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

Aims/hypothesis 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.

Hepatic lipase deficiency produces glucose intolerance, inflammation and hepatic steatosis

“…In this sense, the activation of JNK as a main mechanism for the development of steatohepatitis has been largely described (Schattenberg et al 2006, Tuncman et al 2006, Singh et al 2009. Others have shown a relevant role of p38-activation in fatty liver disease (Menghini et al 2012, Nio et al 2012, Song, et al 2014. In addition, NEFA liberated by HSL activate both p38 and JNK, and p38 mediates proinflammatory cytokine expression in adipose tissue (Mottillo, et al 2010).…”

A Novel Peroxisome Proliferator-activated Receptor (PPAR)α Agonist and PPARγ Antagonist, Z-551, Ameliorates High-fat Diet-induced Obesity and Metabolic Disorders in Mice

“…Real-time Quantitative RT-PCR-Real-time quantitative RT-PCR was performed by the method described previously (30,31). Total RNA was prepared from the epididymal WAT and liver using TRIzol (Invitrogen) according to the manufacturer's instructions.…”

“…The TaqMan probes were used for mouse acyl-CoA oxidase 1 (ACOX1 encoded by Acox1), Mm01184029_m1; CD206 (Mrc1), Mm00485148_m1; CD36 (Cd36), Mm 01135198_m1; CD68 (Cd68), Mm00839636_g1; F4/80 (Emr1), Mm00802530_m1; fatty acid synthase (FAS, Fasn), Mm01253292_m1; IL-1␤ (Il1b), Mm00434228_m1; leptin (Lep), Mm 00434759_m1; lipoprotein lipase (LPL, Lpl), Mm00434764_m1; macrophage-1 antigen (Mac-1, Itgam), Mm00434455_m1; monocyte chemoattractant protein-1 (MCP-1, Ccl2), Mm 00441242_m1; phosphoenolpyruvate carboxykinase (PEPCK, Pck1), Mm 00447183_m1; peroxisome proliferator-activated receptor ␥ coactivator 1␣ (PGC1␣, Ppargc1a), Mm 01344232_g1; sterol regulatory element-binding protein-1c (SREBP-1c, Srebf1), Mm 00550338_m1; TNF-␣ (Tnf), Mm00443260_g1; Toll-like receptor 4 (TLR4, Tlr4), Mm 00494069_m1; uncoupling protein 1 (UCP1, Ucp1), Mm00445273_ m1; uncoupling protein 2 (UCP2, Ucp2), Mm00495907_g1; 36B4 (Rplp0), Mm00725448_s1. The primers and the probe for mouse cyclophilin A (Ppia) were as follows: the forward primer was 5Ј-ggtcctggcatcttgtccat-3Ј, the reverse primer was 5Ј-cagtcttggcagtgcagataaaa-3Ј, and the probe was 5Ј-ctggaccaaacacaaacggttccca-3Ј (31). The relative amount of each transcript was normalized to the amount of Rplp0 or Ppia transcripts as internal standards.…”

TGR5 reduces macrophage migration through mTOR-induced C/EBPβ differential translation

“…Knockout mouse studies have shown that CCR2 and its ligand CCL2 are pivotal in triggering obesity-induced insulin resistance and are required for accumulation of inflammatory macrophages in fat (67)(68)(69)(70). CCL2 was also shown to increase macrophage content via ATM proliferation, in addition to its effect on blood monocyte recruitment (71).…”