Protection from obesity and diabetes by blockade of TGF-β/Smad3 signaling.
Cell Metab, 2011/7/06;14(1):67-79.
Yadav H[1], Quijano C, Kamaraju AK, Gavrilova O, Malek R, Chen W, Zerfas P, Zhigang D, Wright EC, Stuelten C, Sun P, Lonning S, Skarulis M, Sumner AE, Finkel T, Rane SG
Affiliations
PMID: 21723505DOI: 10.1016/j.cmet.2011.04.013
Impact factor: 31.373
Abstract
Imbalances in glucose and energy homeostasis are at the core of the worldwide epidemic of obesity and diabetes. Here, we illustrate an important role of the TGF-β/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(-)(/-) white adipose tissue acquiring the bioenergetic and gene expression profile of brown fat/skeletal muscle. Smad3(-/-) adipocytes demonstrate a marked increase in mitochondrial biogenesis, with a corresponding increase in basal respiration, and Smad3 acts as a repressor of PGC-1α expression. We observe significant correlation between TGF-β1 levels and adiposity in rodents and humans. Further, systemic blockade of TGF-β signaling protects mice from obesity, diabetes, and hepatic steatosis. Together, these results demonstrate that TGF-β signaling regulates glucose tolerance and energy homeostasis and suggest that modulation of TGF-β activity might be an effective treatment strategy for obesity and diabetes.
MeSH terms
Adipose Tissue, Brown; Adipose Tissue, White; Animals; Antibodies; DNA-Binding Proteins; Diabetes Mellitus; Energy Metabolism; Glucose Tolerance Test; Mice; Mice, Knockout; Mice, Obese; Mitochondria; Obesity; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Signal Transduction; Smad3 Protein; Trans-Activators; Transcription Factors; Transforming Growth Factor beta
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