Innate immune cells infiltrate growing adipose and propagate inflammatory clues to metabolically distant tissues, thereby promoting glucose intolerance and insulin resistance. Cytokines of the IL-6 family and gp130 ligands are among such signals. The role played by Oncostatin M (OSM) in the metabolic consequences of overfeeding is debated at least in part because prior studies did not distinguish OSM sources and dynamics. Here, we explored the role of OSM in metabolic responses and used bone marrow transplantation to test the hypothesis that hematopoietic cells are major contributors to the metabolic effects of OSM. We show that OSM is required to adapt during the development of obesity as OSM concentrations are dynamically modulated during high-fat diet (HFD) and Osm-/- mice displayed early-onset glucose intolerance, impaired muscle glucose uptake, worsened liver inflammation and damage. We found that OSM is mostly produced by blood cells, and that deletion of OSM in hematopoietic cells phenocopied glucose intolerance of whole-body Osm-/- mice on HFD, and recapitulated liver damage with increased aminotransferase levels. We thus uncover that modulation of OSM is involved in the metabolic response to overfeeding and that hematopoietic cell-derived OSM can regulate metabolism, likely via multiple effects in different tissues.

中文翻译：

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造血细胞衍生制瘤素 M 的缺失会加重饮食诱导的小鼠代谢异常

先天免疫细胞渗入生长的脂肪并将炎症线索传播到代谢远处的组织，从而促进葡萄糖耐受不良和胰岛素抵抗。IL-6 家族的细胞因子和 gp130 配体属于此类信号。制瘤素 M (OSM) 在过度喂养的代谢后果中所起的作用存在争议，至少部分原因是之前的研究没有区分 OSM 的来源和动态。在这里，我们探讨了 OSM 在代谢反应中的作用，并使用骨髓移植来检验造血细胞是 OSM 代谢作用的主要贡献者这一假设。我们表明 OSM 在肥胖的发展过程中需要适应，因为 OSM 浓度在高脂肪饮食 (HFD) 期间动态调节，并且 Osm-/- 小鼠表现出早发性葡萄糖不耐受，肌肉葡萄糖摄取受损，肝脏炎症和损伤恶化。我们发现 OSM 主要由血细胞产生，并且造血细胞中 OSM 的缺失表型复制了 HFD 全身 Osm-/- 小鼠的葡萄糖耐受不良，并通过转氨酶水平升高重现了肝损伤。因此，我们发现 OSM 的调节参与了对过度喂养的代谢反应，并且造血细胞衍生的 OSM 可以调节代谢，可能通过不同组织中的多种作用。