Effects of Obesity and Insulin on Tissue-Specific Recycling Between Cortisol and Cortisone in Men.

Abstract

11β-Hydroxysteroid dehydrogenase 1 (11βHSD1) reduces inert cortisone into active cortisol but also catalyzes reverse dehydrogenase activity. Drivers of cortisol/cortisone equilibrium are unclear. With obesity, 11βHSD1 transcripts are more abundant in adipose, but the consequences for oxidation vs reduction remain unknown. This work aimed to determine whether 11βHSD1 equilibrium in metabolic tissues is regulated by insulin and obesity. A 2-phase, randomized, crossover, single-blinded study in a clinical research facility was conducted of 10 lean and obese healthy men. 11β-Reductase and 11β-dehydrogenase activities were measured during infusion of 9,11,12,12-[2H]4-cortisol and 1,2-[2H]2-cortisone, respectively, on 2 occasions: once during saline infusion and once during a hyperinsulinemic-euglycemic clamp. Arterialized and venous samples were obtained across forearm skeletal muscle and abdominal subcutaneous adipose. Steroids were quantified by liquid chromatography-tandem mass spectrometry and adipose tissue transcripts by quantitative polymerase chain reaction. Neither whole-body nor tissue-specific rates of production of cortisol or cortisone differed between lean and obese men, however insulin attenuated the diurnal decrease. Whole-body 11β-HSD1 reductase activity tended to be higher in obesity (~ 10%) and was further increased by insulin. Across adipose tissue, 11β-reductase activity was detected in obese individuals only and increased in the presence of insulin (18.99 ± 9.62 vs placebo 11.68 ± 3.63 pmol/100 g/minute; P < .05). Across skeletal muscle, 11β-dehydrogenase activity was reduced by insulin in lean men only (2.55 ± 0.90 vs 4.50 ± 1.42 pmol/100 g/minute, P < .05). Regeneration of cortisol is upregulated by insulin in adipose tissue but not skeletal muscle. In obesity, the equilibrium between 11β-reductase and 11β-dehydrogenase activities likely promotes cortisol accumulation in adipose, which may lead to adverse metabolic consequences.