Objective: The antagonism of Agouti protein (AP) and Agouti-related protein on melanocortin receptors suggests an inhibitory role in the regulation of steroidogenesis. However, we have previously demonstrated that ectopic AP overexpression increased restraint-induced corticosterone release and adrenal reactivity to ACTH in mice. A high steroidogenic response to ACTH may be a consequence of a stimulatory AP action on the adenylate cyclase (AC) and/or intracellular steroidogenic enzymes. The aim of the present study was to estimate the effect of ectopic AP overexpression on the activity of AC and steroidogenic intracellular enzymes. Methods: ACTH and forskolin were used for AC stimulation, and dibutyryl cAMP and progesterone were used for stimulation of intracellular steroidogenic enzymes in isolated adrenal cells in male C57Bl/6J mice of two Agouti genotypes: A y /a (ectopic AP overexpression) and a/a (absence of AP in all tissues). Results: ACTH and forskolin increased cAMP accumulation to the same extent in both A y /a and a/a mouse adrenal cells (P , 0.001; ANOVA), but resulted in higher corticosterone production in A y /a mice (P , 0.001 for ACTH and P , 0.01 for forskolin; ANOVA). Dibutyryl cAMP-and progesterone-induced corticosterone production was higher in A y /a mice than in a/a mice (P , 0.001 for dibutyryl cAMP and P , 0.01 for progesterone; ANOVA). Conclusions: Ectopic AP overexpression increased stimulated corticosterone production and intracellular steroidogenic enzyme reactivity to cAMP without an effect on AC activity.
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