PDF(Pubmed)
Abstract：
Endoplasmic reticulum (ER) homeostasis in the hypothalamus has been implicated in the pathogenesis of certain patho-physiological conditions such as diet-induced obesity (DIO) and type 2 diabetes; however, the significance of ER quality control mechanism(s) and its underlying mechanism remain largely unclear and highly controversial in some cases. Moreover, how the biogenesis of nascent leptin receptor in the ER is regulated remains largely unexplored. Here we report that the SEL1L-HRD1 protein complex of the highly conserved ER-associated protein degradation (ERAD) machinery in POMC neurons is indispensable for leptin signaling in diet-induced obesity. SEL1L-HRD1 ERAD is constitutively expressed in hypothalamic POMC neurons. Loss of SEL1L in POMC neurons attenuates leptin signaling and predisposes mice to HFD-associated pathologies including leptin resistance. Mechanistically, newly synthesized leptin receptors, both wildtype and disease-associated human mutant Cys604Ser (Cys602Ser in mice), are misfolding prone and bona fide substrates of SEL1L-HRD1 ERAD. Indeed, defects in SEL1L-HRD1 ERAD markedly impair the maturation of these receptors and causes their ER retention. This study not only uncovers a new role of SEL1L-HRD1 ERAD in the pathogenesis of diet-induced obesity and central leptin resistance, but a new regulatory mechanism for leptin signaling.
摘要：
下丘脑的内质网（ER）稳态与某些病理生理状况的发病机理有关，例如饮食诱导的肥胖（DIO）和2型糖尿病；然而，ER质量控制机制及其潜在机制的意义在很大程度上仍不清楚,在某些情况下存在很大争议.此外，内质网新生瘦素受体的生物发生是如何被调控的,目前仍未被研究.在这里，我们报告了POMC神经元中高度保守的ER相关蛋白降解（ERAD）机制的SEL1L-HRD1蛋白复合物对于饮食诱导的肥胖中的瘦素信号传导是必不可少的。SEL1L-HRD1ERAD在下丘脑POMC神经元中组成型表达。POMC神经元中SEL1L的缺失减弱瘦素信号传导,并使小鼠易患HFD相关病理,包括瘦素抵抗。机械上,新合成的瘦素受体，野生型和疾病相关的人类突变体Cys604Ser（小鼠中的Cys602Ser），是SEL1L-HRD1ERAD的易折叠和真正的底物。的确,SEL1L-HRD1ERAD的缺陷会明显损害这些受体的成熟并导致其内质网保留。这项研究不仅揭示了SEL1L-HRD1ERAD在饮食诱导的肥胖和中枢瘦素抵抗的发病机制中的新作用，而是一种新的瘦素信号调节机制。
