Genetics of Development and Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA.
Diabetes. 2012 Oct;61(10):2414-23. doi: 10.2337/db11-0915. Epub 2012 May 17.
Lipodystrophies are characterized by a loss of white adipose tissue, which causes ectopic lipid deposition, peripheral insulin resistance, reduced adipokine levels, and increased food intake (hyperphagia). The growth factor myostatin (MSTN) negatively regulates skeletal muscle growth, and mice with MSTN inhibition have reduced adiposity and improved insulin sensitivity. MSTN inhibition may therefore be efficacious in ameliorating diabetes. To test this hypothesis, we inhibited MSTN signaling in a diabetic model of generalized lipodystrophy to analyze its effects on glucose metabolism separate from effects on adipose mass. A-ZIP/F1 lipodystrophic mice were crossed to mice expressing a dominant-negative MSTN receptor (activin receptor type IIB) in muscle. MSTN inhibition in A-ZIP/F1 mice reduced blood glucose, serum insulin, triglyceride levels, and the rate of triglyceride synthesis, and improved insulin sensitivity. Unexpectedly, hyperphagia was normalized by MSTN inhibition in muscle. Blood glucose and hyperphagia were reduced in double mutants independent of the adipokine leptin. These results show that the effect of MSTN inhibition on insulin sensitivity is not secondary to an effect on adipose mass and that MSTN inhibition may be an effective treatment for diabetes. These results further suggest that muscle may play a heretofore unappreciated role in regulating food intake.
脂肪营养不良的特征是白色脂肪组织的丧失，这会导致异位脂质沉积、外周胰岛素抵抗、降低脂肪因子水平和增加食物摄入（贪食症）。生长因子肌肉生长抑制素 (MSTN) 负调节骨骼肌生长，而 MSTN 抑制的小鼠脂肪减少，胰岛素敏感性提高。因此，MSTN 抑制可能在改善糖尿病方面有效。为了验证这一假设，我们在全身性脂肪营养不良的糖尿病模型中抑制 MSTN 信号转导，以分析其对葡萄糖代谢的影响，而不考虑对脂肪质量的影响。A-ZIP/F1 脂肪营养不良小鼠与肌肉中表达显性负性 MSTN 受体（激活素受体 IIB）的小鼠杂交。A-ZIP/F1 小鼠中 MSTN 的抑制降低了血糖、血清胰岛素、甘油三酯水平和甘油三酯合成率，并改善了胰岛素敏感性。出乎意料的是，肌肉中 MSTN 的抑制使贪食症正常化。双突变体中的血糖和贪食症降低与脂肪因子瘦素无关。这些结果表明，MSTN 抑制对胰岛素敏感性的影响不是继发于对脂肪质量的影响，并且 MSTN 抑制可能是治疗糖尿病的有效方法。这些结果进一步表明，肌肉可能在调节食物摄入方面发挥了迄今为止尚未被认识到的作用。
