Endocrine Abstracts

Inactivating mutations of the POMC gene in humans and mice result in a complex phenotype of hyperphagia, obesity and glucocorticoid (GC) deficiency, but without many features of metabolic syndrome. We have previously shown that replacement of GC in Pomc^−/− mice exacerbates their hyperphagia, increases fat mass and elevates plasma leptin and insulin. We have now examined key determinants of glucocorticoid action, including glucocorticoid receptor (GR) and the glucocorticoid amplifying enzyme, 11β-hydroxysteroid dehydrogenase type 1 (11HSD1), in Pomc^−/− mice given corticosterone supplemented water (25 μg/ml) (CORT) for 10 d. CORT significantly increased adipose 11HSD1 mRNA levels in all fat depots in both genotypes without affecting hepatic 11HSD1 mRNA levels. The magnitude of the increase was greater in Pomc^−/− (untreated vs CORT, 0.07±0.02 vs 0.51±0.15, P<0.001 compared to 0.15±0.07 vs 0.31±0.17 P<0.001 in wild type (WT) mice). GR mRNA levels were unaffected by CORT treatment, but were higher in retroperitoneal fat of untreated Pomc^−/− mice compared to WT (WT vs Pomc^−/− 0.714±0.05 vs 0.882±0.044, P=0.05). Lipoprotein lipase mRNA levels were increased in all fat depots in CORT treated Pomc^−/− but were unaffected in WT mice. Despite a significant difference in weight, blood pressure in untreated Pomc^−/− mice was similar to WT. However, CORT in Pomc^−/− mice increased BP (untreated vs CORT, 95.8+5.1 mmHg vs 160.5+4.1 mmHg, respectively, P<0.001) and hepatic angiotensinogen mRNA levels (0.595±0.03 vs 0.76±0.03, P<0.01). Pomc^−/− mice had reduced hepatic PEPCK mRNA levels (WT vs Pomc^−/−, 0.30±0.03 vs 0.150±0.03, P<0.01) but following CORT, PEPCK increased (0.352±0.03, P<0.05) to exceed levels in CORT treated WT mice. These data give insights into why Pomc^−/− mice appear hypersensitive to the adverse metabolic effects of glucocorticoids and suggest that adipose-specific amplification of GC by increased 11HSD1 expression may contribute to the adverse metabolic effects of melanocortin deficiency. They may be of relevance to differential susceptibility to metabolic syndrome in common obesity.