PGC1α protects against hepatic steatosis and insulin resistance via enhancing IL10-mediated anti-inflammatory response.

Inflammatory responses are pivotal incidences in hepatic metabolic derangements. However, the underlying mechanism remains elusive. The present study aimed to evaluate the role of peroxisome proliferator-activated receptor-gamma, coactivator 1 alpha (PGC1 alpha) in IL10-mediated anti-inflammatory response, and its role in hepatic steatosis and insulin resistance. Hepatocyte-specific PGC1 alpha knock-in (LivPGC1 alpha) mice and the control mice were fed high-fat diet (HFD) for 8 weeks. IL-10 neutralizing antibody was injected into the liver of PGC1 alpha mice. A variety of biological and histological approaches were applied to assess hepatic function. We demonstrated that hepatic PGC1 alpha expression was significantly reduced in mice fed HFD. LivPGC1 alpha livers exhibited enhanced gene expressions involving mitochondrial function, and favored an accelerated lipid metabolism upon HFD. Meanwhile, LivPGC1 alpha mice revealed improved hepatic steatosis and insulin resistance. Mechanistically, PGC1 alpha bound and activated the promotor region of IL-10, thereby attenuating inflammatory response in the liver. Administration of IL10 neutralizing antibody to LivPGC1 alpha mice abolished PGC1 alpha-mediated anti-inflammatory effects in mice. Further, IL-10 neutralizing antibody intervention aggravated hepatic steatosis and insulin resistance in LivPGC1 alpha mice. Taken together, our data indicated that hepatic-specific overexpression of PGC1 alpha exerts a beneficial role in the regulation of hepatic steatosis and insulin resistance via enhancing IL10-mediated anti-inflammatory response. Pharmacological activation of PGC1 alpha-IL10 axis may be promising for the treatment of fatty liver diseases.