Weisberg, S. P. et al. CCR2 modulates inflammatory and metabolic effects of high-fat feeding. J. Clin. Invest. 116, 115-124

Department of Medicine, Naomi Berrie Diabetes Center, Columbia University College of Physicians and Surgeons, New York, New York 10032, USA.
Journal of Clinical Investigation (Impact Factor: 13.22). 02/2006; 116(1):115-24. DOI: 10.1172/JCI24335
Source: PubMed


The C-C motif chemokine receptor-2 (CCR2) regulates monocyte and macrophage recruitment and is necessary for macrophage-dependent inflammatory responses and the development of atherosclerosis. Although adipose tissue expression and circulating concentrations of CCL2 (also known as MCP1), a high-affinity ligand for CCR2, are elevated in obesity, the role of CCR2 in metabolic disorders, including insulin resistance, hepatic steatosis, and inflammation associated with obesity, has not been studied. To determine what role CCR2 plays in the development of metabolic phenotypes, we studied the effects of Ccr2 genotype on the development of obesity and its associated phenotypes. Genetic deficiency in Ccr2 reduced food intake and attenuated the development of obesity in mice fed a high-fat diet. In obese mice matched for adiposity, Ccr2 deficiency reduced macrophage content and the inflammatory profile of adipose tissue, increased adiponectin expression, ameliorated hepatic steatosis, and improved systemic glucose homeostasis and insulin sensitivity. In mice with established obesity, short-term treatment with a pharmacological antagonist of CCR2 lowered macrophage content of adipose tissue and improved insulin sensitivity without significantly altering body mass or improving hepatic steatosis. These data suggest that CCR2 influences the development of obesity and associated adipose tissue inflammation and systemic insulin resistance and plays a role in the maintenance of adipose tissue macrophages and insulin resistance once obesity and its metabolic consequences are established.

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Available from: Anthony Ferrante, Dec 22, 2015
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    • "Recently, salicylates (which are among the oldest medical compounds known to humankind) have been found to activate AMPK by direct binding to the same site as A769662[54]. Some direct AMPK activators have been slated for human clinical trials for type 2 diabetes[55], and it remains unclear whether the beneficial effects of long-term salicylate treatment on insulin resistance are mediated by inhibiting of NF-κB signaling, by AMPK activation, or by a combination of these path- ways[56].Galic et al.showed a causal role for macrophage AMPK in the development of insulin resistance[57], and Weisberg et al. showed the importance of Ccr2 in the development of insulin resistance[4]. We showed that A769662 attenuates LPS-induced Ccr2 expression (Fig 2B), which is likely mediated via the NF-κB pathway (Fig 4A and 4B) in an AMPK-dependent manner in RAW264.7 macrophages (Fig 2C). "
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    ABSTRACT: C-C chemokine receptor 2 (Ccr2) is a key pro-inflammatory marker of classic (M1) macrophage activation. Although Ccr2 is known to be expressed both constitutively and inductively, the full regulatory mechanism of its expression remains unclear. AMP-activated protein kinase (AMPK) is not only a master regulator of energy homeostasis but also a central regulator of inflammation. In this study, we sought to assess AMPK's role in regulating RAW264.7 macrophage Ccr2 protein levels in resting (M0) or LPS-induced M1 states. In both M0 and M1 RAW264.7 macrophages, knockdown of the AMPKα1 subunit by siRNA led to increased Ccr2 levels whereas pharmacologic (A769662) activation of AMPK, attenuated LPS-induced increases in Ccr2 expression in an AMPK dependent fashion. The increases in Ccr2 levels by AMPK downregulation were partially reversed by NF-κB inhibition whereas TNF-a inhibition had minimal effects. Our results indicate that AMPK is a negative regulator of Ccr2 expression in RAW264.7 macrophages, and that the mechanism of action of AMPK inhibition of Ccr2 is mediated, in part, through the NF-κB pathway.
    Full-text · Article · Jan 2016 · PLoS ONE
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    • "WAT from obese humans and animals (Weisberg et al., 2003) exhibit increased macrophage numbers. Selective depletion of macrophages or abrogation of the CCR2-MCP-1 (monocyte chemotactic protein-1) cascade that mediates macrophage recruitment reduces WAT inflammation and improves insulin sensitivity in DIO mice (Patsouris et al., 2008; Weisberg et al., 2006). Macrophage polarization also influences obesity. "
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    ABSTRACT: Mast cells (MCs) contribute to the pathogenesis of obesity and diabetes. This study demonstrates that leptin deficiency slants MCs toward anti-inflammatory functions. MCs in the white adipose tissue (WAT) of lean humans and mice express negligible leptin. Adoptive transfer of leptin-deficient MCs expanded ex vivo mitigates diet-induced and pre-established obesity and diabetes in mice. Mechanistic studies show that leptin-deficient MCs polarize macrophages from M1 to M2 functions because of impaired cell signaling and an altered balance between pro- and anti-inflammatory cytokines, but do not affect T cell differentiation. Rampant body weight gain in ob/ob mice, a strain that lacks leptin, associates with reduced MC content in WAT. In ob/ob mice, genetic depletion of MCs exacerbates obesity and diabetes, and repopulation of ex vivo expanded ob/ob MCs ameliorates these diseases.
    Full-text · Article · Oct 2015 · Cell metabolism
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    • "Here, we found that Ccl2 expression in primary adipocytes and WAT was induced by microbial factors in serum and required the presence of MyD88, TRIF, and TLR4. Overexpression of Ccl2 in adipocytes has been shown to result in WAT inflammation and insulin resistance without obesity (Kamei et al., 2006; Kanda et al., 2006), and mice deficient in CCL2, or its receptor chemokine (C-C motif) receptor 2 (CCR2), have reduced WAT inflammation and insulin resistance during a high-fat diet (Kanda et al., 2006; Weisberg et al., 2006). A recent study also reported that CCL2 promotes local proliferation of macrophages in WAT (Amano et al., 2014). "
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    ABSTRACT: Dietary lipids may influence the abundance of circulating inflammatory microbial factors. Hence, inflammation in white adipose tissue (WAT) induced by dietary lipids may be partly dependent on their interaction with the gut microbiota. Here, we show that mice fed lard for 11 weeks have increased Toll-like receptor (TLR) activation and WAT inflammation and reduced insulin sensitivity compared with mice fed fish oil and that phenotypic differences between the dietary groups can be partly attributed to differences in microbiota composition. Trif(-/-) and Myd88(-/-) mice are protected against lard-induced WAT inflammation and impaired insulin sensitivity. Experiments in germ-free mice show that an interaction between gut microbiota and saturated lipids promotes WAT inflammation independent of adiposity. Finally, we demonstrate that the chemokine CCL2 contributes to microbiota-induced WAT inflammation in lard-fed mice. These results indicate that gut microbiota exacerbates metabolic inflammation through TLR signaling upon challenge with a diet rich in saturated lipids. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    Full-text · Article · Aug 2015 · Cell Metabolism
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