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Monocyte chemoattractant protein-1 (MCP-1) deficiency enhances alternatively activated M2 macrophages and ameliorates insulin resistance and fatty liver in lipoatrophic diabetic A-ZIP transgenic mice

Authors
  • Nio, Y.1
  • Yamauchi, T.1
  • Iwabu, M.1, 2
  • Okada-Iwabu, M.1, 3
  • Funata, M.1
  • Yamaguchi, M.1
  • Ueki, K.1
  • Kadowaki, T.1
  • 1 Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan , Tokyo (Japan)
  • 2 Department of Integrated Molecular Science on Metabolic Diseases, 22nd Century Medical and Research Center, Graduate School of Medicine, University of Tokyo, Tokyo, Japan , Tokyo (Japan)
  • 3 Department of Molecular Medicinal Sciences on Metabolic Regulation, 22nd Century Medical and Research Center, Graduate School of Medicine, University of Tokyo, Tokyo, Japan , Tokyo (Japan)
Type
Published Article
Journal
Diabetologia
Publisher
Springer-Verlag
Publication Date
Sep 16, 2012
Volume
55
Issue
12
Pages
3350–3358
Identifiers
DOI: 10.1007/s00125-012-2710-2
Source
Springer Nature
Keywords
License
Yellow

Abstract

Aims/hypothesisMonocyte chemoattractant protein-1 (MCP-1)/chemokine (C-C motif) ligand (CCL) 2 (CCL2) secreted from white adipose tissue (WAT) in obesity has been reported to contribute to tissue macrophage accumulation and insulin resistance by inducing a chronic inflammatory state. MCP-1 has been shown to be elevated in the fatty liver of lipoatrophic A-ZIP-transgenic (A-ZIP-Tg) mice. Treatment of these mice with the CC chemokine receptor (CCR) 2 antagonist has been shown to ameliorate the hyperglycaemia, hyperinsulinaemia and hepatomegaly, in conjunction with reducing liver inflammation. However, since CCR2 antagonists can block not only MCP-1 but also MCP-2 (CCL8) and MCP-3 (CCL7), it remains unclear whether MCP-1 secreted from the liver could contribute to hyperglycaemia, hyperinsulinaemia and hepatomegaly in conjunction with liver inflammation, as well as to the M1 and M2 states of macrophage polarisation.MethodsTo address these issues, we analysed the effects of targeted disruption of MCP-1 in A-ZIP-Tg mice.ResultsMCP-1 deficiency alone or per se resulted in a significant amelioration of insulin resistance in A-ZIP-Tg mice, which was associated with a suppression of extracellular signal-regulated protein kinase (ERK)-1/2 and p38 mitogen-activated protein kinase (p38MAPK) phosphorylation in liver. Although MCP-1 deficiency did not reduce the expression of macrophage markers, it increased the expression of the genes encoding M2 macrophage markers such as Arg1 and Chi3l3, as well as significantly reducing the triacylglycerol content of livers from A-ZIP-Tg mice.Conclusions/ interpretationOur data clearly indicated that MCP-1 deficiency improved insulin resistance and hepatic steatosis in A-ZIP-Tg mice and was associated with switching macrophage polarisation and suppressing ERK-1/2 and p38MAPK phosphorylation.

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