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

Akiko Takikawa, Isao Usui*, Shiho Fujisaka, Masashi Ikutani, Satoko Senda, Shinpei Hattori, Koichi Tsuneyama, Yukiko Koshimizu, Ran Inoue, Ayumi Tanaka-Hayashi, Takashi Nakagawa, Yoshinori Nagai, Kiyoshi Takatsu, Toshiyasu Sasaoka, Hisashi Mori, Kazuyuki Tobe

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)59-68
Number of pages10
JournalDiabetology International
Volume7
Issue number1
DOIs
StatePublished - 2016/03/01

Keywords

  • Adipose tissue
  • HIF-1α
  • Hypoxia
  • Insulin resistance
  • Macrophage
  • Obesity
  • SIRT1

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

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