RESUMO
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-ß/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-ß1 levels and adiposity in rodents and humans. Further, systemic blockade of TGF-ß signaling protects mice from obesity, diabetes, and hepatic steatosis. Together, these results demonstrate that TGF-ß signaling regulates glucose tolerance and energy homeostasis and suggest that modulation of TGF-ß activity might be an effective treatment strategy for obesity and diabetes.
Assuntos
Diabetes Mellitus/prevenção & controle , Obesidade/prevenção & controle , Transdução de Sinais , Proteína Smad3/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Marrom/fisiologia , Tecido Adiposo Branco/metabolismo , Tecido Adiposo Branco/fisiologia , Animais , Anticorpos/imunologia , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Diabetes Mellitus/metabolismo , Metabolismo Energético , Teste de Tolerância a Glucose , Camundongos , Camundongos Knockout , Camundongos Obesos , Mitocôndrias/genética , Mitocôndrias/metabolismo , Mitocôndrias/fisiologia , Obesidade/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo , Proteína Smad3/deficiência , Proteína Smad3/genética , Transativadores/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Fator de Crescimento Transformador beta/antagonistas & inibidores , Fator de Crescimento Transformador beta/imunologiaRESUMO
Pancreatic islet beta-cell dysfunction is a signature feature of Type 2 diabetes pathogenesis. Consequently, knowledge of signals that regulate beta-cell function is of immense clinical relevance. Transforming growth factor (TGF)-beta signaling plays a critical role in pancreatic development although the role of this pathway in the adult pancreas is obscure. Here, we define an important role of the TGF-beta pathway in regulation of insulin gene transcription and beta-cell function. We identify insulin as a TGF-beta target gene and show that the TGF-beta signaling effector Smad3 occupies the insulin gene promoter and represses insulin gene transcription. In contrast, Smad3 small interfering RNAs relieve insulin transcriptional repression and enhance insulin levels. Transduction of adenoviral Smad3 into primary human and non-human primate islets suppresses insulin content, whereas, dominant-negative Smad3 enhances insulin levels. Consistent with this, Smad3-deficient mice exhibit moderate hyperinsulinemia and mild hypoglycemia. Moreover, Smad3 deficiency results in improved glucose tolerance and enhanced glucose-stimulated insulin secretion in vivo. In ex vivo perifusion assays, Smad3-deficient islets exhibit improved glucose-stimulated insulin release. Interestingly, Smad3-deficient islets harbor an activated insulin-receptor signaling pathway and TGF-beta signaling regulates expression of genes involved in beta-cell function. Together, these studies emphasize TGF-beta/Smad3 signaling as an important regulator of insulin gene transcription and beta-cell function and suggest that components of the TGF-beta signaling pathway may be dysregulated in diabetes.
