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

Published on Dec 1, 2016in Diabetes7.199
· DOI :10.2337/db16-0012
Akiko Takikawa5
Estimated H-index: 5
(University of Toyama),
Arshad Mahmood5
Estimated H-index: 5
(University of Toyama)
+ 21 AuthorsKazuyuki Tobe67
Estimated H-index: 67
(University of Toyama)
Abstract
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 VEGF-A. We previously reported that macrophages in crown-like structures (CLSs) are both hypoxic and inflammatory. In the present 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 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 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 LPS-treated bone marrow-derived macrophages directly inhibited the expression of angiogenic factors in 3T3-L1 preadipocytes. Thus, macrophage HIF-1α is involved in not only the formation of CLSs, further enhancing the inflammatory responses, but also 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.
  • References (44)
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References44
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#1Akiko Takikawa (University of Toyama)H-Index: 5
#2Isao Usui (University of Toyama)H-Index: 23
Last. Kazuyuki Tobe (University of Toyama)H-Index: 67
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Chronic inflammation is a pathophysiology of insulin resistance in metabolic diseases, such as obesity and type 2 diabetes. Adipose tissue macrophages (ATMs) play important roles in this inflammatory process. SIRT1 is implicated in the regulation of glucose metabolism in some metabolic tissues, such as liver or skeletal muscle. This study was performed to investigate whether SIRT1 in macrophages played any roles in the regulation of inflammation and glucose metabolism. Myeloid cell-specific SIRT...
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#1Seiji Yamamoto (University of Toyama)H-Index: 27
#2Shumpei NiidaH-Index: 17
Last. Masakiyo Sasahara (University of Toyama)H-Index: 26
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Inflammation-induced endothelial cell-derived extracellular vesicles modulate the cellular status of pericytes
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#2Kyung Cheul Shin (SNU: Seoul National University)H-Index: 4
Last. Jae Bum Kim (SNU: Seoul National University)H-Index: 40
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In obesity, adipose tissue macrophages (ATMs) play a key role in mediating proinflammatory responses in the adipose tissue, which are associated with obesity-related metabolic complications. Recently, adipose tissue hypoxia has been implicated in the regulation of ATMs in obesity. However, the role of hypoxia-inducible factor (HIF)-2α, one of the major transcription factors induced by hypoxia, has not been fully elucidated in ATMs. In this study, we demonstrate that elevation of macrophage HIF-2...
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Summary Adipose tissue hypoxia and inflammation have been causally implicated in obesity-induced insulin resistance. Here, we report that, early in the course of high-fat diet (HFD) feeding and obesity, adipocyte respiration becomes uncoupled, leading to increased oxygen consumption and a state of relative adipocyte hypoxia. These events are sufficient to trigger HIF-1α induction, setting off the chronic adipose tissue inflammatory response characteristic of obesity. At the molecular level, thes...
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Summary The regulatory events guiding progenitor activation and differentiation in adult white adipose tissue are largely unknown. We report that induction of brown adipogenesis by β3-adrenergic receptor (ADRB3) activation involves the death of white adipocytes and their removal by M2-polarized macrophages. Recruited macrophages express high levels of osteopontin (OPN), which attracts a subpopulation of PDGFRα + progenitors expressing CD44, a receptor for OPN. Preadipocyte proliferation is highl...
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Adipocytes have been suggested to arise from prospective progenitors of endothelial or haematopoietic origin. Rodeheffer and colleagues use lineage tracing to rule out that this is the case for white adipocytes, and show that they instead arise from CD24+ cells that are characterized by the expression of PdgfR (platelet-derived growth factor receptor).
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