabolic protection is accompanied by Smad3-deficient white adipose tissue acquiring the bioenergetic and gene expression profile of brown fat/skeletal muscle. Smad3-deficient adipocytes demonstrate a marked increase in mitochondrial biogenesis, with a corresponding increase in basal respiration, and Smad3 acts as a repressor of PGC-1alpha expression. We observe significant correlation between TGF-beta1 levels and adiposity in rodents and humans. Further, systemic blockade of TGF-beta signaling protects mice from obesity, diabetes, and hepatic steatosis. Together, these results demonstrate that TGF-beta signaling regulates glucose tolerance and energy homeostasis and suggest that modulation of TGF-beta activity might be an effective treatment strategy for obesity and diabetes. We continue to examine the mechanistic underpinnings of the above mentioned observations as they related to the role of TGF-beta family signaling in diabetes and obesity pathogenesis.

Project Start
Project End
Budget Start
Budget End
Support Year
6
Fiscal Year
2012
Total Cost
$346,331
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Yadav, Hariom; Rane, Sushil G (2015) Dietary fatty acids: Friends or foes? Obesity (Silver Spring) 23:1329
Tiano, Joseph P; Springer, Danielle A; Rane, Sushil G (2015) SMAD3 negatively regulates serum irisin and skeletal muscle FNDC5 and peroxisome proliferator-activated receptor γ coactivator 1-α (PGC-1α) during exercise. J Biol Chem 290:11431
Tiano, Joseph P; Springer, Danielle A; Rane, Sushil G (2015) SMAD3 negatively regulates serum irisin and skeletal muscle FNDC5 and peroxisome proliferator-activated receptor γ coactivator 1-α (PGC-1α) during exercise. J Biol Chem 290:7671-84
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Yadav, Hariom; Rane, Sushil G (2012) TGF-ýý/Smad3 Signaling Regulates Brown Adipocyte Induction in White Adipose Tissue. Front Endocrinol (Lausanne) 3:35
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