A Role for Oncostatin M in the Impairment of Glucose Homeostasis in Obesity

Abstract

Context Oncostatin M (OSM) plays a key role in inflammation, but its regulation and function during obesity is not fully understood. Objective The aim of this study was to evaluate the relationship of OSM with the inflammatory state that leads to impaired glucose homeostasis in obesity. We also assessed whether OSM immunoneutralization could revert metabolic disturbances caused by a high-fat diet (HFD) in mice. Design 28 patients with severe obesity were included and stratified into two groups: (1) glucose levels <100 mg/dL and (2) glucose levels >100 mg/dL. White adipose tissue was obtained to examine OSM gene expression. Human adipocytes were used to evaluate the effect of OSM in the inflammatory response, and HFD-fed C57BL/6J mice were injected with anti-OSM antibody to evaluate its effects. Results OSM expression was elevated in subcutaneous and visceral fat from patients with obesity and hyperglycemia, and correlated with Glut4 mRNA levels, serum insulin, homeostatic model assessment of insulin resistance, and inflammatory markers. OSM inhibited adipogenesis and induced inflammation in human adipocytes. Finally, OSM receptor knockout mice had increased Glut4 mRNA levels in adipose tissue, and OSM immunoneutralization resulted in a reduction of glucose levels and Ccl2 expression in adipose tissue from HFD-fed mice. Conclusions OSM contributes to the inflammatory state during obesity and may be involved in the development of insulin resistance.

Identification of candidate biomarkers and therapeutic agents for heart failure by bioinformatics analysis

“…Experiments show that expression of FAP (fibroblast activation protein alpha) [66], THBS4 [67], CD27 [68], LEF1 [69], CTHRC1 [70], ESR1 [71], CXCL9 [72], SERPINA3 [73], TRPC4 [74], F13A1 [75], PIK3C2A [76], KCNIP2 [77] and GPR4 [78] contributed to myocardial infarction. MFAP4 [79], ALOX15 [80], COL1A1 [81], APOA1 [82], PDE5A [83] [154], OSMR (oncostatin M receptor) [155] and IL15RA [156] are involved in development of obesity, but these genes might be key for progression of HF. CTSG (cathepsin G) is a protein coding gene plays important roles in aortic aneurysms [157].…”

Adipocyte Oncostatin Receptor Regulates Adipose Tissue Homeostasis and Inflammation

“…However, it should be noted that the OSM doses used in these mouse experiments were very high (12.5 ng/g body weight, administered twice daily) and may have caused indirect effects on fat mass. The anti-adipogenic effects of OSM have also been shown in human preadipocytes (13). In regard to the molecular mechanisms involved in the impairment of adipogenesis, OSM has been shown to inhibits C/EBPa and PPARg (peroxisome proliferator-activated receptor g) expression, two key transcription factors involved in adipogenesis (40,44).…”

“…The molecular signaling caused by OSM-OSMRß interaction has been suggested to modulate several inflammatory processes, including obesity-related insulin resistance ( 11 , 13 ). One of several mechanisms involved in the ability of excess OSM to promote metabolic dysfunction is the control of adipogenesis.…”

“…Although SDF-1 and PAI-1 may play a role in OSM function in AT, no rigorous studies have identified or directly evaluated OSM-regulated genes in adipocytes. Interestingly, in vitro experiments in brown adipocytes have demonstrated that OSM signaling via the OSMRß results in an increase in TNFα and MCP-1 (or C-C Motif Chemokine Ligand 2, Ccl2) mRNA levels, and interleukin 6 protein and each of these cytokines are involved in the recruitment and activation of macrophages in AT ( 13 , 41 ). Therefore, it is reasonable to predict that in obesity, the overexpression of OSM by immune cells, including macrophages, is acting on adipocytes to induce the secretion of inflammatory cytokines that promote infiltration and activation of more macrophages.…”

“…Proinflammatory cytokines made in AT can inhibit adipocyte differentiation and induce insulin resistance in adipocytes, and modulation of both these processes in AT has systemic effects (8)(9)(10). Although less studied than other AT cytokines, OSM clearly contributes to AT homeostasis (11)(12)(13), and increased OSM levels in AT promote systemic metabolic dysfunction through effects on both adipocyte development and adipose tissue function.…”