The melanocortin-3 receptor is a pharmacological target for the regulation of anorexia.
The melanocortin-3 receptor is a pharmacological target for the regulation of anorexia.
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DOI：
10.1126/scitranslmed.abd6434
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发表时间：
2021-04-21
影响因子：
17.1
通讯作者：
中科院分区：
文献类型：
--
作者：
下丘脑AgRP（Agouti相关蛋白）神经元的消融已知会导致致命的厌食症，而它们的激活会刺激贪婪的进食并抑制其他动机状态，包括恐惧和焦虑。尽管AgRP神经元在双向控制进食中起着关键作用，但目前还没有专门针对该回路的治疗方法。黑皮质素-3受体（MC 3R）在多个脑区域中表达，并且在小鼠和人类的一些脑区域中表现出表达的性别二型性。MC 3R缺失产生了多种形式的性二态性厌食症，类似于人类神经性厌食症的方面。而在AgRP神经元中，MC 3R的表达无性别差异，97%的神经元表达MC 3R。弓形MC 3R神经元的化学遗传学操作和MC 3R的药理学操作各自对雄性和雌性小鼠的摄食行为产生了有效的双向调节，而MC 3R表达细胞的全局消融产生了致命的厌食症。MC 3R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，MC 3R的主要作用似乎是调节雄性和雌性小鼠的AgRP电路，在摄食行为中，性二型位点发挥专门和从属的作用。因此，MC 3R是以厌食症为特征的疾病的潜在治疗靶标，以及减肥治疗的潜在靶标。
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.
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影响因子：
16.2
作者：
Burnett CJ;Li C;Webber E;Tsaousidou E;Xue SY;Brüning JC;Krashes MJ
通讯作者：
Krashes MJ
影响因子：
64.5
作者：
Dietrich MO;Zimmer MR;Bober J;Horvath TL
通讯作者：
Horvath TL
影响因子：
13.6
作者：
Ghamari-Langroudi M;Cakir I;Lippert RN;Sweeney P;Litt MJ;Ellacott KLJ;Cone RD
通讯作者：
Cone RD
影响因子：
15.9
作者：
Krashes, Michael J.;Koda, Shuichi;Lowell, Bradford B.
通讯作者：
Lowell, Bradford B.
影响因子：
15.9
作者：
Klawonn, Anna Mathia;Fritz, Michael;Engblom, David
通讯作者：
Engblom, David