Endocrine Abstracts

Obese humans and rats exhibit altered glucocorticoid metabolism; increased regeneration of glucocorticoid by adipose 11HSD1 and inactivation by hepatic A-ring reductases. The mechanisms remain unclear; candidates include resistance to insulin-mediated regulation, and secondary effects of adipose products eg TNFalpha. To explore temporal associations between changes in glucocorticoid metabolism, insulin resistance and obesity, we examined effects of high-fat feeding in rats.
Male Wistar rats were weaned onto a high-fat (HF; 45% kcal from fat) or control (10% fat) diet. After 3 and 20 weeks, 8 animals per group had oral glucose tolerance tests and blood was sampled at 0800h and 1900h before culling. After 3 weeks, HF rats showed no differences in weight or plasma corticosterone; but were glucose intolerant (120 minute plasma glucose: 8.6 plus/minus 0.8 vs 6.5 plus/minus 1.0 mM, mean plus/minus SE, p<0.05); had lower 11HSD1 activity in liver (by 21%, p<0.01), subcutaneous (by 62%, p<0.01), retroperitoneal (by 34%, p<0.01) and omental fat (by 32%, p<0.05); and higher hepatic 5beta-reductase activity (by 255%, p<0.05). After 20 weeks, HF rats remained hyperglycaemic and were hyperinsulinaemic (p<0.05) and in addition were obese (618 plus/minus 17 vs 540 plus/minus 20g, p<0.05); with lower 1900h plasma corticosterone (795 plus/minus 23 vs 1023 plus/minus 66 nM, p<0.01). However, after 20 weeks HF feeding, differences in 11HSD1 and 5beta-reductase activities were no longer apparent.
These data indicate dissociation between hyperinsulinaemia, obesity, and determinants of glucocorticoid action during HF feeding. Acutely, HF induces glucose intolerance without obesity, decreased 11HSD1, increased 5 beta-reductase, and normal plasma corticosterone; this predicts lower intracellular corticosterone, which may ameliorate metabolic consequences of HF. Chronically, in contrast, HF induces obesity accompanied by hypercorticosteronaemia and increasing 11HSD1 activity. This suggests that increased tissue concentrations of glucocorticoids in obesity are related to increased fat mass, rather than to its dietary or metabolic antecedents.