title: 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.
abstract: 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.
authors.affiliation: Department of Medicinal Chemistry, University of Minnesota , Minneapolis, Minnesota 55455, United States.
authors.forename: Cody J
authors.initials: CJ
authors.lastname: Lensing
authors.affiliation: Department of Medicinal Chemistry, University of Minnesota , Minneapolis, Minnesota 55455, United States.
authors.forename: Danielle N
authors.initials: DN
authors.lastname: Adank
authors.affiliation: Department of Medicinal Chemistry, University of Minnesota , Minneapolis, Minnesota 55455, United States.
authors.forename: Skye R
authors.initials: SR
authors.lastname: Doering
authors.affiliation: Department of Medicinal Chemistry, University of Minnesota , Minneapolis, Minnesota 55455, United States.
authors.forename: Stacey L
authors.initials: SL
authors.lastname: Wilber
authors.affiliation: Department of Pharmacodynamics, College of Pharmacy, University of Florida , Gainesville, Florida 32611, United States.
authors.forename: Amy
authors.initials: A
authors.lastname: Andreasen
authors.affiliation: Department of Pharmacodynamics, College of Pharmacy, University of Florida , Gainesville, Florida 32611, United States.
authors.forename: Jay W
authors.initials: JW
authors.lastname: Schaub
authors.affiliation: Department of Pharmacodynamics, College of Pharmacy, University of Florida , Gainesville, Florida 32611, United States.
authors.forename: Zhimin
authors.initials: Z
authors.lastname: Xiang
authors.affiliation: 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.
authors.forename: Carrie
authors.initials: C
authors.lastname: Haskell-Luevano
mesh_terms: D000818:Animals; D004435:Eating / Q000187:drug effects; D004734:Energy Metabolism / Q000187:drug effects*; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009842:Oligopeptides / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology; D019894:Peptide YY / Q000494:pharmacology; D000070780:Perilipin-2 / Q000235:genetics / Q000378:metabolism; D011333:Pro-Opiomelanocortin / Q000235:genetics / Q000378:metabolism; D044104:Receptor, Melanocortin, Type 3 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D044105:Receptor, Melanocortin, Type 4 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D012737:Sex Factors; D013329:Structure-Activity Relationship; D013997:Time Factors
chemical_list: D009842:Oligopeptides; D010446:Peptide Fragments; D000070780:Perilipin-2; D044104:Receptor, Melanocortin, Type 3; D044105:Receptor, Melanocortin, Type 4; C000624248:SKY-2-23-7; D019894:Peptide YY; C061785:peptide YY (3-36); D011333:Pro-Opiomelanocortin
keywords: GPCR; Melanotropin; RT-PCR; TSE cages; gender differences; gene expression; hypothalamus; sex; sexual dimorphism; α-MSH