HIF-1α in Myeloid Cells Promotes Adipose Tissue Remodeling Toward Insulin Resistance.
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.
First Department of Internal Medicine, University of Toyama, Toyama, Japan.
Akiko
A
Takikawa
First Department of Internal Medicine, University of Toyama, Toyama, Japan.
Arshad
A
Mahmood
First Department of Internal Medicine, University of Toyama, Toyama, Japan.
Allah
A
Nawaz
First Department of Internal Medicine, University of Toyama, Toyama, Japan.
Tomonobu
T
Kado
First Department of Internal Medicine, University of Toyama, Toyama, Japan.
Keisuke
K
Okabe
Department of Pathology, University of Toyama, Toyama, Japan.
Seiji
S
Yamamoto
First Department of Internal Medicine, University of Toyama, Toyama, Japan.
Aminuddin
A
Aminuddin
First Department of Internal Medicine, University of Toyama, Toyama, Japan.
Satoko
S
Senda
Department of Diagnostic Pathology, University of Toyama, Toyama, Japan.|Department of Pathology and Laboratory Medicine, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan.
Koichi
K
Tsuneyama
Department of Immunobiology and Pharmacological Genetics, Advanced Biomedicine Genome Pharmaceutical Science, Graduate School of Medicine and Pharmaceutical Science for Research, University of Toyama, Toyama, Japan.
Masashi
M
Ikutani
Department of Immunobiology and Pharmacological Genetics, Advanced Biomedicine Genome Pharmaceutical Science, Graduate School of Medicine and Pharmaceutical Science for Research, University of Toyama, Toyama, Japan.
Yasuharu
Y
Watanabe
Division of Kampo Diagnostics, Institute of Natural Medicine, University of Toyama, Toyama, Japan.
Yoshiko
Y
Igarashi
Department of Immunobiology and Pharmacological Genetics, Advanced Biomedicine Genome Pharmaceutical Science, Graduate School of Medicine and Pharmaceutical Science for Research, University of Toyama, Toyama, Japan.|PRESTO, Japan Science and Technology Agency, Saitama, Japan.
Yoshinori
Y
Nagai
Department of Immunobiology and Pharmacological Genetics, Advanced Biomedicine Genome Pharmaceutical Science, Graduate School of Medicine and Pharmaceutical Science for Research, University of Toyama, Toyama, Japan.|Toyama Prefectural Institute for Pharmaceutical Research, Toyama, Japan.
Kiyoshi
K
Takatsu
Department of Pathology and Laboratory Medicine, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan.
Keiichi
K
Koizumi
Department of Diagnostic Pathology, University of Toyama, Toyama, Japan.
Johji
J
Imura
Department of Life Science and Medical Bioscience, School of Advanced Science and Engineering, Waseda University, Tokyo, Japan.
Nobuhito
N
Goda
Department of Pathology, University of Toyama, Toyama, Japan.
Masakiyo
M
Sasahara
Department of Molecular Metabolic Regulation, Diabetes Research Center, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan.
Michihiro
M
Matsumoto
Department of Disease Control, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan.
Kumiko
K
Saeki
Frontier Research Core for Life Science, University of Toyama, Toyama, Japan.
Takashi
T
Nakagawa
First Department of Internal Medicine, University of Toyama, Toyama, Japan.
Shiho
S
Fujisaka
First Department of Internal Medicine, University of Toyama, Toyama, Japan tobe@med.u-toyama.ac.jp isaousui-tym@umin.ac.jp.
Isao
I
Usui
First Department of Internal Medicine, University of Toyama, Toyama, Japan tobe@med.u-toyama.ac.jp isaousui-tym@umin.ac.jp.
Kazuyuki
K
Tobe
D041721:3T3-L1 Cells; D000273:Adipose Tissue / Q000378:metabolism*; D042683:Angiopoietin-1 / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D059305:Diet, High-Fat / Q000009:adverse effects; D005260:Female; D016220:Fibroblast Growth Factor 1 / Q000378:metabolism; D051526:Fibroblast Growth Factor 10 / Q000378:metabolism; D005951:Glucose Tolerance Test; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D007249:Inflammation / Q000209:etiology / Q000378:metabolism; D007333:Insulin Resistance / Q000235:genetics*; D008264:Macrophages / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D022423:Myeloid Cells / Q000378:metabolism*; D009389:Neovascularization, Pathologic / Q000209:etiology / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D042683:Angiopoietin-1; C467628:Angpt1 protein, mouse; C496464:Fgf10 protein, mouse; D051526:Fibroblast Growth Factor 10; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D042461:Vascular Endothelial Growth Factor A; D016220:Fibroblast Growth Factor 1