Lack of Oncostatin M Receptor β Leads to Adipose Tissue Inflammation and Insulin Resistance by Switching Macrophage Phenotype

Oncostatin M (OSM), a member of the IL-6 family of cytokines, plays important roles in a variety of biological functions, including inflammatory responses. However, the roles of OSM in metabolic diseases are unknown. We herein analyzed the metabolic parameters of OSM receptor β subunit-deficient (OSMRβ −/− ) mice under normal diet conditions. At 32 weeks of age, OSMRβ −/− mice exhibited mature-onset obesity, severer hepatic steatosis, and insulin resistance. Surprisingly, insulin resistance without obesity was observed in OSMRβ −/− mice at 16 weeks of age, suggesting that insulin resistance precedes obesity in OSMRβ −/− mice. Both OSM and OSMRβ were expressed strongly in the adipose tissue and little in some other metabolic organs, including the liver and skeletal muscle. In addition, OSMRβ is mainly expressed in the adipose tissue macrophages (ATMs) but not in adipocytes. In OSMRβ −/− mice, the ATMs were polarized to M1 phenotypes with the augmentation of adipose tissue inflammation. Treatment of OSMRβ −/− mice with an anti-inflammatory agent, sodium salicylate, improved insulin resistance. In addition, the stimulation of a macrophage cell line, RAW264.7, and peritoneal exudate macrophages with OSM resulted in the increased expression of M2 markers, IL-10, arginase-1, and CD206. Furthermore, treatment of C57BL/6J mice with OSM increased insulin sensitivity and polarized the phenotypes of ATMs to M2. Thus, OSM suppresses the development of insulin resistance at least in part through the polarization of the macrophage phenotypes to M2, and OSMRβ −/− mice provide a unique mouse model of metabolic diseases. Background: OSM, a member of IL-6 family of cytokines, is involved in many inflammatory diseases. Results: OSMRβ −/− mice exhibited phenotypic changes in ATMs to M1, increased proinflammatory cytokines in the adipose tissue, and systemic insulin resistance. Conclusion: OSMRβ −/− mice exhibited adipose tissue inflammation and insulin resistance preceding obesity. Significance: OSMRβ −/− mice constitute a unique mouse model of metabolic disorders.