Loss of Hematopoietic Cell-Derived Oncostatin M Worsens Diet-Induced Dysmetabolism in Mice

Innate immune cells infiltrate growing adipose tissue 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 because OSM concentrations are dynamically modulated during high-fat diet (HFD) and Osm(-/-) mice displayed early-onset glucose intolerance, impaired muscle glucose uptake, and worsened liver inflammation and damage. We found that OSM is mostly produced by blood cells and deletion of OSM in hematopoietic cells phenocopied glucose intolerance of whole-body Osm(-/-) mice fed a HFD and recapitulated liver damage with increased aminotransferase levels. We thus uncovered 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.

Automated summary

Innate immune cells infiltrate and spread inflammatory signals in growing adipose tissue, leading to glucose intolerance and insulin resistance in distant tissues. Oncostatin M (OSM), a cytokine, is debated for its role in the metabolic consequences of overfeeding. Through this study, it was found that OSM is required during obesity development, as its concentrations are dynamically regulated during a high-fat diet. Osm(-/-) mice showed glucose intolerance, impaired muscle glucose uptake, and worsened liver inflammation and damage, demonstrating the importance of OSM in adapting to overfeeding.