Exogenous Steatosis and Hepatic Insulin Resistance Are Early Consequences of High Fat Feeding

Lanthier, Nicolas [UCL] Petit, M. [UCL] Lebrun, Valérie [UCL] Molendi, O. [UCL] Cani, Patrice D. [UCL] Horsmans, Yves Leclercq, Isabelle [UCL] et al.[show all]

(eng) Background and aims: High fat feeding leads to obesity and insulin resistance. Here, we examined the initial pathways involved in hepatic fat accumulation and insulin resistance and their consequences on whole-body glucose homeostasis. Methods: Male 5 weeks old C57BL/6J mice were fed a standard or a high fat diet (HFD-60 kcal % fat) for three days. Body weight, blood glucose and insulin were followed. Hepatic steatosis was assessed on liver histology and by measurement of hepatic lipid content. The hyperinsulinemic-euglycemic clamp technique evaluated insulin sensitivity in vivo. The insulin signalling pathway was analysed in the liver and in the muscle following intravenous injection of insulin. RT-qPCR was used to examine mRNA expression of hepatic genes involved in lipid metabolism. Results: After three days of HFD feeding, the body weight gain is significantly higher than in controls, correlated with a higher liver weight, in relation with a 4 fold increase in hepatic lipid content. Hepatic expression of the fatty acid transporter CD36 is up-regulated compatible with increased FA uptake. In contrast, transcription factor SREBP-1c is inactivated together with downregulation of enzymes involved in lipogenic pathways such as SCD-1 and FAS, while genes encoding for enzymes involved in oxidation are increased. HFD-fed animals have higher blood glucose and insulin levels. Insulin resistance in the HFD group is confirmed by the hyperinsulinemic-euglycemic clamp with a lower glucose infusion rate necessary to maintain euglycaemia, mainly owed to a significant reduction in insulin-stimulated inhibition of hepatic glucose production. It was accompanied by inhibition of insulin-dependent activation of the insulin receptor/Akt pathway in the liver but not in the muscle. Conclusion: High fat feeding induces early dysregulation of hepatic insulin sensitivity and lipid metabolism. Acute changes in hepatic lipid content are primarily due to increase uptake of dietary fatty acids which is not sufficiently counterbalanced by inhibition of de novo lipid synthesis and increased FA burning. The rapid insulin resistance is, at least partly, explained by impaired insulin receptor phosphorylation in the liver. This suggests that those initial metabolic changes in the liver may be pivotal for further progression to metabolic syndrome.