The adipocyte-derived hormone leptin and the pancreatic beta cell-derived hormone insulin each function as afferent signals to the hypothalamus in an endocrine feedback loop that regulates body adiposity. Although these two hormones, and the receptors on which they act, are unrelated and structurally distinct, they exert overlapping effects in the arcuate nucleus, a key hypothalamic area involved in energy homeostasis. Defects in either insulin or leptin signaling in the brain result in hyperphagia, disordered glucose homeostasis, and reproductive dysfunction. To explain this striking physiological overlap, we hypothesize that hypothalamic insulin and leptin signaling converge upon a single intracellular signal transduction pathway, known as the insulin-receptor-substrate phosphatidylinositol 3-kinase pathway. Here we synthesize data from a variety of model systems in which such "cross-talk" between insulin and leptin signal transduction has either been observed or can be inferred, discuss our own data demonstrating that insulin and leptin both activate hypothalamic phosphatidylinositol 3-kinase signaling, and discuss the significance of such convergence with respect to neuronal function in normal individuals and in pathological states such as obesity. Identification of the key early molecular events mediating the action of both insulin and leptin in hypothalamic neurons promises new insight into the regulation of these neurons in health and disease.

中文翻译：

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重新审视胰岛素和瘦素：具有重叠生理和细胞内信号能力的肥胖信号

脂肪细胞衍生的激素瘦素和胰腺β细胞衍生的激素胰岛素各自在调节身体肥胖的内分泌反馈回路中充当下丘脑的传入信号。尽管这两种激素及其作用的受体互不相关且结构不同，但它们在弓状核中发挥重叠作用，弓状核是参与能量稳态的关键下丘脑区域。大脑中胰岛素或瘦素信号传导的缺陷会导致进食过多、葡萄糖稳态失调和生殖功能障碍。为了解释这种惊人的生理重叠，我们假设下丘脑胰岛素和瘦素信号会聚集在单一的细胞内信号转导通路上，称为胰岛素受体底物磷脂酰肌醇 3-激酶通路。在这里，我们从各种模型系统中合成数据，其中观察到或可以推断出胰岛素和瘦素信号转导之间的这种“串扰”，讨论我们自己的数据，证明胰岛素和瘦素都激活下丘脑磷脂酰肌醇 3-激酶信号传导，并讨论这种收敛对正常个体和病理状态（如肥胖）的神经元功能的重要性。鉴定介导下丘脑神经元中胰岛素和瘦素作用的关键早期分子事件有望对这些神经元在健康和疾病中的调节提供新的见解。讨论我们自己的数据，证明胰岛素和瘦素都激活下丘脑磷脂酰肌醇 3-激酶信号传导，并讨论这种收敛对正常个体和病理状态（如肥胖）的神经元功能的重要性。鉴定介导下丘脑神经元中胰岛素和瘦素作用的关键早期分子事件有望对这些神经元在健康和疾病中的调节提供新的见解。讨论我们自己的数据，证明胰岛素和瘦素都激活下丘脑磷脂酰肌醇 3-激酶信号，并讨论这种收敛对正常个体和病理状态（如肥胖）的神经元功能的重要性。鉴定介导下丘脑神经元中胰岛素和瘦素作用的关键早期分子事件有望对这些神经元在健康和疾病中的调节提供新的见解。