Searchable abstracts of presentations at key conferences in endocrinology
Endocrine Abstracts (2010) 21 P186

Diabetes and metabolism

Circadian rhythmicity is altered in hepatic corticosterone-related genes from diet induced obese mice

Erika Harno1, Alice Yu2, Henry Brown2, Andrew Turnbull2, Brendan Leighton2 & Anne White1


1University of Manchester, Manchester, UK; 2CVGI, AstraZeneca, Alderley Park, UK.


Increased corticosterone (cortisol in humans) in liver has important adverse effects on glucose metabolism and is therefore a target for diabetes treatments. The functional effects of corticosterone depend on circulating levels as well as tissue regeneration by 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1) and inactivation by steroid 5-α-reductase type I (5αR). This study investigates how obesity affects diurnal changes in circulating corticosterone, the genes controlling tissue bioavailability and glucocorticoid receptor (GR) expression.

Male C57Bl6/Jax mice were fed chow or 60% kcal from fat diet for 13 weeks before being euthanised at each of 10 time points (n=6) around the predicted peak and nadir of corticosterone. Plasma samples were taken for corticosterone and proopiomelanocortin (POMC) measurement and liver samples for qPCR analysis.

In obese mice, POMC concentrations were increased at both nadir (lean 249.3±32 versus obese 395.8±26 pmol/l, P<0.001) and peak (lean 253.2±33 versus obese 295.3±17 pmol/l, P<0.01). Corticosterone was also increased at nadir (lean 78.2±9 versus obese 183.7±29 ng/ml, P<0.01) and peak (lean 149.0±22 versus obese 338.0±25 ng/ml, P<0.001). In lean mice, 11β-HSD1 has a diurnal rhythm, being higher at the nadir, which is lost in obese mice because of decreased levels at the nadir. In contrast 5αR mRNA was reduced in obese mice at both nadir (62%) and peak (74%). GR mRNA was decreased in obese mice by 42% at nadir (P<0.001) and 36% at peak (P<0.05). A similar decrease was observed in its coregulator, PGC-1.

In summary, the HPA axis is upregulated in obese mice. The loss of diurnal rhythm of 11β-HSD1 in liver leads to decreased mRNA expression at the corticosterone nadir implying reduced tissue corticosterone. Conversely decreases in 5αR expression may lead to increased tissue corticosterone. Importantly, the decreased expression of GR and PGC-1 in liver could limit the effects of excess corticosterone in obesity.

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