Energy adaptation to glucocorticoid-induced hyperleptinemia in human beings

Recombinant leptin therapy potently decreases food intake and body weight in aleptinemic individuals with leptin gene mutations. However, it is unknown whether manipulation of endogenous leptin secretion alters ingestive behavior in otherwise healthy subjects. We therefore assessed energy consumption during administration of hydrocortisone (HC), a known leptin secretagogue. Six healthy adults were admitted overnight on 2 occasions and given HC (12.5 mg/h IV) or saline infusion for 24 hours (8:00 am-8:00 am) in a randomized crossover design. Total energy and macronutrient intake was calculated using a computerized nutrient analysis program. Blood sampling for measurement of leptin, cortisol, glucose, and insulin was performed at baseline and every 1 to 2 hours. A rise in plasma leptin level was noted after ∼5 hours of HC infusion and was sustained throughout the study period. The total energy consumed was 3004 ± 231 kcal for saline and 2486 ± 214 kcal for HC (P = .005); breakfast energy values on day 1 were similar but energy values consumed at lunch, dinner, and day 2 breakfast were all significantly lower during induced hyperleptinemia. Analysis of macronutrients indicated significant decreases in carbohydrate and fat intake during glucocorticoid-induced hyperleptinemia as compared with placebo. These results indicate that stimulation of native leptin secretion decreases energy consumption, similar to the effect observed with recombinant leptin therapy. To our knowledge, this is the first report documenting anti-ingestive responses to a leptin secretagogue. Because chronic glucocorticoid therapy is fraught with adverse effects, we suggest that nonsteroidal or steroidomimetic leptin secretagogues may be good candidates for anorectic and antiobesity drug development.