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

  1. Werner A Scherbaum
  1. Department of Internal Medicine III, University of Leipzig Leipzig
  2. Diabetes Research Institute at the University of Diisseldorf Diisseldorf, Germany
  1. Address correspondence and reprint requests to Dr. Stefan R. Bornstein, Department of Internal Medicine III, University of Leipzig, Phillip-Rosenthal-Str. 27, 04103 Leipzig, Germany.

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 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.

  • Received March 24, 1997.
  • Revision received April 30, 1997.
  • Accepted April 30, 1997.
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