Upregulation of Xbp1 in NPY/AgRP neurons reverses diet-induced obesity and ameliorates leptin and insulin resistance

IF 2.5 3区医学 Q3 ENDOCRINOLOGY & METABOLISM

Neuropeptides Pub Date : 2024-08-06 DOI:10.1016/j.npep.2024.102461

Jason Ajwani, Eunsang Hwang, Bryan Portillo, Linh Lieu, Briana Wallace, Anita Kabahizi, Zhenyan He, Yanbin Dong, Kyle Grose, Kevin W. Williams

引用次数: 0

Abstract

The molecular mechanisms underlying neuronal leptin and insulin resistance in obesity and diabetes are not fully understood. In this study, we show that induction of the unfolded protein response transcription factor, spliced X-box binding protein 1 (Xbp1s), in Agouti-Related Peptide (AgRP) neurons alone, is sufficient to not only protect against but also significantly reverse diet-induced obesity (DIO) as well as improve leptin and insulin sensitivity, despite activation of endoplasmic reticulum stress. We also demonstrate that constitutive expression of Xbp1s in AgRP neurons contributes to improved insulin sensitivity and glucose tolerance. Together, our results identify critical molecular mechanisms linking ER stress in arcuate AgRP neurons to acute leptin and insulin resistance as well as liver glucose metabolism in DIO and diabetes.

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上调 NPY/AgRP 神经元中的 Xbp1 可逆转饮食引起的肥胖，并改善瘦素和胰岛素抵抗。

肥胖症和糖尿病中神经元瘦素和胰岛素抵抗的分子机制尚不完全清楚。在这项研究中，我们发现，尽管激活了内质网应激，但在阿古提相关肽（AgRP）神经元中单独诱导未折叠蛋白反应转录因子--剪接的 X-box 结合蛋白 1（Xbp1s），不仅足以防止而且还能显著逆转饮食诱导的肥胖（DIO），以及改善瘦素和胰岛素敏感性。我们还证明了 Xbp1s 在 AgRP 神经元中的组成型表达有助于改善胰岛素敏感性和葡萄糖耐受性。总之，我们的研究结果确定了将弓状AgRP神经元中的ER应激与急性瘦素和胰岛素抵抗以及DIO和糖尿病中的肝糖代谢联系起来的关键分子机制。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Neuropeptides 医学-内分泌学与代谢

CiteScore

5.40

自引率

6.90%

发文量

审稿时长

>12 weeks

期刊介绍： The aim of Neuropeptides is the rapid publication of original research and review articles, dealing with the structure, distribution, actions and functions of peptides in the central and peripheral nervous systems. The explosion of research activity in this field has led to the identification of numerous naturally occurring endogenous peptides which act as neurotransmitters, neuromodulators, or trophic factors, to mediate nervous system functions. Increasing numbers of non-peptide ligands of neuropeptide receptors have been developed, which act as agonists or antagonists in peptidergic systems. The journal provides a unique opportunity of integrating the many disciplines involved in all neuropeptide research. The journal publishes articles on all aspects of the neuropeptide field, with particular emphasis on gene regulation of peptide expression, peptide receptor subtypes, transgenic and knockout mice with mutations in genes for neuropeptides and peptide receptors, neuroanatomy, physiology, behaviour, neurotrophic factors, preclinical drug evaluation, clinical studies, and clinical trials.