Hepatic Oncostatin M Receptor β Regulates Obesity-Induced Steatosis and Insulin Resistance

The liver is an essential insulin-responsive organ that is critical for maintaining glucose homeostasis and lipid metabolism. Oncostatin M receptor beta chain (OSMR beta) is implicated in adipose tissue- and immune cell-mediated metabolic regulation. However, the role of hepatocyte-derived OSMR beta in metabolic disorders remains unclear. Here, we report on the central role of OSMR beta in the protection against obesity and deregulation of glucose and Lipids. We observed significantly varied expression levels of OSMR beta in hepatic tissues in both human samples and mouse models of nonalcoholic fatty liver disease. Mice lacking either whole-body or hepatic OSMR beta displayed exacerbated diet-induced insulin resistance, hepatic steatosis, and inflammation, both in diet-induced and genetically (ob/ob) obese mice. These adverse effects were markedly attenuated by hepatocyte-specific overexpression of OSMR beta. Mechanistically, we showed that OSMR beta phosphorylates and activates the Janus kinase 2 (JAK2)/STAT3 signaling pathway in the Liver. More importantly, the liver-restricted overexpression of STAT3 rescued glucose tolerance and ameliorated hepatic steatosis and inflammation in OSMR beta knockout mice, whereas OSMR beta overexpression failed to protect against hepatic steatosis, insulin resistance, and hepatic inflammation in STAT3-deficient mice. Thus, activation of STAT3 is both sufficient and required to produce OSMR beta-mediated beneficial effects. In conclusion, hepatic OSMR beta expression alleviates obesity-induced hepatic insulin resistance and steatosis through the activation of JAK2/STAT3 signaling cascades.