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MANF in POMC neurons promotes brown adipose tissue thermogenesis and protects against diet-induced obesity

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posted on 2022-08-12, 15:51 authored by Qin Tang, Qinhui Liu, Jiahui Li, Jiamin Yan, Xiandan Jing, Jinhang Zhang, Yan Xia, Ying Xu, Yanping Li, Jinhan He

Mesencephalic astrocyte-derived neurotrophic factor (MANF) is an emerging regulator in metabolic control. Hypothalamic pro-opimelanocortin (POMC) neurons play critical roles in maintaning whole-body energy homeostasis. Whether MANF in POMC neurons is required for the proper regulation of energy balance remains unknown. Here, we showed that mice lacking MANF in POMC neurons were more prone to develop diet-induced obesity. In addition, the ablation of MANF induced endoplasmic reticulum (ER) stress and leptin resistance in the hypothalamus, reduced POMC expression and post-translational processing, and ultimately decreased sympathetic nerve activity and thermogenesis in brown adipose tissue (BAT). Conversely, MANF overexpression in hypothalamic POMC neurons attenuated ER stress, increased POMC expression and processing, and then stimulated sympathetic innervation and activity in BAT, resulting in increased BAT thermogenesis, thus protecting mice against dietary obesity. Overall, our findings provide evidence that MANF is required for POMC neurons to combat obesity. 

Funding

This work was supported by the National Natural Science Foundation of China (82025007, 81930020, 81873662, and 81870599), Research funding from Sichuan Province (2021YJ0458), Post-Doctor Research Project, West China Hospital of Sichuan University (2020HXBH095).

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