Insulin resistance and hepatic fat accumulation are features of metabolic syndrome, although the mechanisms remain unclear. The cellular-stress responsive kinase, p38 Mitogen Activated Protein Kinase (p38), has controversial roles in regulating glucose and lipid metabolism in vivo. Here we show that liver-specific p38 stimulates hepatic triglyceride accumulation and contributes to the development of high fat diet (HFD)-induced insulin resistance. Liver-specific p38 knockout mice (p38KO) and wild type controls (WT) were fed a HFD or control diet for one week. Glucose tolerance tests revealed that HFD-fed p38KO mice had improved glucose tolerance compared to HFD-fed WT mice. Moreover, hyperinsulinemic-euglycemic clamps were performed to assess insulin sensitivity. HFD-fed p38KO mice were protected from reduced whole-body insulin action seen in HFD-fed WT mice, having similar glucose infusion rates as WT mice fed a control diet. To assess hepatic triglyceride accumulation, liver sections were stained with Oil Red-O post diet treatment. HFD-fed WT mice had significantly greater hepatic triglycerides, represented as a percentage of total liver area, compared to HFD-fed p38KO mice. In accordance with reduced hepatic triglyceride accumulation, decreasing trends in triglyceride secretion rates and plasma ApoB protein expression were reported between HFD-fed p38KO and HFD-fed WT mice following Poloxamer-407 injections. Overall, our data suggest that genetic inhibition of hepatic p38 may provide benefit in controlling heightened hepatic fat accumulation and reduced insulin sensitivity observed in HFD models.


S.L. Rivers: None. H. Wang: None. L. Lam: None. A. Giacca: Research Support; Self; Jazz Pharmaceuticals.


Canadian Institutes of Health Research

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