Deficiency of OncostatinMReceptor β (OSMR β) Exacerbates High-fat Diet-induced Obesity and Related Metabolic Disorders in Mice

Background: Obesity is associated with adipose tissue inflammation, insulin resistance, and hepatic steatosis. Results: OSM receptor (OSMR)-deficient mice fed a high-fat diet exhibited severe obesity, adipose tissue inflammation, insulin resistance, and hepatic steatosis. Conclusion: OSM signaling has suppressive effects on the deterioration of obesity-induced metabolic disorders. Significance: These results indicate that OSM signaling may be a promising therapeutic target of obesity-induced metabolic disorders. Oncostatin M (OSM) belongs to the IL-6 family of cytokines and has diverse biological effects, including the modulation of inflammatory responses. In the present study we analyzed the roles of OSM signaling in obesity and related metabolic disorders. Under a high-fat diet condition, OSM receptor subunit-deficient (OSMR-/-) mice exhibited increases in body weight and food intake compared with those observed in WT mice. In addition, adipose tissue inflammation, insulin resistance, and hepatic steatosis were more severe in OSMR-/- mice than in wild-type (WT) mice. These metabolic phenotypes did not improve when OSMR-/- mice were pair-fed with WT mice, suggesting that the effects of OSM signaling on these phenotypes are independent of the increases in the body weight and food intake. In the liver of OSMR-/- mice, the insulin-induced phosphorylation of p70 S6 kinase remained intact, whereas insulin-induced FOXO1 phosphorylation was impaired. In addition, OSMR-/- mice displayed a higher expression of genes related to de novo lipogenesis in the liver than WT mice. Furthermore, treatment of genetically obese ob/ob mice with OSM improved insulin resistance, adipose tissue inflammation, and hepatic steatosis. Intraportal administration of OSM into ob/ob mice activated STAT3 and increased the expression of long-chain acyl-CoA synthetase (ACSL) 3 and ACSL5 with decreased expression of fatty acid synthase in the liver, suggesting that OSM directly induces lipolysis and suppresses lipogenesis in the liver of obese mice. These findings suggest that defects in OSM signaling promote the deterioration of high-fat diet-induced obesity and related metabolic disorders.