title: Evidence for a novel peripheral action of leptin as a metabolic signal to the adrenal gland: leptin inhibits cortisol release directly.
abstract: 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 17alpha mRNA following incubation with ACTH (10 nmol/l) and leptin (10-1,000 ng/ml) was analyzed by Northern blot. Adrenocortical cells were characterized by immunohistochemical staining for 17alpha-hydroxyprogesterone. Leptin (10-1,000 ng/ml) inhibited basal and ACTH-stimulated 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/l) was blunted to 55.2 +/- 27%. At more physiological concentrations of ACTH (0.1 nmol/l), 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/l). Addition of OB protein (10-1,000 ng/ml) led to a dose-dependent reduction of ACTH-stimulated cytochrome P450 17alpha 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.
authors.affiliation: Department of Internal Medicine III, University of Leipzig, Germany.
authors.forename: S R
authors.initials: SR
authors.lastname: Bornstein
authors.forename: K
authors.initials: K
authors.lastname: Uhlmann
authors.forename: A
authors.initials: A
authors.lastname: Haidan
authors.forename: M
authors.initials: M
authors.lastname: Ehrhart-Bornstein
authors.forename: W A
authors.initials: WA
authors.lastname: Scherbaum
mesh_terms: D000311:Adrenal Glands / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D000324:Adrenocorticotropic Hormone / Q000494:pharmacology*; D000818:Animals; D002417:Cattle; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D006854:Hydrocortisone / Q000378:metabolism*; D020738:Leptin; D008297:Male; D051379:Mice; D011506:Proteins / Q000494:pharmacology* / Q000502:physiology; D012333:RNA, Messenger / Q000032:analysis / Q000235:genetics; D011994:Recombinant Proteins / Q000494:pharmacology; D013254:Steroid 17-alpha-Hydroxylase / Q000187:drug effects* / Q000235:genetics
chemical_list: D020738:Leptin; D011506:Proteins; D012333:RNA, Messenger; D011994:Recombinant Proteins; D000324:Adrenocorticotropic Hormone; D013254:Steroid 17-alpha-Hydroxylase; D006854:Hydrocortisone