Evidence for a Novel Peripheral Action of Leptin as a Metabolic Signal to the Adrenal Gland: Leptin Inhibits Cortisol Release Directly Free

The crucial role of glucocorticoids in obesity and insulin resistance and the actions of the OB protein leptin on the hypothalamic-pituitary-adrenal (HPA) axis suggest that there is an important interaction of leptin with the glucocorticoid system. Therefore, we designed a study to test the effect of leptin directly on adrenocortical steroidogenesis. Primary cultures of bovine adrenocortical cells were incubated with increasing concentrations (10–1,000 ng/ml) of recombinant mouse leptin for 24 h, and the effects of leptin on basal and ACTH-stimulated cortisol secretion were determined. The accumulation of P450 17α mRNA following incubation with ACTH (10 nmol/1) and leptin (10–1,000 ng/ml) was analyzed by Northern blot. Adrenocortical cells were characterized by immunohistochemical staining for 17α-hydroxyprogesterone. Leptin (10–1,000 ng/ml) inhibited basal and ACTHstimulated cortisol release. At a concentration that occurs in obese individuals in vivo (100 ng/ml), it reduced basal cortisol secretion to 52.7 ± 37% (mean ± SE). The rise in cortisol secretion following maximal ACTH stimulation (10 nmol/1) was blunted to 55.2 ± 27%. At more physiological concentrations of ACTH (0.1 nmol/1), the inhibition of cortisol release by coincubation with low doses of leptin (10 ng/ml) was even more pronounced, leading to a reduction to 32.8% (1,248 ± 134 vs. 410 ± 157 nmol/1). Addition of OB protein (10–1,000 ng/ml) led to a dose-dependent reduction of ACTH-stimulated cytochrome P450 17α mRNA accumulation (from 80 to 45%), suggesting that leptin regulates adrenal steroidogenesis at the transcriptional level. These data clearly demonstrate that leptin inhibits cortisol production in adrenocortical cells and therefore appears to be a metabolic signal that directly acts on the adrenal gland.