Overexpression of agouti protein and stress responsiveness in mice

Ectopic overexpression of agouti protein, an endogenous antagonist of melan ocortin receptors' linked to the beta -actin promoter (BAPa) in mice, produ ces a phenotype of yellow coat color, Type II diabetes, obesity and increas ed somatic growth. Spontaneous overexpression of agouti increases stress-in duced weight loss. In these experiments, other aspects of stress responsive ness were tested in 12-week-old male wild-type mice and BAPa mice. Two hour s of restraint on three consecutive days produced greater increases in cort icosterone and post-stress weight loss in BAPa than wild-type mice. In Expe riment 2, anxiety-type behavior was measured immediately after 12 min of re straint. This mild stress did not produce many changes indicative of anxiet y, but BAPa. mice spent more time in the dark side of a light-dark box and less time in the open arms of an elevated plus maze than restrained wild-ty pe mice. In a defensive withdrawal test, grooming was increased by restrain t in all mice, but the duration of each event was substantially shorter in BAPa mice, possibly due to direct antagonism of the MC4-R by agouti protein . Thus, BAPa mice showed exaggerated endocrine and energetic responses to r estraint stress with small differences in anxiety-type behavior compared wi th wild-type mice. These results are consistent with observations in other transgenic mice in which the melanocortin system is disrupted, but contrast with reports that acute blockade of central melanocortin receptors inhibit s stress-induced hypophagia. Thus, the increased stress responsiveness in B APa mice may be a developmental compensation for chronic inhibition of mela nocortin receptors. (C) 2001 Elsevier Science Inc. All rights reserved.