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首页> 外文期刊>Molecular and Cellular Biology >Signaling through Tyr985 of Leptin Receptor as an Age/Diet-Dependent Switch in the Regulation of Energy Balance
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Signaling through Tyr985 of Leptin Receptor as an Age/Diet-Dependent Switch in the Regulation of Energy Balance

机译：瘦素受体通过Tyr985信号作为能量平衡调节中的年龄/饮食依赖开关

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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.
机译：瘦素通过中央激活由瘦素受体的长形式Ob-Rb介导的多个信号通路来调节能量稳态。瘦素抵抗是肥胖病原体发展的基础，肥胖与环境因素密切相关。为了进一步了解瘦素信号转导机制的生理功能，我们构建了一种敲除小鼠系（Y985F），其表达突变体Ob-Rb，并用苯丙氨酸替代Tyr 985 （三种胞内酪氨酸之一）介导瘦素的信号传导作用。出人意料的是，虽然纯合的年轻Y985F动物稍瘦一些，但它们却表现出成年发作或饮食引起的肥胖。重要的是，年龄依赖性和饮食引起的能量平衡恶化均与明显的瘦素抵抗同时发生，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（瘦素的关键负调节剂）的表达显着升高。信号。因此，这些结果揭示了Try 985 介导的信号在能量代谢中的独特二元作用，充当了年龄/饮食依赖性调节开关，以抵消与年龄相关的肥胖或饮食诱导的肥胖。

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