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.
Copyright © 2011 Elsevier Inc. All rights reserved.
Publication types
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Research Support, N.I.H., Intramural
MeSH terms
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Adipose Tissue, Brown / metabolism
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Adipose Tissue, Brown / physiology
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Adipose Tissue, White / metabolism
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Adipose Tissue, White / physiology
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Animals
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Antibodies / immunology
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism
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Diabetes Mellitus / metabolism
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Diabetes Mellitus / prevention & control*
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Energy Metabolism
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Glucose Tolerance Test
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Mice
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Mice, Knockout
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Mice, Obese
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Mitochondria / genetics
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Mitochondria / metabolism
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Mitochondria / physiology
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Obesity / metabolism
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Obesity / prevention & control*
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Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
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Signal Transduction*
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Smad3 Protein / deficiency
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Smad3 Protein / genetics
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Smad3 Protein / metabolism*
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Trans-Activators / metabolism
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Transcription Factors / genetics
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Transcription Factors / metabolism
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Transforming Growth Factor beta / antagonists & inhibitors
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Transforming Growth Factor beta / immunology
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Transforming Growth Factor beta / metabolism*
Substances
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Antibodies
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DNA-Binding Proteins
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Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
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Ppargc1a protein, mouse
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Prdm16 protein, mouse
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Smad3 Protein
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Trans-Activators
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Transcription Factors
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Transforming Growth Factor beta