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Dietary Macronutrient Content Alters Cortisol Metabolism Independently of Body Weight Changes in Obese Men

Endocrinology Unit (R.H.S., D.J.W., N.M.M., R.A., B.R.W.), Centre for Cardiovascular Science, Queen’s Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, United Kingdom; Division of Obesity and Metabolic Health (A.M.J., G.E.L.), Rowett Research Institute, Aberdeen AB21 9SB, United Kingdom; and Mass Spectrometry Core Laboratory (N.Z.M.H., R.A., B.R.W.), Wellcome Trust Clinical Research Facility, Queen’s Medical Research Institute, Edinburgh EH16 4TJ, United Kingdom

Address all correspondence and requests for reprints to: Dr. Roland H. Stimson, University of Edinburgh, Endocrinology Unit, Centre for Cardiovascular Science, Queen’s Medical Research Institute, 47 Little France Crescent, Edinburgh EH16 4TJ, Scotland, United Kingdom. E-mail: roland.stimson{at}ed.ac.uk.

Context: Dietary macronutrient composition influences cardiometabolic 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-[²H]₄-cortisol infusion, HF-LC but not MF-MC increased 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) activity (rates of appearance of cortisol and 9,12,12-[²H]₃-cortisol) and reduced urinary excretion of 5- and 5ß-reduced [²H]₄-cortisol metabolites and [²H]₄-cortisol clearance. HF-LC also reduced 24-h urinary 5- and 5ß-reduced endogenous cortisol metabolites but did not alter plasma cortisol or diurnal salivary cortisol rhythm. In sc abdominal adipose tissue, 11ß-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 11ß-HSD1 and reduces cortisol inactivation by A-ring reductases in liver without affecting sc adipose 11ß-HSD1. Alterations in cortisol metabolism may be a consequence of macronutrient dietary content and may mediate effects of diet on metabolic health.

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