Glutamatergic melanocortin‐4 receptor neurons regulate body weight. Issue 5 (20th April 2023)

• Record Type: Journal Article
• Authors: Liu, Haodong; Li, Xiaojing; Li, Penghui; Hai, Rihan; Li, Jiacheng; Fan, Qi; Wang, Xing; Chen, Yujie; Cao, Xiaojuan; Zhang, Xiaoyu; Gao, Ruifeng; Wang, Kun; Du, Chenguang
• Is Part Of: FASEB journal. Volume 37:Issue 5(2023)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2023-04-20
• Subjects: body weight -- glutamate -- locus coeruleus -- Melanocortin‐4 receptor, melanocortin, neurons -- paraventricular hypothalamic nucleus -- RRID: 007914 -- RRID: 016963; Biology -- Periodicals; Biology, Experimental -- Periodicals; 570
• DOI: 10.1096/fj.202201786R
• Languages: English
• ISSNs: 0892-6638

Abstract

Abstract: The locus coeruleus (LC), enriched in vesicular glutamate transporter 2 (VGlut2) neurons, is a potential homeostasis‐regulating hub. However, the identity of melanocortin‐4 receptor (MC4R) neurons in the paraventricular nucleus (PVN) of the hypothalamus, PVN VGlut2::MC4R and LC VGlut2::MC4R regulation of body weight, and axonal projections of LC VGlut2 neurons remain unclear. Conditional knockout of MC4R in chimeric mice was used to confirm the effects of VGlut2. Interscapular brown adipose tissue was injected with pseudorabies virus to study the central nervous system projections. We mapped the LC VGlut2 circuitry. Based on the Cre–LoxP recombination system, specific knockdown of MC4R in VGlut2 neurons resulted in weight gain in chimeric mice. Adeno‐associated virus‐mediated knockdown of MC4R expression in the PVN and LC had potential superimposed effects on weight gain, demonstrating the importance of VGlut2 neurons. Unlike these wide‐ranging efferent projections, the PVN, hypothalamic arcuate nucleus, supraoptic nucleus of the lateral olfactory tegmental nuclei, and nucleus tractus solitarius send excitatory projections to LC VGlut2 neurons. The PVN → LC glutamatergic MC4R long‐term neural circuit positively affected weight management and could help treat obesity. Abstract : Upstream glutamatergic MC4R neurons controlling IBAT are mainly distributed in the PVN and LC. Specific inactivation of MC4R expression in VGlut2 neurons led to weight gain. Virus tracing showed that LC VGlut2 neurons send glutamatergic projections directly to the PVN.