RESUMO
BACKGROUND: The enzyme 11-beta hydroxysteroid dehydrogenase type 1 (HSD11B1) converts inactive cortisone to active cortisol in a process mediated by the enzyme hexose-6-phosphate dehydrogenase (H6PD). The generation of cortisol from this reaction may increase intra-abdominal cortisol levels and contribute to the physiopathogenesis of obesity and metabolic syndrome (MetS). The relationship of HSD11B1 rs45487298 and H6PD rs6688832 polymorphisms with obesity and MetS was studied. We also studied how HSD11B1 abdominal subcutaneous (SAT) and visceral adipose tissue (VAT) gene expression is related to body fat distribution. METHODS: Rates of obesity and MetS features were cross-sectionally analyzed according to these polymorphisms in 1006 Brazilian white patients with type 2 diabetes (T2DM). Additionally, HSD11B1 expression was analyzed in VAT and SAT in a different cohort of 28 participants with and without obesity who underwent elective abdominal operations. RESULTS: Although polymorphisms of the two genes were not individually associated with MetS features, a synergistic effect was observed between both. Carriers of at least three minor alleles exhibited lower BMI compared to those with two or fewer minor alleles adjusting for gender and age (27.4 ± 4.9 vs. 29.3 ± 5.3 kg/m2; P = 0.005; mean ± SD). Obesity frequency was also lower in the first group (24.4% vs. 41.6%, OR = 0.43, 95% CI 0.21-0.87; P = 0.019). In the second cohort of 28 subjects, HSD11B1 gene expression in VAT was inversely correlated with BMI (r = - 0.435, P = 0.034), waist circumference (r = - 0.584, P = 0.003) and waist-to-height ratio (r = - 0.526, P = 0.010). CONCLUSIONS: These polymorphisms might interact in the protection against obesity in T2DM individuals. Obese individuals may have decreased intra-abdominal VAT HSD11B1 gene expression resulting in decreasing intra-abdominal cortisol levels as a compensatory mechanism against central and general adiposity.
RESUMO
Metabolic syndrome is an array of closely metabolic disorders that includes glucose intolerance/insulin resistance, central obesity, dyslipidemia, and hypertension. Fructose, a highly lipogenic sugar, has profound metabolic effects in adipose tissue, and has been associated with the etiopathology of many components of the metabolic syndrome. In adipocytes, the enzyme 11 ß-HSD1 amplifies local glucocorticoid production, being a key player in the pathogenesis of central obesity and metabolic syndrome. 11 ß-HSD1 reductase activity is dependent on NADPH, a cofactor generated by H6PD inside the endoplasmic reticulum. Our focus was to explore the effect of fructose overload on epididymal white adipose tissue (EWAT) machinery involved in glucocorticoid production and NADPH and oxidants metabolism. Male Sprague-Dawley rats fed with a fructose solution (10% (w/v) in tap water) during 9 weeks developed some characteristic features of metabolic syndrome, such as hypertriglyceridemia, and hypertension. In addition, high levels of plasma and EWAT corticosterone were detected. Activities and expressions of H6PD and 11 ß-HSD1, NAPDH content, superoxide anion production, expression of NADPH oxidase 2 subunits, and indicators of oxidative metabolism were measured. Fructose overloaded rats showed an increased potential in oxidant production respect to control rats. In parallel, in EWAT from fructose overloaded rats we found higher expression/activity of H6PD and 11 ß-HSD1, and NADPH/NADP+ ratio. Our in vivo results support that fructose overload installs in EWAT conditions favoring glucocorticoid production through higher H6PD expression/activity supplying NADPH for enhanced 11 ß-HSD1 expression/activity, becoming this tissue a potential extra-adrenal source of corticosterone under these experimental conditions.