Transforming Growth Factor - Beta Superfamily Signaling in Diabetes and Obesity

转化生长因子 - 糖尿病和肥胖症中的β超家族信号传导

• 批准号: 10004448
• 负责人: Sushil Rane
• 金额: $ 44.23万
• 依托单位: NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10004448
• 关键词: Adipocytes; Adipose tissue; Bioenergetics; Biogenesis; Brown Fat; Cells; Diabetes Mellitus; Diet; Exercise; Family; Fatty Liver; Gene Expression Profile; Glucose; Homeostasis; Human; Inhibin-beta Subunits; Metabolic; Metabolism; Mitochondria; Mus; Obese Mice; Obesity; Obesity Epidemic; Pathogenesis; Receptor Signaling; Regulation; Respiration; Rodent; Role; Sampling; Signal Pathway; Signal Transduction; Skeletal Muscle; TGFB1 gene; Transforming Growth Factor beta; Transforming Growth Factor beta Receptors; effective therapy; established cell line; glucose tolerance; hepatic gluconeogenesis; human disease; lipid biosynthesis; mouse model; treatment strategy; virtual

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.

葡萄糖和能量稳态的不平衡是肥胖和糖尿病在世界范围内流行的核心。我们发现了TGF-β/Smad 3信号通路在调节葡萄糖和能量稳态中的重要作用。Smad 3缺陷型小鼠免受饮食诱导的肥胖和糖尿病的影响。有趣的是，代谢保护伴随着Smad 3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。Smad 3缺陷型脂肪细胞表现出线粒体生物合成的显著增加，基础呼吸相应增加，Smad 3作为PGC-1 α表达的阻遏物。我们在啮齿动物和人类中观察到TGF-β 1水平与肥胖之间的显著相关性。此外，全身阻断TGF-β信号传导可保护小鼠免于肥胖、糖尿病和肝脂肪变性。我们最近发现，TGF-β调节肌细胞因子鸢尾素在运动的背景下。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TGF-β活性的调节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结果的机制基础，因为它们与TGF-β家族信号传导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受体信号传导在调节肝脏脂肪生成和米色脂肪生成中的作用。