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

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-?/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-1? expression. We observe significant correlation between TGF-?1 levels and adiposity in rodents and humans. Further, systemic blockade of TGF-? signaling protects mice from obesity, diabetes, and hepatic steatosis. Together, these results demonstrate that TGF-? signaling regulates glucose tolerance and energy homeostasis and suggest that modulation of TGF-? activity might be an effective treatment strategy for obesity and diabetes.

SUBMITTER: Yadav H

PROVIDER: S-EPMC3169298 | biostudies-literature | 2011 Jul

REPOSITORIES: biostudies-literature

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

Yadav Hariom H Quijano Celia C Kamaraju Anil K AK Gavrilova Oksana O Malek Rana R Chen Weiping W Zerfas Patricia P Zhigang Duan D Wright Elizabeth C EC Stuelten Christina C Sun Peter P Lonning Scott S Skarulis Monica M Sumner Anne E AE Finkel Toren T Rane Sushil G SG

Cell metabolism 20110701 1

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(-/-) adip ...[more]

PMID: 21723505

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Project description:Prevailing insulin resistance and the resultant hyperglycemia elicits a compensatory response from pancreatic islet beta cells (β-cells) that involves increases in β-cell function and β-cell mass. However, the sustained metabolic stress eventually leads to β-cell failure characterized by severe β-cell dysfunction and progressive loss of β-cell mass. Whereas, β-cell dysfunction is relatively well understood at the mechanistic level, the avenues leading to loss of β-cell mass are less clear with reduced proliferation, dedifferentiation, and apoptosis all potential mechanisms. Butler and colleagues documented increased β-cell apoptosis in pancreas from lean and obese human Type 2 diabetes (T2D) subjects, with no changes in rates of β-cell replication or neogenesis, strongly suggesting a role for apoptosis in β-cell failure. Here, we describe a permissive role for TGF-β/Smad3 in β-cell apoptosis. Human islets undergoing β-cell apoptosis release increased levels of TGF-β1 ligand and phosphorylation levels of TGF-β's chief transcription factor, Smad3, are increased in human T2D islets suggestive of an autocrine role for TGF-β/Smad3 signaling in β-cell apoptosis. Smad3 phosphorylation is similarly increased in diabetic mouse islets undergoing β-cell apoptosis. In mice, β-cell-specific activation of Smad3 promotes apoptosis and loss of β-cell mass in association with β-cell dysfunction, glucose intolerance, and diabetes. In contrast, inactive Smad3 protects from apoptosis and preserves β-cell mass while improving β-cell function and glucose tolerance. At the molecular level, Smad3 associates with Foxo1 to propagate TGF-β-dependent β-cell apoptosis. Indeed, genetic or pharmacologic inhibition of TGF-β/Smad3 signals or knocking down Foxo1 protects from β-cell apoptosis. These findings reveal the importance of TGF-β/Smad3 in promoting β-cell apoptosis and demonstrate the therapeutic potential of TGF-β/Smad3 antagonism to restore β-cell mass lost in diabetes.

Dataset Information

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

Publications

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

Similar Datasets

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