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

Hypoxia leading to stabilization of hypoxia-inducible factor 1 alpha (HIF-1 alpha) 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 HIF-1 alpha protected against high-fat diet (HFD)-induced AT dysfunction. Prolyl hydroxylases (PHDs) are key regulators of HIF-1 alpha. We examined the effects of myeloid cellspecific upregulation and stabilization of HIF-1 alpha via deletion of prolyl-hydroxylase 2 (Phd2) and whether interleulcin-1 receptor associated kinase-M (Irak-M), a known downstream target of HIF-1 alpha, contributes to HIF-1 alpha-induced AT dysfunction. Our data show that with HFD. HIF-1 alpha and Irak-M expressions were increased in the AT macrophages of Phd2(flox/flox)/LysMcre mice compared with LysMcre mice. With HFD, Phd2(flox/flox)/LysMcre mice exhibited increased AT inflammation, fibrosis, and systemic insulin resistance compared with control mice. Furthermore, Phd2(flox/flox)/LysMcre mice bone marrowderived macrophages exposed to hypoxia in vitro also had increased expressions of both HIF-1 alpha and Irak-M. In wild-type mice, HFD induced upregulation of both HIF-1 alpha and Irak-M in adipose tissue. Despite equivalent expression of HIF-1 alpha compared with wild-type mice, globally-deficient Irak-M mice fed a HFD exhibited less macrophage infiltration, decreased inflammation and fibrosis and improved glucose tolerance. Global Irak-M deficiency was associated with an alternatively-activated macrophage phenotype in the AT after HFD. Together, these data show for the first time that an Irak-Mdependent mechanism likely mediates obesity-related AT dysfunction in conjunction with HIF-1 alpha upregulation.