HIF-1α in Myeloid Cells Promotes Adipose Tissue Remodeling Toward Insulin Resistance

• DOI: 10.2337/db16-0012
• Publication Date: 2016-09-14T01:49:49Z
• Authors: Akiko Takikawa; Arshad Mahmood; Allah Nawaz; Tomonobu Kado; Keisuke Okabe; Seiji Yamamoto; Aminuddin Aminuddin; Satoko Senda; Koichi Tsuneyama; Masashi Ikutani; Yasuharu Watanabe; Yoshiko Igarashi; Yoshinori Nagai; Kiyoshi Takatsu; Keiichi Koizumi; Johji Imura; Nobuhito Goda; Masakiyo Sasahara; Michihiro Matsumoto; Kumiko Saeki; Takashi Nakagawa; Shiho Fujisaka; Isao Usui; Kazuyuki Tobe
• Keywords: Inflammation; Male; Mice, Knockout; 0301 basic medicine; Neovascularization, Pathologic; Macrophages; Glucose Tolerance Test; Diet, High-Fat; Hypoxia-Inducible Factor 1, alpha Subunit; 3. Good health; Mice, Inbred C57BL; Mice; 03 medical and health sciences; Adipose Tissue; 3T3-L1 Cells; Angiopoietin-1; Animals; Fibroblast Growth Factor 1; Female; Myeloid Cells; Insulin Resistance; Fibroblast Growth Factor 10; Cells, Cultured

Adipose tissue hypoxia is an important feature of pathological adipose tissue expansion. Hypoxia-inducible factor-1α (HIF-1α) in adipocytes reportedly induces oxidative stress and fibrosis, rather than neoangiogenesis via vascular endothelial growth factor (VEGF)-A. We previously reported that macrophages in crown-like structures (CLSs) are both hypoxic and inflammatory. In the current study, we examined how macrophage HIF-1α is involved in high-fat diet (HFD)–induced inflammation, neovascularization, hypoxia, and insulin resistance using mice with myeloid cell–specific HIF-1α deletion that were fed an HFD. Myeloid cell–specific HIF-1α gene deletion protected against HFD-induced inflammation, CLS formation, poor vasculature development in the adipose tissue, and systemic insulin resistance. Despite a reduced expression of Vegfa in epididymal white adipose tissue (eWAT), the preadipocytes and endothelial cells of HIF-1α–deficient mice expressed higher levels of angiogenic factors, including Vegfa, Angpt1, Fgf1, and Fgf10 in accordance with preferable eWAT remodeling. Our in vitro study revealed that lipopolysaccharide-treated bone marrow–derived macrophages directly inhibited the expression of angiogenic factors in 3T3-L1 preadipocytes. Thus, macrophage HIF-1α is involved not only in the formation of CLSs, further enhancing the inflammatory responses, but also in the inhibition of neoangiogenesis in preadipocytes. We concluded that these two pathways contribute to the obesity-related physiology of pathological adipose tissue expansion, thus causing systemic insulin resistance.