Protection from obesity and diabetes by blockade of TGF-β/Smad3 signaling

Cell Metab. 2011 Jul 6;14(1):67-79. doi: 10.1016/j.cmet.2011.04.013.


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.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Adipose Tissue, Brown / metabolism
  • Adipose Tissue, Brown / physiology
  • Adipose Tissue, White / metabolism
  • Adipose Tissue, White / physiology
  • Animals
  • Antibodies / immunology
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Diabetes Mellitus / metabolism
  • Diabetes Mellitus / prevention & control*
  • Energy Metabolism
  • Glucose Tolerance Test
  • Mice
  • Mice, Knockout
  • Mice, Obese
  • Mitochondria / genetics
  • Mitochondria / metabolism
  • Mitochondria / physiology
  • Obesity / metabolism
  • Obesity / prevention & control*
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Signal Transduction*
  • Smad3 Protein / deficiency
  • Smad3 Protein / genetics
  • Smad3 Protein / metabolism*
  • Trans-Activators / metabolism
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Transforming Growth Factor beta / antagonists & inhibitors
  • Transforming Growth Factor beta / immunology
  • Transforming Growth Factor beta / metabolism*


  • Antibodies
  • DNA-Binding Proteins
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Ppargc1a protein, mouse
  • Prdm16 protein, mouse
  • Smad3 Protein
  • Trans-Activators
  • Transcription Factors
  • Transforming Growth Factor beta

Associated data

  • GEO/GSE28598