Deletion of SIRT1 in myeloid cells impairs glucose metabolism with enhancing inflammatory response to adipose tissue hypoxia

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• 作者：Akiko Takikawa ; Isao Usui ; Shiho Fujisaka ; Masashi Ikutani…
• 关键词：SIRT1 ; Adipose tissue ; Macrophage ; Hypoxia ; Insulin resistance ; Obesity ; HIF ; 1α
• 刊名：Diabetology International
• 出版年：2016
• 出版时间：March 2016
• 年：2016
• 卷：7
• 期：1
• 页码：59-68
• 全文大小：1,006 KB
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• 作者单位：Akiko Takikawa (1)
  Isao Usui (1)
  Shiho Fujisaka (1)
  Masashi Ikutani (2)
  Satoko Senda (1)
  Shinpei Hattori (3)
  Koichi Tsuneyama (4)
  Yukiko Koshimizu (1)
  Ran Inoue (5)
  Ayumi Tanaka-Hayashi (5)
  Takashi Nakagawa (6)
  Yoshinori Nagai (2)
  Kiyoshi Takatsu (7)
  Toshiyasu Sasaoka (3)
  Hisashi Mori (5)
  Kazuyuki Tobe (1)
  
  1. First Department of Internal Medicine, University of Toyama, 2630 Sugitani, Toyama, 930-0194, Japan
  2. Department of Immunobiology and Pharmacological Genetics, Graduate School of Medicine and Pharmaceutical Science for Research, University of Toyama, Toyama, Japan
  3. Department of Clinical Pharmacology, University of Toyama, Toyama, Japan
  4. Department of Diagnostic Pathology, University of Toyama, Toyama, Japan
  5. Department of Molecular Neuroscience, University of Toyama, Toyama, Japan
  6. Frontier Research Core for Life Science, University of Toyama, Toyama, Japan
  7. Toyama Prefectural Institute for Pharmaceutical Research, Toyama, Japan
  
• 刊物主题：Diabetes; Metabolic Diseases; Endocrinology;
• 出版者：Springer Japan
• ISSN：2190-1686

文摘

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 SIRT1-knockout mice were originally generated and analyzed under chow-fed and high-fat-fed conditions. Myeloid cell-specific SIRT1 deletion impaired insulin sensitivity and glucose tolerance assessed by the glucose- or insulin-tolerance test, which was associated with the enhanced expression of inflammation-related genes in epididymal adipose tissue of high-fat-fed mice. Interestingly, the M1 ATMs from the SIRT1-knockout mice showed more hypoxic and inflammatory phenotypes than those from control mice. The expressions of some inflammatory genes, such as Il1b and Nos2, which were induced by in vitro hypoxia treatment, were further enhanced by SIRT1 deletion along with the increased acetylation of HIF-1α in cultured macrophages. These results suggest that deletion of SIRT1 in myeloid cells impairs glucose metabolism by enhancing the hypoxia and inflammatory responses in ATMs, thereby possibly representing a novel therapeutic target for metabolic diseases, such as type 2 diabetes.