Obese Zucker (fa/fa) rats exhibit normal target sensitivity to corticosterone and increased drive to adrenocorticotropin during the diurnal trough

Abstract

Genetically obese Zucker (fa/fa) rats exhibit numerous metabolic and endocrine disorders associated with modest hypercorticosteronemia and reported changes in peripheral target tissue sensitivity to glucocorticoids. In this study we investigated phenotypic differences in basal and stress-induced ACTH and corticosterone (B) secretion in intact and adrenalectomized lean and obese male Zucker rats. In addition, we determined whether differences in the sensitivity to B of plasma ACTH and insulin secretion as well as other peripheral B targets could be observed between the two phenotypes. There were no significant differences in basal ACTH or B in either the morning (AM) or evening (PM) in intact obese and lean rats; however, mean B was increased in the obese rats in the AM, and signs of chronically increased adrenocortical activity were observed, including increased adrenal weight and intraadrenal phenylethanolamine-N-methyl transferase activity and decreased thymus weight. In a second experiment, B was significantly elevated 3 min after either administration in obese compared to lean rats; however, there was no significant difference in B between the groups at 10 min, nor were ACTH levels at these times different. Five days after adrenalectomy with sc B replacement, ACTH was decreased as a function of B in both phenotypes under AM basal and stress conditions. The IC50 values for inhibition of basal ACTH by B were 3.16 and 4.17 micrograms/dl in lean and obese rats, respectively. Under stress conditions, the IC50 values were not different (4.39 micrograms/dl for lean and 4.24 micrograms/dl for obese rats). B dose-dependent increases in body and epididymal fat depot weights were greater in obese than in lean rats, an expected result because of elevated insulin levels in this group. Insulin exhibited only small B-dependent increases, and thymus weight decreased in a B-dependent fashion; there were no differences in the sensitivity to B of these measures between lean and obese rats. We conclude that 1) there is no evidence for altered sensitivity to B in obese rats for any of the B-sensitive end points measured; and 2) basal adrenocortical activity is slightly elevated, and the sensitivity of ACTH to B feedback is decreased in obese rats under AM conditions in the absence of external stress.