Endocrine Abstracts

Case reports in humans implicate glucocorticoid (GC) excess, through exogenous administration or endogenous overproduction, as a cause of non-alcoholic fatty liver disease. In rodents, massive doses of GCs have induced fatty liver when liver fat was measured in the fasting state. The mechanisms through which GCs might induce fatty liver are unknown, but are thought to be secondary to insulin resistance/hyperinsulinaemia. In this study, we examined the effect of dexamethasone (DEX) or corticosterone (CORT) on plasma glucose and insulin levels, and liver triglycerides (TG) content in mice.

C57B6/J mice were injected daily with 100ug/kg or 1mg/kg of DEX, or 30mg/kg CORT, for 3 weeks. Control animals received vehicle injections; n=6 per group. Animals were killed in the ad lib fed state. In a separate cohort, mice received 1mg/kg DEX or vehicle for 3 weeks and were killed after 6 or 16 hours fasting. Liver triglycerides were extracted with propan-2-ol and quantified with a commercial colorimetric assay.

GC-treated animals did not gain weight and had no change in fat pad weight/body weight ratios; HPA axis was suppressed as were thymus and spleen sizes. GCs induced hyperinsulinaemia, but not hyperglycaemia. Although fasting increased liver TG (2.4-fold), there was no effect of GCs, either in the ad lib fed state (e.g. DEX 1mg/kg 10.0 plus/minus 1.7 umol/g liver vs 9.8 plus/minus 2.7, p=0.8) or after fasting.

These data show that moderate or high dose glucocorticoid exposure does not cause fatty liver, or exacerbate liver fat accumulation during fasting, in C57BL/6 mice despite inducing insulin resistance. Unlike humans, mice do not reliably become obese with exogenous GC therapy; if GCs do induce fatty liver in humans, it may be that increased free fatty acid supply to the liver from peripheral adipose tissue is more important than direct effects on hepatic insulin sensitivity.