Dynamic responses to leptin secretagogues in lean, obese, and massively obese men and women.

BACKGROUND/AIM: Basal plasma leptin levels are higher in women than in men and also higher in obese than in lean subjects, but the dynamic leptin secretion has not been well studied. We tested whether the leptin secretory response to glucocorticoid or insulin differs by gender and adiposity status. METHODS: Seventy-nine nondiabetic adults, comprising lean [body mass index (BMI; kg/m(2)) < or =25; n = 27], obese (BMI 30-40; n = 28), and massively obese (BMI >40; n = 24) subjects, participated in two separate studies. In study 1, the subjects received oral dexamethasone (4 mg), with blood sampling before and 8 and 16 h after ingestion. In study 2, the subjects underwent a two-step hyperinsulinemic (1.0 mU.kg(-1)/min for 3 h, then 2.0 mU.kg(-1)/min for 3 h), euglycemic (approximately 100 mg/dl) clamp. Blood samples were obtained at baseline and every 20 min during the clamp. RESULTS: Basal and stimulated leptin levels were higher in women than in men, and higher in the obese groups than in lean subjects. The percentage increase above baseline leptin was similar among men and women within each group, but was approximately 30% lower in massively obese compared to lean subjects. CONCLUSION: Leptin secretory responses to glucocorticoid or insulin stimulation are preserved across a broad adiposity range, with higher absolute responses in women than in men.

Inhibition of cortisol biosynthesis decreases circulating leptin levels in obese humans.

CONTEXT: Glucocorticoids increase both appetite and leptin secretion; the hyperleptinemic effect might be a counterregulatory response to the orexigenic effect of glucocorticoids. However, the effect of glucocorticoid inhibition on leptin production has not been reported. OBJECTIVE: We tested the hypothesis that if glucocorticoid-induced hyperleptinemia plays a physiological role, then inhibition of endogenous cortisol biosynthesis should decrease leptin secretion. DESIGN: A randomized, placebo-controlled, cross-over study design was used. SETTING: The study was carried out at a General Clinical Research Center. PARTICIPANTS: Eight obese subjects (four men, four women; mean age, 30.4 +/- 1.56 yr; mean body mass index, 42.0 +/- 1.33 kg/m2) participated in the study. INTERVENTION: The subjects were treated with metyrapone (750 mg every 4 h) or placebo for 24 h during two overnight admissions, 2 wk apart. Blood sampling for measurement of cortisol, leptin glucose, insulin, and C-peptide was performed hourly for 6 h and every 2 h for 24 h. MAIN OUTCOME MEASURE: The change in plasma leptin from baseline during metyrapone vs. placebo treatment was measured. RESULTS: Metyrapone treatment was associated with a significant decrease in plasma cortisol level; the cortisol nadir was 4.84 +/- 1.22 microg/dl during placebo and 2.80 +/- 0.65 microg/dl during metyrapone treatment (P = 0.009). Compared with placebo, metyrapone treatment was associated with a significant reduction in circulating leptin levels and marked attenuation of the nocturnal rise in plasma leptin (+28.45 +/- 11.12% vs. +55.51 +/- 5.42%; P = 0.01). CONCLUSIONS: We conclude that metyrapone-induced inhibition of cortisol biosynthesis results in hypoleptinemia, which indicates that glucocorticoids may play an important role in the physiological regulation of leptin.

Leptin response to glucocorticoid occurs at physiological doses and is abolished by fasting.

OBJECTIVE: To examine the effects of graded doses of hydrocortisone (HC) on leptin secretion, and determine the effect of fasting. RESEARCH METHODS AND PROCEDURES: This was a randomized, placebo-controlled, crossover study, with a 1-week "washout" period between interventions. Eight healthy subjects [age = 36 +/- 2.3 years (+/-SE), body mass index = 31.5 +/- 1.6 kg/m(2)] completed the dose-response study in which an intravenous infusion of saline (placebo) or HC (30 or 100 mg) was administered for 24 hours. Four healthy subjects (age = 35.2 +/- 3.0 years, body mass index = 27.1 +/- 2.1 kg/m(2)) completed the fasting study, which entailed continuous infusion of saline, HC (300 mg/24 hours) in the fed state, or HC (300 mg/24 hours) with total caloric deprivation for 24 hours. Blood sampling was performed every 1 to 2 hours for measurement of leptin, cortisol, insulin, and glucose levels. RESULTS: Peak hyperleptinemia occurred after 16 hours of HC infusion; peak/baseline leptin levels were 129% (placebo), 140% (30 mg of HC for 24 hours, p = 0.05), and 185% (100 mg of HC for 24 hours, p < 0.01). During infusion of HC (300 mg/24 hours or placebo), the peak/baseline plasma leptin levels were 16.1 +/- 5.8/12.8 +/- 5.9 ng/mL (placebo with food, 126%), 14.6 +/- 6.0/12.5 +/- 6.5 ng/mL (HC fasting, 117%), and 32.5 +/- 12.5/12.0 +/- 8.4 ng/mL (HC with food, 271%, p < 0.001). DISCUSSION: Leptin secretory responses occur at physiological doses of HC, are obliterated by fasting, and thus may be of metabolic significance.