Transforming Growth Factor - Beta Superfamily Signaling in Diabetes and Obesity

血糖和能量平衡失衡是肥胖和糖尿病全球流行的核心。我们发现了转化生长因子-β/Smad3信号通路在调节血糖和能量平衡方面的重要作用。Smad3基因缺陷的小鼠可以预防饮食引起的肥胖和糖尿病。有趣的是，代谢保护伴随着缺乏SMAD3的白色脂肪组织获得棕色脂肪/骨骼肌的生物能量和基因表达谱。Smad3基因缺陷的脂肪细胞表现出明显的线粒体生物合成增加，相应地基础呼吸增加，Smad3是PGC-1α表达的抑制因子。在啮齿动物和人类中，我们观察到转化生长因子-β1水平与肥胖显著相关。此外，全身阻断转化生长因子-β信号可以保护小鼠免受肥胖、糖尿病和肝脏脂肪变性的影响。我们最近已经证明，转化生长因子-β在运动中调节肌动因子虹膜蛋白。综上所述，这些结果表明，转化生长因子-β信号调节糖耐量和能量平衡，提示调节转化生长因子-β活性可能是肥胖和糖尿病的有效治疗策略。我们继续研究上述观察的机制基础，因为它们与转化生长因子-β家族信号在糖尿病和肥胖症发病机制中的作用有关。我们最近发现了转化生长因子-β受体信号在调节肝脏糖异生和米黄色脂肪生成中的作用。

Imbalances in glucose and energy homeostasis are at the core of the worldwide epidemic of obesity and diabetes. We uncovered an important role of the TGF-beta/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-deficient white adipose tissue acquiring the bioenergetic and gene expression profile of brown fat/skeletal muscle. Smad3-deficient adipocytes demonstrate a marked increase in mitochondrial biogenesis, with a corresponding increase in basal respiration, and Smad3 acts as a repressor of PGC-1alpha expression. We observe significant correlation between TGF-beta1 levels and adiposity in rodents and humans. Further, systemic blockade of TGF-beta signaling protects mice from obesity, diabetes, and hepatic steatosis. We have recently shown that TGF-beta regulates the myokine irisin in the context of exercise. Together, these results demonstrate that TGF-beta signaling regulates glucose tolerance and energy homeostasis and suggest that modulation of TGF-beta activity might be an effective treatment strategy for obesity and diabetes. We continue to examine the mechanistic underpinnings of the above mentioned observations as they related to the role of TGF-beta family signaling in diabetes and obesity pathogenesis. We have reecntly uncovered a role for TGF-beta receptor signaling in regulation of hepatic gluconeogenesis and beige adipogenesis.