POMC 神经元中的 Sestrin2 通过 mTOR 信号调节能量平衡和肥胖相关代谢紊乱

IF 4.8 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Journal of Nutritional Biochemistry Pub Date : 2024-07-25 DOI:10.1016/j.jnutbio.2024.109703
Huiling Hu , Xiaoxia Lu , Yuqing He , Jing Li , Shoujie Wang , Zhijun Luo , Ying Wang , Jie Wei , Hao Huang , Chaohui Duan , Nannan Sun
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引用次数: 0

摘要

Sestrin2 是一种高度保守的蛋白质,可在各种压力条件下被诱导。研究发现,哺乳动物雷帕霉素靶蛋白(mTOR)的信号通路在调节葡萄糖和脂质代谢中至关重要。然而,Sestrin2 在下丘脑,特别是在前绒毛膜促皮质素(POMC)神经元中对能量平衡控制的确切参与仍不确定。本研究旨在探讨 Sestrin2 在下丘脑 POMC 神经元中调控能量平衡的功能作用,并揭示其潜在机制。因此,我们将编码或沉默Sestrin2的Cre依赖性AAV病毒注射到Pomc-cre转基因小鼠的下丘脑ARC中。结果表明,Sestrin2在POMC神经元中的过表达可改善高脂饮食(HFD)诱导的肥胖,并增加能量消耗。相反,POMC 神经元中 Sestrin2 的缺失会导致小鼠易患高脂饮食诱发的肥胖症。此外,Sestrin2过表达小鼠交感神经支配的增加也增强了棕色脂肪组织的产热和腹股沟白色脂肪组织的脂肪分解。进一步研究发现,Sestrin2过表达抑制了下丘脑POMC神经元的mTOR信号通路,这可能是这些小鼠减轻高氟酸膳食引起的系统性代谢紊乱的原因。总之,我们的研究结果表明,POMC神经元中的Sestrin2通过抑制mTOR通路,在HFD诱发肥胖的情况下维持能量平衡方面发挥了关键作用,为了解下丘脑神经元如何响应营养信号以防止肥胖相关的代谢功能障碍提供了新的视角。
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Sestrin2 in POMC neurons modulates energy balance and obesity related metabolic disorders via mTOR signaling

Sestrin2 is a highly conserved protein that can be induced under various stress conditions. Researches have revealed that the signaling pathway of the mammalian target of rapamycin (mTOR) is essential in modulating both glucose and lipid metabolism. However, the precise involvement of Sestrin2 in the hypothalamus, particularly in pro-opiomelanocortin (POMC) neurons, in control of energy homeostasis remains uncertain. In this study, we aimed to investigate the functional role of Sestrin2 in hypothalamic POMC neurons in regulation of energy balance, as well as revealing the underlying mechanisms. Therefore, cre-dependent AAV virus encoding or silencing Sestrin2 was injected into the hypothalamic ARC of pomc-cre transgenic mice. The results demonstrated that Sestrin2 overexpression in POMC neurons ameliorated high-fat diet (HFD)-induced obesity and increased energy expenditure. Conversely, Sestrin2 deficiency in POMC neurons predisposed mice to HFD induced obesity. Additionally, the thermogenesis of brown adipose tissue and lipolysis of inguinal white adipose tissue were both enhanced by the increased sympathetic nerve innervation in Sestrin2 overexpressed mice. Further exploration revealed that Sestrin2 overexpression inhibited the mTOR signaling pathway in hypothalamic POMC neurons, which may account for the alleviation of systematic metabolic disturbance induced by HFD in these mice. Collectively, our findings demonstrate that Sestrin2 in POMC neurons plays a pivotal role in maintaining energy balance in a context of HFD-induced obesity by inhibiting the mTOR pathway, providing new insights into how hypothalamic neurons respond to nutritional signals to protect against obesity-associated metabolic dysfunction.

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来源期刊
Journal of Nutritional Biochemistry
Journal of Nutritional Biochemistry 医学-生化与分子生物学
CiteScore
9.50
自引率
3.60%
发文量
237
审稿时长
68 days
期刊介绍: Devoted to advancements in nutritional sciences, The Journal of Nutritional Biochemistry presents experimental nutrition research as it relates to: biochemistry, molecular biology, toxicology, or physiology. Rigorous reviews by an international editorial board of distinguished scientists ensure publication of the most current and key research being conducted in nutrition at the cellular, animal and human level. In addition to its monthly features of critical reviews and research articles, The Journal of Nutritional Biochemistry also periodically publishes emerging issues, experimental methods, and other types of articles.
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