Context: Administration of glucocorticoids increases serum leptin levels in lean and obese individuals. A morning meal produces an increase in insulin, a cortisol peak and an increase of leptin; these changes do not occur during fasting.

Objective: To investigate whether inhibiting endogenous cortisol secretion with metyrapone decreases 24-h serum leptin levels and to determine whether a meal-related mid-morning surge in cortisol is a prerequisite for the meal-entrained nocturnal rise in leptin.

Design: Randomized, cross-over study design.

Setting: General Clinical Research Center

Participants: Lean males.

Intervention: Study 1: Seven lean men were studied for 24 h while their endogenous cortisol secretions were manipulated as follows: 1) CONTROL; 2) Cortisol suppression by metyrapone (MET); 3) MET + oral hydrocortisone (at 9:00) (MET+CORT). Subjects were all fed a eucaloric diet (2 meals: 11:00 and 17:00). Study 2: Six men were studied without pharmacological intervention for 24-h on two occasions: once under a complete fast (FAST) and once in a feeding condition (one meal at 11:00) (FED).

Main Outcome Measure: Serum leptin.

Results: MET significantly suppressed serum cortisol at 8:00, mid-morning and over the 24 h period. As a result of cortisol suppression, 24-h serum leptin levels were decreased vs. CONTROL, despite similar insulin responses to meals. Administering a single dose of hydrocortisone to MET subjects potently stimulated serum leptin compared with MET alone.

Conclusions: Our data demonstrate that endogenous cortisol secretion is necessary for the maintenance of serum leptin levels over 24 h in lean, normally fed males.