Agouti yellow mutation increases adrenal response to ACTH in mice

Abstract

Objective: Agouti protein (AP) and agouti-related protein with a similar sequence and action are endogenous antagonists of melanocortin receptors, implicated in the control of the hypothalamo-pituitary-adrenal (HPA) axis. Dominant mutation of the agouti gene (agouti yellow (Ay)) in heterozygous Ay/a mice leads to ectopic overexpression of AP and produces an obese phenotype. The existing data on the HPA function in Ay/a-mice are equivocal; therefore, the present study aimed to assess HPA function in 3-month-old male C57BI/6J mice of two agouti genotypes: Ay/a (ectopic AP overexpression) and a/a (absence of AP). Design and methods: In order to evaluate the HPA function, activating (15-min restriction, ACTH-induced corticosterone production in vitro) and inhibiting (i.p. injection of dexamethasone, 0.02 μg/g body weight) stimuli were employed. To estimate the effect of obesity on some HPA functions, Ay/a males were subdivided into obese and non-obese groups. Results: Basal plasma concentrations of ACTH and corticosterone; basal corticosterone production in vitro; and feedback inhibition of resting corticosterone levels by dexamethasone were similar in Ay/a- and a/a-mice. Restraint-induced plasma corticosterone was greater in obese and non-obese Ay/a-mice than in a/a-mice, whereas restraint-induced plasma ACTH levels were similar. Adrenal cell responses to ACTH (10-13-10-10 M) were higher in obese and non-obese Ay/a-mice than in a/a-mice. Dexamethasone, injected 3 h prior to stress, inhibited stress-induced corticosterone levels by a significantly greater amount in Ay/a-mice than in a/a-mice. Conclusions: AP may have both stimulating and inhibiting influences on the HPA axis. AP overproduction increased the response of the HPA to short-restraint stress due to increased adrenal responsiveness to ACTH; this result was not effected by obesity development. © 2004 Society of the European Journal of Endocrinology.