Journal
JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM
Volume 106, Issue 3, Pages E1206-E1220Publisher
ENDOCRINE SOC
DOI: 10.1210/clinem/dgaa896
Keywords
cortisol; cortisone; 11 beta-hydroxysteroid dehydrogenase 1; insulin; obesity
Categories
Funding
- British Heart Foundation [RG/11/4/28734]
- Centre for Research Excellence
- Wellcome Trust [107049/Z/15/Z]
- CSO [SCAF/17/02]
- Wellcome Trust [107049/Z/15/Z] Funding Source: Wellcome Trust
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Insulin upregulates cortisol regeneration in adipose tissue but not in skeletal muscle. In obesity, the balance between 11 beta-reductase and 11 beta-dehydrogenase activities likely leads to cortisol accumulation in adipose tissue, which may have adverse metabolic consequences.
Context: 11 beta-Hydroxysteroid dehydrogenase 1 (11 beta HSD1) reduces inert cortisone into active cortisol but also catalyzes reverse dehydrogenase activity. Drivers of cortisol/cortisone equilibrium are unclear. With obesity, 11 beta HSD1 transcripts are more abundant in adipose, but the consequences for oxidation vs reduction remain unknown. Objective: This work aimed to determine whether 11 beta HSD1 equilibrium in metabolic tissues is regulated by insulin and obesity. Methods: A 2-phase, randomized, crossover, single-blinded study in a clinical research facility was conducted of 10 lean and obese healthy men. 11 beta-Reductase and 11 beta-dehydrogenase activities were measured during infusion of 9,11,12,12-[H-2](4)-cortisol and 1,2-[H-2](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. Results: 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 11 beta-HSD1 reductase activity tended to be higher in obesity (similar to 10%) and was further increased by insulin. Across adipose tissue, 11 beta-reductase activity was detected in obese individuals only and increased in the presence of insulin (18.999.62 vs placebo 11.68 +/- 3.63 pmol/100 g/minute; P<.05). Across skeletal muscle, 11 beta-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). Conclusions: Regeneration of cortisol is upregulated by insulin in adipose tissue but not skeletal muscle. In obesity, the equilibrium between 11 beta-reductase and 11 beta-dehydrogenase activities likely promotes cortisol accumulation in adipose, which may lead to adverse metabolic consequences.
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