Macrophage HIF-1α mediates obesity-related adipose tissue dysfunction via interleukin-1 receptor-associated kinase M.

Hypoxia leading to stabilization of hypoxia-inducible factor 1α (HIF-1α) serves as an early upstream initiator for adipose tissue (AT) dysfunction. Monocyte-derived macrophage infiltration in AT contributes to inflammation, fibrosis and obesity-related metabolic dysfunction. It was previously reported that myeloid cell-specific deletion of protected against high-fat diet (HFD)-induced AT dysfunction. Prolyl hydroxylases (PHDs) are key regulators of HIF-1α. We examined the effects of myeloid cell-specific upregulation and stabilization of via deletion of prolyl-hydroxylase 2 () and whether interleukin-1 receptor associated kinase-M (), a known downstream target of , contributes to -induced AT dysfunction. Our data show that with HFD, and expressions were increased in the AT macrophages of / mice compared with mice. With HFD, / mice exhibited increased AT inflammation, fibrosis, and systemic insulin resistance compared with control mice. Furthermore, / mice bone marrow-derived macrophages exposed to hypoxia in vitro also had increased expressions of both and . In wild-type mice, HFD induced upregulation of both and in adipose tissue. Despite equivalent expression of compared with wild-type mice, globally-deficient mice fed a HFD exhibited less macrophage infiltration, decreased inflammation and fibrosis and improved glucose tolerance. Global deficiency was associated with an alternatively-activated macrophage phenotype in the AT after HFD. Together, these data show for the first time that an -dependent mechanism likely mediates obesity-related AT dysfunction in conjunction with upregulation.