Lensing Cody J, Adank Danielle N, Doering Skye R, Wilber Stacey L, Andreasen Amy, Schaub Jay W, Xiang Zhimin, Haskell-Luevano Carrie
Department of Medicinal Chemistry, University of Minnesota , Minneapolis, Minnesota 55455, United States.
Department of Pharmacodynamics, College of Pharmacy, University of Florida , Gainesville, Florida 32611, United States.
ACS Chem Neurosci. 2016 Sep 21;7(9):1283-91. doi: 10.1021/acschemneuro.6b00156. Epub 2016 Jul 22.
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.
黑皮质素-4受体（MC4R）已被指明是诸如厌食症、恶病质和肥胖症等代谢紊乱的治疗靶点。当前研究调查了15 nM的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，该拮抗剂是一种对黑皮质素-3受体（MC3R）具有3700 nM拮抗活性且MC3R和MC4R激动活性极小的物质。当在TSE代谢笼中监测雄性和雌性小鼠时，在食物摄入量、呼吸交换率（RER）和能量消耗方面观察到了性别特异性反应。7.5 nmol剂量的SKY2-23-7增加了雄性小鼠的食物摄入量，提高了RER，并呈现出能量消耗降低的趋势。然而，该化合物在7.5 nmol剂量时对雌性小鼠的食物摄入量和RER影响极小。2.5 nmol剂量的SKY2-23-7显著增加了雌性小鼠的食物摄入量、RER和能量消耗，而在该剂量下对雄性小鼠影响极小。观察到的SKY2-23-7给药引起的性别差异促成了一种新型化学探针的发现，该探针可用于阐明黑皮质素途径中存在的性别二态性的分子机制。为了进一步探究黑皮质素性别二态性，对下丘脑基因表达进行了检测。MC3R和阿黑皮素原（POMC）的mRNA表达在两性之间无显著差异。然而，刺鼠相关肽（AGRP）的表达在雌性小鼠中显著更高，这可能是SKY2-23-7观察到的性别特异性效应的一种可能机制。
