Ac-Trp-DPhe(p-I)-Arg-Trp-NH2, a 250-Fold Selective Melanocortin-4 Receptor (MC4R) Antagonist over the Melanocortin-3 Receptor (MC3R), Affects Energy Homeostasis in Male and Female Mice Differently.
Ac-Trp-DPhe(p-I)-Arg-Trp-NH2, a 250-Fold Selective Melanocortin-4 Receptor (MC4R) Antagonist over the Melanocortin-3 Receptor (MC3R), Affects Energy Homeostasis in Male and Female Mice Differently.
复制标题
Ac-Trp-DPhe(p-I)-Arg-Trp-NH2 是一种对 Melanocortin-3 受体 (MC3R) 具有 250 倍选择性的 Melanocortin-4 受体 (MC4R) 拮抗剂，对雄性和雌性小鼠的能量稳态有不同的影响。
DOI：
10.1021/acschemneuro.6b00156
复制
发表时间：
2016
影响因子：
5
通讯作者：
Haskell-Luevano,Carrie
中科院分区：
文献类型：
--
作者：
Lensing,CodyJ;Adank,DanielleN;Doering,SkyeR;Wilber,StaceyL;Andreasen,Amy;Schaub,JayW;Xiang,Zhimin;Haskell-Luevano,Carrie
黑皮质素-4 受体 (MC4R) 已被认为是厌食症、恶病质和肥胖等代谢性疾病的治疗靶点。目前的研究调查了 15 nM MC4R 拮抗剂 SKY2-23-7 Ac-Trp-DPhe(p-I)-Arg-Trp-NH2 对能量稳态的体内影响，这是一种 3700 nM 黑皮质素 3 受体 (MC3R) 拮抗剂，具有最小的 MC3R 和 MC4R 激动剂活性。当监测 TSE 代谢笼中的雄性和雌性小鼠时，在食物摄入、呼吸交换比 (RER) 和能量消耗方面观察到性别特异性反应。 7.5 nmol 剂量的 SKY2-23-7 增加了雄性小鼠的食物摄入量，增加了 RER，并有减少能量消耗的趋势。然而，这种化合物在 7.5 nmol 剂量下对雌性小鼠的食物摄入量和 RER 的影响很小。 2.5 nmol 剂量的 SKY2-23-7 显着增加雌性食物摄入量、RER 和能量消耗，而该剂量对雄性小鼠的影响最小。观察到的 SKY2-23-7 给药的性别差异导致发现了一种新的化学探针，用于阐明黑皮质素途径中存在的性别二态性的分子机制。为了进一步探讨黑皮质素的性别二态性，检查了下丘脑基因表达。 MC3R 和阿片黑皮质素原 (POMC) 的 mRNA 表达在性别之间没有显着差异。然而，雌性小鼠中刺鼠相关肽 (AGRP) 的表达显着较高，这可能是 SKY2-23-7 观察到的性别特异性效应的可能机制。
The melanocortin-4 receptor (MC4R) has been indicated as a therapeutic target for metabolic disorders such as anorexia, cachexia, and obesity. The current study investigates the in vivo effects on energy homeostasis of a 15 nM MC4R antagonist SKY2-23-7, Ac-Trp-DPhe(p-I)-Arg-Trp-NH2, that is a 3700 nM melanocortin-3 receptor (MC3R) antagonist with minimal MC3R and MC4R agonist activity. When monitoring both male and female mice in TSE metabolic cages, sex-specific responses were observed in food intake, respiratory exchange ratio (RER), and energy expenditure. A 7.5 nmol dose of SKY2-23-7 increased food intake, increased RER, and trended toward decreasing energy expenditure in male mice. However, this compound had minimal effect on female mice’s food intake and RER at the 7.5 nmol dose. A 2.5 nmol dose of SKY2-23-7 significantly increased female food intake, RER, and energy expenditure while having a minimal effect on male mice at this dose. The observed sex differences of SKY2-23-7 administration result in the discovery of a novel chemical probe for elucidating the molecular mechanisms of the sexual dimorphism present within the melanocortin pathway. To further explore the melanocortin sexual dimorphism, hypothalamic gene expression was examined. The mRNA expression of the MC3R and proopiomelanocortin (POMC) were not significantly different between sexes. However, the expression of agouti-related peptide (AGRP) was significantly higher in female mice which may be a possible mechanism for the sex-specific effects observed with SKY2-23-7.