Dorsal raphe nucleus MC4R-GABAergic neurons regulate feeding and anxiety

IF 6.6 2区医学 Q1 ENDOCRINOLOGY & METABOLISM

Molecular Metabolism Pub Date : 2025-06-30 DOI:10.1016/j.molmet.2025.102199

Satoshi Yamagata , Francesca Copperi , Gavin Thomas White , Jung Dae Kim , Sabrina Diano

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引用次数: 0

Abstract

Objective

The melanocortin receptor 4 (MC4R) plays a key role in the CNS regulation of metabolism. In addition to its role within the hypothalamus, other brain areas, including the dorsal raphe nucleus (DRN), express MC4R. However, the identity and role of these neurons in metabolism regulation are not fully understood. We performed studies to address these questions.

Methods

We generated Mc4r-cre;Vgat-FlpO and Mc4r-cre;Vglut2-FlpO mice to determine the contribution of these MC4R neuronal populations in DRN. We then chemogenetically activated or inhibited the GABAergic and glutamatergic populations of MC4R. Finally, we selectively deleted MC4R from these two neuronal populations and studied the impact on whole-body metabolism.

Results

We found that about 60% of DRN MC4R neurons are GABAergic (Vgat), while only about 20% are glutamatergic (Vglut2). Most of the projections onto DRN neurons originated from the arcuate nucleus (ARC)-POMC neurons, and only a small input from the nucleus of the solitary tract (NTS)-POMC neurons was identified. Significant projections of DRN MC4R/Vgat neurons were observed in the paraventricular nucleus of the hypothalamus (PVN). Chemogenetic activation or inhibition of MC4R/Vgat neurons increased or inhibited food intake, respectively. No effects were observed when the same approach was used in MC4R/Vglut2 neurons. Furthermore, only chemogenetic manipulation of the MC4R/Vgat neurons affected anxiety-like behavior, which was associated with changes in serotonin staining in the DRN. Finally, MC4R-selective deletion in Vgat but not Vglut2 neurons affected whole-body metabolism.

Conclusions

These findings suggest that DRN MC4R/Vgat neurons receiving projections from the ARC POMC neurons and projecting to the hypothalamic PVN play a role in metabolism regulation. In addition, this same DRN neuronal subpopulation affects anxiety-like behavior by modulating DRN serotonin neurons.

查看原文本刊更多论文

中缝背核mc4r - gaba能神经元调节摄食和焦虑。

目的：黑素皮质素受体4 （melanocortin receptor 4, MC4R）在中枢神经系统代谢调控中起关键作用。除了在下丘脑中发挥作用外，包括中缝背核（DRN）在内的其他大脑区域也表达MC4R。然而，这些神经元在代谢调节中的身份和作用尚不完全清楚。我们进行了研究来解决这些问题。方法：我们生成MC4R -cre；Vgat-FlpO和MC4R -cre；Vglut2-FlpO小鼠，以确定这些MC4R神经元群在DRN中的贡献。然后，我们通过化学遗传学激活或抑制MC4R的gaba能和谷氨酸能群体。最后，我们选择性地从这两个神经元群中删除MC4R，并研究其对全身代谢的影响。结果：我们发现DRN MC4R神经元约60%为gabaergy (Vgat)，而仅约20%为谷氨酸能（Vglut2）。大多数DRN神经元的投射来自弓形核(ARC)-POMC神经元，只有一小部分输入来自孤立束核(NTS)-POMC神经元。在下丘脑室旁核（PVN）观察到显著的DRN MC4R/Vgat神经元的突起。化学发生激活或抑制MC4R/Vgat神经元分别增加或抑制食物摄入。当同样的方法用于MC4R/Vglut2神经元时，未观察到任何影响。此外，只有MC4R/Vgat神经元的化学发生操作才会影响焦虑样行为，这与DRN中血清素染色的变化有关。最后，Vgat而Vglut2神经元的mc4r选择性缺失影响了全身代谢。结论：这些发现提示DRN MC4R/Vgat神经元接受ARC POMC神经元的投射并投射到下丘脑PVN，参与代谢调节。此外，同样的DRN神经元亚群通过调节DRN血清素神经元来影响焦虑样行为。

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

Molecular Metabolism ENDOCRINOLOGY & METABOLISM-

CiteScore

14.50

自引率

2.50%

发文量

219

审稿时长

43 days

期刊介绍： Molecular Metabolism is a leading journal dedicated to sharing groundbreaking discoveries in the field of energy homeostasis and the underlying factors of metabolic disorders. These disorders include obesity, diabetes, cardiovascular disease, and cancer. Our journal focuses on publishing research driven by hypotheses and conducted to the highest standards, aiming to provide a mechanistic understanding of energy homeostasis-related behavior, physiology, and dysfunction. We promote interdisciplinary science, covering a broad range of approaches from molecules to humans throughout the lifespan. Our goal is to contribute to transformative research in metabolism, which has the potential to revolutionize the field. By enabling progress in the prognosis, prevention, and ultimately the cure of metabolic disorders and their long-term complications, our journal seeks to better the future of health and well-being.