Dietary macronutrient content alters cortisol metabolism independently of body weight changes in obese men

Context: Dietary macronutrient composition influences cardio-metabolic health independently of obesity. Both dietary fat and insulin alter glucocorticoid metabolism in rodents and, acutely, in humans. However, whether longer- term differences in dietary macronutrients affect cortisol metabolism in humans and contribute to the tissue- specific dysregulation of cortisol metabolism in obesity is unknown. Objective: The objective of the study was to test the effects of dietary macronutrients on cortisol metabolism in obese men. Design: The study consisted of two randomized, crossover studies. Setting: The study was conducted at a human nutrition unit. Participants: Participants included healthy obese men. Interventions, Outcome Measures, and Results: Seventeen obese men received 4 wk ad libitum high fat- low carbohydrate ( HF- LC) ( 66% fat, 4% carbohydrate) vs. moderate fat- moderate carbohydrate ( MF- MC) diets ( 35% fat, 35% carbohydrate). Six obese men participated in a similar study with isocaloric feeding. Both HF- LC and MF- MC diets induced weight loss. During 9,11,12,12-[ (2)H](4)- cortisol infusion, HF- LC but not MF- MC increased 11 beta-hydroxysteroid dehydrogenase type 1 ( 11 beta- HSD1) activity ( rates of appearance of cortisol and 9,12,12-[(2)H](3)- cortisol) and reduced urinary excretion of 5 alpha- and 5 beta- reduced [(2)H](4)- cortisol metabolites and [(2)H](4)- cortisol clearance. HF- LC also reduced 24- h urinary 5 alpha- and 5 beta- reduced endogenous cortisol metabolites but did not alter plasma cortisol or diurnal salivary cortisol rhythm. In sc abdominal adipose tissue, 11 beta-HSD1 mRNA and activity were unaffected by diet. Conclusions: A low- carbohydrate diet alters cortisol metabolism independently of weight loss. In obese men, this enhances cortisol regeneration by 11 beta- HSD1 and reduces cortisol inactivation by A- ring reductases in liver without affecting sc adipose 11 beta- HSD1. Alterations in cortisol metabolism may be a consequence of macronutrient dietary content and may mediate effects of diet on metabolic health.