Centre for Hormone Research (S.W.Y., V.C.R., G.A.W., M.A.S.), Murdoch Childrens Research Institute and Royal Children's Hospital, and Department of Paediatrics (S.W.Y., V.C.R., G.A.W., M.A.S.), University of Melbourne, Melbourne, Victoria 3052, Australia; Department of Physiology (S.W.Y., B.A.H., I.J.C., M.A.S.), Monash University, Melbourne, Victoria 3800, Australia; and Institute of Sport, Exercise and Active Living and the College of Health and Biomedicine (G.K.M.), Victoria University, Melbourne, Victoria 3011, Australia.
Endocrinology. 2014 Jun;155(6):2133-43. doi: 10.1210/en.2013-2099. Epub 2014 Mar 21.
Leptin is produced from white adipose tissue and acts primarily to regulate energy balance. Obesity is associated with leptin resistance and increased circulating levels of leptin. Leptin has recently been shown to influence levels of IGF binding protein-2 (IGFBP-2), a protein that is reduced in obesity and type 2 diabetes. Overexpression of IGFBP-2 protects against obesity and type 2 diabetes. As such, IGFBP-2 signaling may represent a novel pathway by which leptin regulates insulin sensitivity. We sought to investigate how leptin regulates skeletal muscle IGFBP-2 levels and to assess the impact of this on insulin signaling and glucose uptake. In vitro experiments were undertaken in cultured human skeletal myotubes, whereas in vivo experiments assessed the effect of intracerebroventricular leptin on peripheral skeletal muscle IGFBP-2 expression and insulin sensitivity in sheep. Leptin directly increased IGFBP-2 mRNA and protein in human skeletal muscle through both signal transducer and activator of transcription-3 and phosphatidylinositol 3-kinase signaling, in parallel with enhanced insulin signaling. Silencing IGFBP-2 lowered leptin- and insulin-stimulated protein kinase B phosphorylation and glucose uptake. In in vivo experiments, intracerebroventricular leptin significantly increased hind-limb skeletal muscle IGFBP-2, an effect completely blocked by concurrent peripheral infusion of a β-adrenergic blocking agent. Sheep receiving central leptin showed improvements in glucose tolerance and circulating insulin levels after an iv glucose load. In summary, leptin regulates skeletal muscle IGFBP-2 by both direct peripheral and central (via the sympathetic nervous system) mechanisms, and these likely impact on peripheral insulin sensitivity and glucose metabolism.
瘦素由白色脂肪组织产生，主要作用是调节能量平衡。肥胖与瘦素抵抗和循环中瘦素水平升高有关。最近的研究表明，瘦素可以影响胰岛素样生长因子结合蛋白-2（IGFBP-2）的水平，IGFBP-2 在肥胖和 2 型糖尿病中减少。IGFBP-2 的过表达可以预防肥胖和 2 型糖尿病。因此，IGFBP-2 信号可能代表了瘦素调节胰岛素敏感性的新途径。我们试图研究瘦素如何调节骨骼肌 IGFBP-2 水平，并评估其对胰岛素信号和葡萄糖摄取的影响。体外实验在培养的人骨骼肌成肌细胞中进行，而体内实验则评估了脑室内给予瘦素对绵羊外周骨骼肌 IGFBP-2 表达和胰岛素敏感性的影响。瘦素通过信号转导和转录激活因子 3 和磷脂酰肌醇 3-激酶信号通路直接增加人骨骼肌中的 IGFBP-2 mRNA 和蛋白，同时增强胰岛素信号。沉默 IGFBP-2 降低了瘦素和胰岛素刺激的蛋白激酶 B 磷酸化和葡萄糖摄取。在体内实验中，脑室内给予瘦素显著增加了后肢骨骼肌 IGFBP-2，这一效应被外周给予β-肾上腺素能阻滞剂完全阻断。接受中枢瘦素的绵羊在静脉注射葡萄糖负荷后，葡萄糖耐量和循环胰岛素水平得到改善。总之，瘦素通过外周和中枢（通过交感神经系统）机制调节骨骼肌 IGFBP-2，这些机制可能影响外周胰岛素敏感性和葡萄糖代谢。
