Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 294 Taiyuan Road, Shanghai 200031, China.
Mol Cell Biol. 2010 Apr;30(7):1650-9. doi: 10.1128/MCB.01307-09. Epub 2010 Jan 19.
Leptin regulates energy homeostasis through central activation of multiple signaling pathways mediated by Ob-Rb, the long form of leptin receptor. Leptin resistance underlies the pathogenic development of obesity, which is closely associated with environmental factors. To further understand the physiological function of leptin signaling mechanisms, we generated a knock-in line of mice (Y985F) expressing a mutant Ob-Rb with a phenylalanine substitution for Tyr985, one of the three intracellular tyrosines that mediate leptin's signaling actions. Surprisingly, whereas young homozygous Y985F animals were slightly leaner, they exhibit adult-onset or diet-induced obesity. Importantly, both age-dependent and diet-induced deterioration of energy balance was paralleled with pronounced leptin resistance, which was largely attributable to attenuation of leptin-responsive hypothalamic STAT3 activation as well as prominently elevated expression of hypothalamic SOCS3, a key negative regulator of leptin signaling. Thus, these results unmask distinct binary roles for Try985-mediated signaling in energy metabolism, acting as an age/diet-dependent regulatory switch to counteract age-associated or diet-induced obesity.
瘦素通过 Ob-Rb（瘦素受体的长型）介导的多个信号通路的中枢激活来调节能量稳态。瘦素抵抗是肥胖发病的基础，它与环境因素密切相关。为了进一步了解瘦素信号机制的生理功能，我们生成了一种表达突变型 Ob-Rb 的敲入系小鼠（Y985F），该突变型 Ob-Rb 的 Tyr985 被苯丙氨酸取代，Tyr985 是介导瘦素信号作用的三个细胞内酪氨酸之一。令人惊讶的是，尽管年轻的纯合子 Y985F 动物稍显瘦小，但它们表现出成年发病或饮食诱导的肥胖。重要的是，年龄依赖性和饮食诱导的能量平衡恶化与明显的瘦素抵抗平行，这主要归因于瘦素反应性下丘脑 STAT3 激活的减弱以及下丘脑 SOCS3 的显著升高，SOCS3 是瘦素信号的关键负调控因子。因此，这些结果揭示了 Try985 介导的信号在能量代谢中的独特二元作用，作为一种年龄/饮食依赖性调节开关，对抗与年龄相关或饮食诱导的肥胖。
