Obesity/Metabolic syndrome (insulin resistance, hypertension, cardiovascular disease) has reached epidemic levels in western societies. Aberrantly elevated glucocorticoid amplification by intracellular enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD-1) within adipose tissue might explain the striking similarities between idiopathic obesity/metabolic syndrome and Cushings syndrome, causes by plasma GC excess. A major contributor to obesity/metabolic syndrome is increased consumption of high fat foods. Specifically, saturated fats are associated with obesity and insulin resistance whereas unsaturated fats are reported to ameliorate metabolic disease. Chronic high fat feeding decreases adipose 11β-HSD1 in mice, possibly counteracting metabolic disease. Here we compare the effects of diets enriched in saturated and unsaturated fats on peripheral GC metabolism. Male C57BL/6J mice (n=12/group) were fed stearate-(saturated), oleate-(monounsaturated), safflower oil- (polyunsaturated) enriched diets (45% as fat) or control diet. Groups were pair-fed to control diet. Body weight was measured for 4-weeks. Plasma insulin, glucose (6 h fasting, a.m., p.m.), corticosterone (a.m., p.m.), adipose and liver 11β-HSD1 (activity, mRNA) and GR (mRNA) levels were determined (mRNA levels determined relative to 18S/U1 RNA; reported as arbitrary units (AU)). The stearate group lost weight (−14.5±1.5% BW, P=0.004), whereas oleate (+11.1±2%, P=0.001) and safflower groups gained weight (+6.6±2.4%, P=0.008). Stearate lowered morning insulin (0.8±0.1 pg/ml vs control 4.2±1.0 pg/ml, P=0.012) but increased corticosterone levels (138±26 nmol/l vs control 13±4 nmol/l, P=0.001). In adipose, stearate increased 11β-HSD1 activity (41±3% conversion 11-dehydrocorticosterone to corticosterone vs control; 28±5%, P=0.03) but decreased GR mRNA levels (68±3 vs control; 102±6 A.U. P=0.05). Stearate increased liver 11β-HSD1 mRNA levels (5.9±0.9 vs control; 1.4±0.6 AU, P=0.001) with a similar trend in GR mRNA. These data suggest that a diet enriched only in saturated fat increases adipose and liver 11β-HSD1 activity. There appears to be a reciprocal down-regulation of adipose GR, possibly limiting GC action. Stearate diet also perturbed the hypothalamic-pituitary-adrenal axis. These changes would be expected to exacerbate insulin resistance.
01 - 05 Apr 2006
European Society of Endocrinology