1 research outputs found
Ac-Trp-DPhe(p-I)-Arg-Trp-NH<sub>2</sub>, a 250-Fold Selective Melanocortin‑4 Receptor (MC4R) Antagonist over the Melanocortin‑3 Receptor (MC3R), Affects Energy Homeostasis in Male and Female Mice Differently
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-DPheÂ(p-I)-Arg-Trp-NH<sub>2</sub>, 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