Tumor necrosis factor-α converting enzyme inactivation ameliorates high-fat diet-induced insulin resistance and altered energy homeostasis

Hidehiro Kaneko, Toshihisa Anzai, Keisuke Horiuchi, Kokichi Morimoto, Atsushi Anzai, Toshiyuki Nagai, Yasuo Sugano, Yuichiro Maekawa, Hiroshi Itoh, Tsutomu Yoshikawa, Yasunori Okada, Satoshi Ogawa, Keiichi Fukuda

Research output: Contribution to journalArticlepeer-review

15 Citations (Scopus)

Abstract

Background: Tumor necrosis factor (TNF)-α, which is released as a soluble form by ectodomain shedding of TNF-α converting enzyme (Tace), is known to play a pivotal role in obesity-induced insulin resistance. The role of Tace in obesity-induced metabolic disorders was to be clarified in this study. Methods and Results: Transgenic mice with temporal systemic Tace deletion (TaceMx1) and their non-transgenic littermates (CON) were fed a standard diet or a high-fat diet (HFD) from 6 weeks of age. The increased body, liver and epididymal adipose tissue (EAT) weights, systolic blood pressure, and fasting glucose and lipid levels and decreased serum adiponectin level 12 weeks after starting a HFD were suppressed by Tace inactivation. A HFD/ TaceMx1 showed ameliorated glucose tolerance and insulin sensitivity compared with HFD/CON. Indirect calorimetry showed that energy expenditure and oxidation of both fat and carbohydrate were higher in HFD/TaceMx1 than HFD/CON. Marked hepatosteatosis, increased triglyceride content and TNF-α expression in liver, and increased adipocyte size, macrophage infiltration and TNF-α and monocyte chemoattractant protein-1 expression in EAT induced by a HFD were attenuated in HFD/TaceMx1. Conclusions: Inactivation of Tace suppressed HFD-induced obesity, insulin resistance, hepatosteatosis and adipose tissue remodeling in association with increased energy expenditure, suggesting an important role of Tace in the development of obesity-induced metabolic disorders.

Original languageEnglish
Pages (from-to)2482-2490
Number of pages9
JournalCirculation Journal
Volume75
Issue number10
DOIs
Publication statusPublished - 2011 Oct

Keywords

  • Cytokine
  • Inflammation
  • Insulin resistance
  • Metabolism
  • Obesity

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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