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 17a 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 17a-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 17a 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.

Nutrition-induced differences in body composition, compensatory growth and endocrine status in growing pigs ,

“…The role of leptin as an adipostat is confirmed by the increases in plasma leptin levels (Table 4; P , 0.05) at the end of the restriction phase and when AA intake was reduced. The observation that leptin inhibits cortisol synthesis by adrenal cells (Bornstein et al, 1997;Pralong et al, 1998) is supported by the negative correlation observed in this experiment between plasma circulating leptin and cortisol (P , 0.01; r 5 20.74). In contrast, the observation that leptin increases GH plasma concentration (Barb et al, 1998) is supported by the positive correlation between plasma levels of the two hormones observed in this experiment (P , 0.01; r 5 0.81).…”

The leptin hypothesis of depression: a potential link between mood disorders and obesity?

“…In addition, administration of leptin in developing rats increases the expression of the glucocorticoid receptor in the PVN and hippocampus [51], presumably leading to increased sensitivity of the glucocorticoid receptor. On the other hand, the leptin receptor is present in the adrenal gland, and leptin treatment can directly inhibit basal and ACTH-stimulated cortisol release from adrenal gland in both humans and rodents [52,53]. Collectively, these data support the notion that leptin is capable of regulating the HPA axis at multiple levels.…”

Effects of leptin on adipose tissue lipoprotein lipase in the obese ob/ob mouse

“…The latter indeed exerts a strong attenuating action on the hypothalamic-pituitary-adrenal axis 32 and was shown to directly inhibit cortisol release by bovine adrenocortical cells in primary culture. 33 The leptin-induced decrease in body weight was largely due to a reduction in fat, rather than lean mass, as suggested by the strong relationship between body weight and the sum of the two white adipose depots (r 0.95, P`0.0001) and the lack of effect of leptin on vastus lateralis weight. Comparable observations have been reported in lean and obese mice injected with leptin for 28 d. 7 There is substantial evidence that leptin reduces fat mass not only by reducing food intake, but also by stimulating thermogenesis.…”