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

Tadasuke Komori,Minoru Tanaka,Emiko Senba,Atsushi Miyajima,Yoshihiro Morikawa

doi:10.1074/jbc.m113.461905

Tadasuke Komori, Minoru Tanaka + Show 3 more

Open Access

https://doi.org/10.1074/jbc.m113.461905

Copy DOI

Abstract

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.

Highlights

Oncostatin M (OSM), a member of IL-6 family of cytokines, is involved in many inflammatory diseases
OSM belongs to the IL-6 family of cytokines, including IL-6, IL-11, leukemia inhibitory factor, ciliary neurotrophic factor, and cardiotrophin-1 [30] and exhibits a variety of physiological functions, including the development of neurons and hepatocytes, hematopoiesis, and the modulation of inflammatory responses [21, 31,32,33]
It is well established that the balance between pro- and antiinflammatory cytokines secreted from the adipose tissue is important for systemic insulin sensitivity

Summary

Background

OSM, a member of IL-6 family of cytokines, is involved in many inflammatory diseases. Insulin resistance without obesity was observed in OSMR␤؊/؊ mice at 16 weeks of age, suggesting that insulin resistance precedes obesity in OSMR␤؊/؊ mice Both OSM and OSMR␤ were expressed strongly in the adipose tissue and little in some other metabolic organs, including the liver and skeletal muscle. OSM suppresses the development of insulin resistance at least in part through the polarization of the macrophage phenotypes to M2, and OSMR␤؊/؊ mice provide a unique mouse model of metabolic diseases. TNF-␣, a potent proinflammatory cytokine, is produced by M1 ATMs [7, 15] and directly induces insulin resistance by inhibiting the insulin signaling and insulin-stimulated glucose transport, mainly in the skeletal muscle and white adipose tissue [16, 17]. In the present study we have addressed this question using OSMR␤-deficient (OSMR␤Ϫ/Ϫ) mice

EXPERIMENTAL PROCEDURES

RESULTS

DISCUSSION