Transforming Growth Factor - Beta Superfamily Signaling in Diabetes and Obesity

葡萄糖和能量稳态失衡是全球肥胖和糖尿病流行的核心原因。我们发现了tgf - β /Smad3信号通路在调节葡萄糖和能量稳态中的重要作用。缺乏smad3的小鼠可以避免饮食引起的肥胖和糖尿病。有趣的是，代谢保护伴随着smad3缺陷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。缺乏Smad3的脂肪细胞显示出线粒体生物发生的显著增加，相应的基础呼吸增加，Smad3作为pgc -1 α表达的抑制因子。我们观察到tgf - β 1水平与啮齿动物和人类肥胖之间存在显著相关性。此外，全身性阻断tgf - β信号可以保护小鼠免受肥胖、糖尿病和肝脂肪变性的影响。我们最近表明，tgf - β调节运动背景下的肌因子鸢尾素。总之，这些结果表明tgf - β信号调节葡萄糖耐量和能量稳态，并表明调节tgf - 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tgf - β家族信号在糖尿病和肥胖发病机制中的作用有关。我们最近发现了tgf - β受体信号在调节肝脏糖异生和米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.