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

Abstract

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 <i>Hif-1α</i> 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 <i>Hif-1α</i> via deletion of prolyl-hydroxylase 2 (<i>Phd2</i>) and whether interleukin-1 receptor associated kinase-M (<i>Irak-M</i>), a known downstream target of <i>Hif-1α</i>, contributes to <i>Hif-1α</i>-induced AT dysfunction. Our data show that with HFD, <i>Hif-1α</i> and <i>Irak-M</i> expressions were increased in the AT macrophages of <i>Phd2^flox/flox</i>/<i>LysMcre</i> mice compared with <i>LysMcre</i> mice. With HFD, <i>Phd2^flox/flox</i>/<i>LysMcre</i> mice exhibited increased AT inflammation, fibrosis, and systemic insulin resistance compared with control mice. Furthermore, <i>Phd2^flox/flox</i>/<i>LysMcre</i> mice bone marrow-derived macrophages exposed to hypoxia in vitro also had increased expressions of both <i>Hif-1α</i> and <i>Irak-M</i>. In wild-type mice, HFD induced upregulation of both <i>HIF-1a</i> and <i>Irak-M</i> in adipose tissue. Despite equivalent expression of <i>Hif-1α</i> compared with wild-type mice, globally-deficient <i>Irak-M</i> mice fed a HFD exhibited less macrophage infiltration, decreased inflammation and fibrosis and improved glucose tolerance. Global <i>Irak-M</i> deficiency was associated with an alternatively-activated macrophage phenotype in the AT after HFD. Together, these data show for the first time that an <i>Irak-M</i>-dependent mechanism likely mediates obesity-related AT dysfunction in conjunction with <i>Hif-1α</i> upregulation.