title: 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.
abstract: OBJECTIVE
  Monocyte 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.
  
  
  METHODS
  To address these issues, we analysed the effects of targeted disruption of MCP-1 in A-ZIP-Tg mice.
  
  
  RESULTS
  MCP-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/ INTERPRETATION:                  Our 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.
authors.affiliation: Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Nio
authors.forename: T
authors.initials: T
authors.lastname: Yamauchi
authors.forename: M
authors.initials: M
authors.lastname: Iwabu
authors.forename: M
authors.initials: M
authors.lastname: Okada-Iwabu
authors.forename: M
authors.initials: M
authors.lastname: Funata
authors.forename: M
authors.initials: M
authors.lastname: Yamaguchi
authors.forename: K
authors.initials: K
authors.lastname: Ueki
authors.forename: T
authors.initials: T
authors.lastname: Kadowaki
mesh_terms: D052436:Adipose Tissue, White / Q000378:metabolism*; D000818:Animals; D018932:Chemokine CCL2 / Q000172:deficiency*; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism; D003923:Diabetes Mellitus, Lipoatrophic / Q000378:metabolism*; D005234:Fatty Liver / Q000378:metabolism*; D007333:Insulin Resistance; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D020935:MAP Kinase Signaling System; D008262:Macrophage Activation; D008264:Macrophages / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D010766:Phosphorylation; D014157:Transcription Factors / Q000235:genetics; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; C406806:Tg(AZIP-F)1Vsn protein, mouse; D014157:Transcription Factors; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases