Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109, USA.
Department of Molecular Physiology and Biophysics, School of Medicine, Vanderbilt University, Nashville, TN 37240, USA.
Sci Transl Med. 2021 Apr 21;13(590). doi: 10.1126/scitranslmed.abd6434.
Ablation of hypothalamic AgRP (Agouti-related protein) neurons is known to lead to fatal anorexia, whereas their activation stimulates voracious feeding and suppresses other motivational states including fear and anxiety. Despite the critical role of AgRP neurons in bidirectionally controlling feeding, there are currently no therapeutics available specifically targeting this circuitry. The melanocortin-3 receptor (MC3R) is expressed in multiple brain regions and exhibits sexual dimorphism of expression in some of those regions in both mice and humans. MC3R deletion produced multiple forms of sexually dimorphic anorexia that resembled aspects of human anorexia nervosa. However, there was no sexual dimorphism in the expression of MC3R in AgRP neurons, 97% of which expressed MC3R. Chemogenetic manipulation of arcuate MC3R neurons and pharmacologic manipulation of MC3R each exerted potent bidirectional regulation over feeding behavior in male and female mice, whereas global ablation of MC3R-expressing cells produced fatal anorexia. Pharmacological effects of MC3R compounds on feeding were dependent on intact AgRP circuitry in the mice. Thus, the dominant effect of MC3R appears to be the regulation of the AgRP circuitry in both male and female mice, with sexually dimorphic sites playing specialized and subordinate roles in feeding behavior. Therefore, MC3R is a potential therapeutic target for disorders characterized by anorexia, as well as a potential target for weight loss therapeutics.
下丘脑 AgRP（Agouti 相关蛋白）神经元的消融已知会导致致命性厌食症，而其激活会刺激暴食，并抑制包括恐惧和焦虑在内的其他动机状态。尽管 AgRP 神经元在双向控制进食方面起着至关重要的作用，但目前尚无专门针对该回路的治疗方法。黑皮质素-3 受体 (MC3R) 在多个脑区表达，并且在小鼠和人类的一些脑区中表现出表达的性别二态性。MC3R 缺失产生了多种形式的性别二态性厌食症，类似于人类神经性厌食症的某些方面。然而，AgRP 神经元中 MC3R 的表达没有表现出性别二态性，其中 97%表达 MC3R。弓状核 MC3R 神经元的化学遗传操作和 MC3R 的药理学操作都对雄性和雌性小鼠的进食行为产生了强大的双向调节作用，而 MC3R 表达细胞的全局消融则导致致命性厌食症。MC3R 化合物对进食的药理学作用依赖于小鼠中完整的 AgRP 回路。因此，MC3R 的主要作用似乎是调节雄性和雌性小鼠的 AgRP 回路，而性别二态性部位在进食行为中发挥专门的次要作用。因此，MC3R 是一种治疗以厌食症为特征的疾病的潜在治疗靶点，也是一种治疗体重减轻的潜在靶点。
