Hepatic p38α at the forefront of diet-induced insulin resistance and hepatic steatosis

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 wk 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 to 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.<b>NEW & NOTEWORTHY</b> Our data indicate that hepatocyte-specific p38α KO mice are protected from <i>1</i>) HFD-induced hepatic insulin resistance in part through reduced interleukin-6 (IL-6) secretion; <i>2</i>) peripheral insulin resistance via decreased hepatic triglyceride (TG) secretion and muscle fat accumulation; and <i>3</i>) hepatic steatosis through reduced proliferator-activated receptor gamma (PPAR-γ) regulating perilipin gene expression. We thus provide new evidence on the potential of selective p38α inhibition as a new treatment for insulin resistance and hepatic steatosis.