Gender-specific Links Between Hepatic 11β Reduction of Cortisone and Adipokines

OBJECTIVE: Reduction of cortisone to cortisol is mediated by 11β-hydroxysteroid dehydrogenase type 1 (11βHSD1), a putative key enzyme in obesity-related complications. Experimental studies suggest that adipokines, notably leptin and tumor necrosis factor-α (TNF-α), are of importance for 11βHSD1 activity. We hypothesized that the regulation of hepatic preceptor glucocorticoid metabolism is gender-specific and associated with circulating levels of leptin and TNF-α receptors and/or sex hormones. RESEARCH METHODS AND PROCEDURES: A total of 34 males and 38 women (14 premenopausal and 22 postmenopausal) underwent physical examination and fasting blood sampling. Insulin sensitivity was tested by euglycemic hyperinsulinemic clamps, and hepatic 11βHSD1 enzyme activity was estimated by the conversion of orally-ingested cortisone to cortisol. RESULTS: Hepatic 11βHSD1 activity was negatively associated with leptin and soluble TNF (sTNF) r1 and sTNFr2 in males. These correlations remained significant after adjustment for age and insulin sensitivity, and for sTNF-α receptors also after adjustment of BMI and waist circumference. In contrast, 11β reduction of cortisone was positively associated to leptin in females after adjustment for BMI and waist circumference. DISCUSSION: Hepatic 11β reduction shows different links to circulating adipocyte-derived hormones in males and females. This emphasizes the need for further studies on tissue-specific regulation of 11βHSD1 in both genders.