Lipid-induced hepatic insulin resistance

principal function of insulin in the liver is to suppress glucose production when blood glucose concentrations increase. This process is impaired in hepatic insulin resistance and contributes to postprandial hyperglycemia. The development of hepatic insulin resistance is very closely linked to non alcoholic fatty liver disease (NAFLD), and is a major factor in the pathogenesis of type 2 diabetes (T2D). Yet, the molecular mechanisms regarding the pathogenesis have remained elusive. Among several proposed mechanisms, two main schools of thought have gained support for hepatic insulin resistance associated with NAFLD. Briefly, the first proposes that excess lipid delivery to the liver and/or reductions in fatty acid oxidation, results in accumulation of intracellular diacyglycerols (DAGs). This increase in hepatic DAG content leads to activation of PKCε which, in turn, inhibits insulin-stimulated insulin receptor kinase phosphorylation of IRS proteins and impairs activation of downstream signaling [1, 2] (Figure 1). According to the other school of thought, saturated fatty acids induce insulin resistance by activating inflammatory TLR-4 signaling through the adaptor protein MyD88 leading to increased de novo ceramide synthesis, accumulation of ceramides and ceramide-mediated inhibition of insulin signaling through inhibition of Akt phosphorylation [3]. In this model, TLR-4 signaling and ceramide synthesis are both critical for saturated fat-induced hepatic insulin resistance while unsaturated lipid-induced insulin resistance is independent of the TLR-4 receptor and ceramide synthesis [3]. In a recently published study from our group [4], we tested these hypotheses. The specific aims were to examine: 1) how saturated and unsaturated fat-feeding affects hepatic accumulation of DAGs and ceramides as well as hepatic insulin signaling, and 2) the postulated role of the TLR-4/MyD88 signaling pathway in mediating saturated fat-induced hepatic accumulation of ceramides and hepatic insulin resistance. To address these aims, we conducted experiments in rats fed high fat diets enriched with either saturated or unsaturated fat for three days. This is a well-established Editorial rodent model of selective lipid-induced hepatic insulin resistance. Further, to evaluate the putative role of TLR-4 receptor signaling in saturated lipid-induced insulin resistance, we conducted studies in normal mice treated with antisense oligonucleotides (ASOs) knocking down hepatic TLR-4 or MyD88 expression as well as in TLR-4 deficient mice, and tested how hepatic insulin sensitivity and ceramide/DAG content was affected by exposure to saturated fats. We found that saturated or unsaturated fat-feeding in rats resulted in steatosis, increased intrahepatic DAG content, PKCε activation and impairment of insulin-stimulated IRS2-associated PI3-kinase signaling. …