Possa-Paranhos Ingrid Camila, Butts Jared, Pyszka Emma, Nelson Christina, Congdon Samuel, Cho Dajin, Sweeney Patrick
Department of Molecular and Integrative Physiology, University of Illinois Urbana-Champaign, Urbana, IL, USA.
University of Illinois Urbana-Champaign Neuroscience Program, Urbana, IL, USA.
J Physiol. 2025 Jan;603(2):379-410. doi: 10.1113/JP286699. Epub 2024 Dec 24.
Although mammals resist both acute weight loss and weight gain, the neural circuitry mediating bi-directional defense against weight change is incompletely understood. Global constitutive deletion of the melanocortin-3-receptor (MC3R) impairs the behavioural response to both anorexic and orexigenic stimuli, with MC3R knockout mice demonstrating increased weight gain following anabolic challenges and increased weight loss following anorexic challenges (i.e. impaired energy rheostasis). However, the brain regions mediating this phenotype are not well understood. Here, we utilized MC3R floxed mice and viral injections of Cre-recombinase to selectively delete MC3R from the medial hypothalamus (MH) in adult mice. Behavioural assays were performed on these animals to test the role of MC3R in MH in the acute response to orexigenic and anorexic challenges. Complementary chemogenetic approaches were used in MC3R-Cre mice to localize and characterize the specific medial hypothalamic brain regions mediating the role of MC3R in energy homeostasis. Finally, we performed RNAscope in situ hybridization to map changes in the mRNA expression of MC3R, pro-opiomelanocortin and agouti-related peptide following energy rheostatic challenges, as well as to characterize the MC3R expressing cells in dorsal MH. Our results demonstrate that MC3R deletion in MH increases feeding and weight gain following high-fat diet feeding, and enhances the anorexic effects of semaglutide, in a sexually dimorphic manner. Furthermore, although the arcuate nucleus exerts an important role in MC3R-mediated effects on energy homeostasis, viral deletion in the dorsal MH also resulted in altered energy rheostasis, indicating that brain regions outside of the arcuate nucleus also contribute to the role of MC3R in energy rheostasis. Together, these results demonstrate that MC3R-mediated effects on energy rheostasis result from the loss of MC3R signalling in medial hypothalamic neurons and suggest an important role for dorsal-MH MC3R signalling in energy rheostasis. KEY POINTS: Melanocortin-3-receptor (MC3R) signalling regulates energy rheostasis in adult mice. Medial hypothalamus regulates energy rheostasis in adult mice. Energy rheostatic stimuli alter mRNA levels of agouti-related peptide, pro-opiomelanocortin and MC3R. Dorsal-medial hypothalamus (DMH) MC3R neurons increase locomotion and energy expenditure. MC3R cell types in DMH are sexually dimorphic.
尽管哺乳动物既能抵抗急性体重减轻，也能抵抗体重增加，但介导双向体重变化防御的神经回路仍未被完全理解。黑皮质素-3-受体（MC3R）的全身性组成性缺失会损害对厌食和促食欲刺激的行为反应，MC3R基因敲除小鼠在合成代谢刺激后体重增加，在厌食刺激后体重减轻（即能量稳态受损）。然而，介导这种表型的脑区尚未得到充分了解。在这里，我们利用MC3R条件性敲除小鼠和病毒注射Cre重组酶，选择性地在成年小鼠的内侧下丘脑（MH）中删除MC3R。对这些动物进行行为分析，以测试MC3R在MH中对促食欲和厌食刺激的急性反应中的作用。在MC3R-Cre小鼠中使用互补的化学遗传学方法，来定位和表征介导MC3R在能量稳态中作用的特定内侧下丘脑脑区。最后，我们进行了RNAscope原位杂交，以绘制能量稳态挑战后MC3R、阿黑皮素原和刺鼠相关肽mRNA表达的变化，并表征背侧MH中表达MC3R的细胞。我们的结果表明，MH中MC3R的缺失会增加高脂饮食喂养后的进食量和体重增加，并以性别二态性的方式增强司美格鲁肽的厌食作用。此外，尽管弓状核在MC3R介导的能量稳态效应中发挥重要作用，但背侧MH中的病毒删除也导致能量稳态改变，表明弓状核以外的脑区也参与了MC3R在能量稳态中的作用。总之，这些结果表明，MC3R介导的能量稳态效应是由于内侧下丘脑神经元中MC3R信号的丧失，并提示背侧MH的MC3R信号在能量稳态中起重要作用。要点：黑皮质素-3-受体（MC3R）信号调节成年小鼠的能量稳态。内侧下丘脑调节成年小鼠的能量稳态。能量稳态刺激会改变刺鼠相关肽、阿黑皮素原和MC3R的mRNA水平。背内侧下丘脑（DMH）的MC3R神经元增加运动和能量消耗。DMH中的MC3R细胞类型具有性别二态性。
