Deficiency of oncostatin M receptor β (OSMRβ) exacerbates high-fat diet-induced obesity and related metabolic disorders in mice.
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 β subunit-deficient (OSMRβ(-/-)) 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 OSMRβ(-/-) mice than in wild-type (WT) mice. These metabolic phenotypes did not improve when OSMRβ(-/-) 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 OSMRβ(-/-) mice, the insulin-induced phosphorylation of p70 S6 kinase remained intact, whereas insulin-induced FOXO1 phosphorylation was impaired. In addition, OSMRβ(-/-) 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.
From the Department of Anatomy and Neurobiology, Wakayama Medical University, Wakayama 641-8509, Japan and.
Tadasuke
T
Komori
Laboratory of Cell Growth and Differentiation, Institute of Molecular and Cellular Biosciences, The University of Tokyo, Tokyo 113-0032, Japan.
Minoru
M
Tanaka
From the Department of Anatomy and Neurobiology, Wakayama Medical University, Wakayama 641-8509, Japan and.
Emiko
E
Senba
Laboratory of Cell Growth and Differentiation, Institute of Molecular and Cellular Biosciences, The University of Tokyo, Tokyo 113-0032, Japan.
Atsushi
A
Miyajima
From the Department of Anatomy and Neurobiology, Wakayama Medical University, Wakayama 641-8509, Japan and yoshim@wakayama-med.ac.jp.
Yoshihiro
Y
Morikawa
D000273:Adipose Tissue / Q000187:drug effects; D000818:Animals; D059305:Diet, High-Fat / Q000009:adverse effects*; D006965:Hyperplasia / Q000139:chemically induced / Q000378:metabolism; D007333:Insulin Resistance; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000473:pathology; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D008659:Metabolic Diseases / Q000139:chemically induced* / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D065626:Non-alcoholic Fatty Liver Disease / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D009765:Obesity / Q000139:chemically induced* / Q000378:metabolism* / Q000473:pathology; D053683:Oncostatin M / Q000494:pharmacology; D053681:Oncostatin M Receptor beta Subunit / Q000172:deficiency*; D015398:Signal Transduction / Q000187:drug effects
D053681:Oncostatin M Receptor beta Subunit; D053683:Oncostatin M
Adipose Tissue; Cytokine; Hepatic Steatosis; High-fat Diet; Inflammation; Insulin Resistance; Obesity