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.

中文翻译：

---

POMC 神经元中的 MANF 促进棕色脂肪组织产热并防止饮食引起的肥胖

中脑星形胶质细胞衍生的神经营养因子 (MANF) 是代谢控制中的新兴调节因子。下丘脑阿黑皮素原 (POMC) 神经元在维持全身能量稳态中起着关键作用。POMC 神经元中的 MANF 是否需要适当调节能量平衡仍然未知。在这里，我们发现 POMC 神经元中缺乏 MANF 的小鼠更容易出现饮食诱导的肥胖。此外，MANF 的消融诱导下丘脑内质网 (ER) 应激和瘦素抵抗，降低 POMC 表达和翻译后加工，最终降低棕色脂肪组织 (BAT) 中的交感神经活动和产热。相反，MANF 在下丘脑 POMC 神经元中的过度表达减弱了 ER 应激，增加了 POMC 的表达和处理，然后刺激 BAT 中的交感神经支配和活动，导致 BAT 产热增加，从而保护小鼠免受饮食性肥胖。总的来说，我们的研究结果提供了证据，证明 MANF 是 POMC 神经元对抗肥胖所必需的。