Insulin action is of particular importance in liver during the fasted-to-fed transition. Insulin then stimulates glycogen repletion, glycolysis, and hepatic lipogenesis and suppresses hepatic PDK4 protein expression and HGP. In PPARα −/− mice, it was observed that all these insulin actions were impaired, and therefore these mice were denoted as insulin resistant [20, 35, 39, 44]. For example, differential expression between the fasted and fed state of several insulin-responsive genes was lost in PPARα −/− mice [35]. Both in the fed and fasted state, G6P dehydrogenase (G6PDH) and Taldo expression levels were lower in PPARα −/− mice and during refeeding, induction of glucokinase expression was blunted [35]. Because SREBP-1c is a major mediator of insulin action on hepatic glycolytic and lipogenic gene expression [59], lower SREBP-1c expression levels in liver of PPARα −/− mice also point to reduced hepatic insulin sensitivity.
