| First Author | Poblete JMS | Year | 2020 |
| Journal | Am J Physiol Endocrinol Metab | Volume | 318 |
| Issue | 5 | Pages | E689-E700 |
| PubMed ID | 32154744 | Mgi Jnum | J:296815 |
| Mgi Id | MGI:6469089 | Doi | 10.1152/ajpendo.00174.2019 |
| Citation | Poblete JMS, et al. (2020) Macrophage HIF-1alpha mediates obesity-related adipose tissue dysfunction via interleukin-1 receptor-associated kinase M. Am J Physiol Endocrinol Metab 318(5):E689-E700 |
| abstractText | Hypoxia leading to stabilization of hypoxia-inducible factor 1alpha (HIF-1alpha) 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-1alpha protected against high-fat diet (HFD)-induced AT dysfunction. Prolyl hydroxylases (PHDs) are key regulators of HIF-1alpha. We examined the effects of myeloid cell-specific upregulation and stabilization of Hif-1alpha via deletion of prolyl-hydroxylase 2 (Phd2) and whether interleukin-1 receptor associated kinase-M (Irak-M), a known downstream target of Hif-1alpha, contributes to Hif-1alpha-induced AT dysfunction. Our data show that with HFD, Hif-1alpha 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 marrow-derived macrophages exposed to hypoxia in vitro also had increased expressions of both Hif-1alpha and Irak-M. In wild-type mice, HFD induced upregulation of both HIF-1a and Irak-M in adipose tissue. Despite equivalent expression of Hif-1alpha 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-M-dependent mechanism likely mediates obesity-related AT dysfunction in conjunction with Hif-1alpha upregulation. |
