Glucocorticoids dramatically increase hepatic insulin resistance and steatosis in the presence of high fat feeding

Abstract

Non alcoholic fatty liver disease (NALFD) occurs as a result of lipid excess and is associated with features of the metabolic syndrome including insulin resistance and central obesity. Chronic elevations of the stress hormones glucocorticoids (GCs), or consumption of a high fat diet (HFD) can result in symptoms of the metabolic syndrome, and may contribute to NAFLD. Objective Determine whether chronically elevated GCs combined with HFD will result in NALFD. Hypothesis GCs and HFD will act synergistically to result in insulin resistance, central obesity and NAFLD. Methods At 6 weeks of age, male Sprague Dawley rats were implanted with corticosterone (CORT) pellets to chronically elevate plasma GC levels, or wax pellets to serve as controls. Animals from each group were subdivided to receive either a 60% HFD or standard rodent diet (Chow) for 2 weeks (n=6 per group). Results Hepatic triglyceride content and visceral adiposity mass were elevated 2-fold in the CORT+ high fat (CF) group relative to Wax Chow (WC) controls (p<0.05). CF group rapidly developed severe insulin resistance (HOMA-IR >30-fold vs. WC, p<0.05). Expression of the transcription factor FOXO1 and gluconeogenic enzymes were increased by 75% and 25% respectively relative to WC (p<0.05). Conclusion Chronically elevated GCs combined with HFD synergistically induce insulin resistance, uncontrolled gluconeogenesis and hepatic lipid accumulation.