Hepatic p38α at the forefront of high fat diet-induced insulin resistance, hepatic steatosis, and liver-periphery cross-talk

Mitogen-activated protein kinases play an essential role in the onset of hepatic metabolic dysregulation; however, current data fail to establish a definitive role for p38. We generated a hepatocyte-specific p38α knockout (p38α KO) mouse model to investigate the role of p38α in regulating hepatic glucose and lipid metabolism following 1 week of high-fat diet (HFD) feeding. Short-term HFD-feeding increased hepatic p38 activation in mice. Hepatocyte-specific p38α KO mice were protected from the development of HFD-induced hepatic insulin resistance, in part due the abolition of circulating interleukin-6 (IL-6). Unexpectedly, hepatocyte-specific p38α KO mice were also protected from HFD-induced peripheral insulin resistance. The liver-peripheral tissue axis underlying the onset of HFD-mediated peripheral insulin resistance may be explained by muscle fat accumulation promoted by p38α-mediated hepatic triglyceride (TG) secretion. HFD-induced activation of p38α promoted TG accumulation in the liver, potentially via enhanced expression of peroxisome proliferator-activated receptor gamma (PPAR-γ) and subsequent regulation of perilipin gene expression. Overall, our data provide compelling evidence that selective p38α inhibition may offer a new approach for the treatment of insulin resistance and hepatic steatosis.