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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    • "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.
    Cell Metabolism 08/2015; 22(4). DOI:10.1016/j.cmet.2015.07.026 · 17.57 Impact Factor
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    • "Additionally, even in studies showing that deficiency or antagonism of chemokines decreases ATM number during obesity, macrophage accumulation during high fat diet (HFD) feeding is never completely abolished [13,19e23]. Furthermore, several models with deficiencies in chemoattractant molecules demonstrate a pronounced decrease in circulating inflammatory monocytes without a corresponding large reduction in ATM number [21] [24]. Together these findings suggest that recruitment-independent mechanisms may also contribute to the accumulation of proinflammatory macrophages in obese AT. "
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    ABSTRACT: Objective: Macrophage accumulation in adipose tissue (AT) during obesity contributes to inflammation and insulin resistance. Recruitment of monocytes to obese AT has been the most studied mechanism explaining this accumulation. However, recent evidence suggests that recruitment-independent mechanisms may also regulate pro-inflammatory AT macrophage (ATM) numbers. The role of increased ATM survival during obesity has yet to be explored. Results: We demonstrate that activation of apoptotic pathways is significantly reduced in ATMs from diet-induced and genetically obese mice. Concurrently, pro-survival Bcl-2 family member protein levels and localization to the mitochondria is elevated in ATMs from obese mice. This increased pro-survival signaling was associated with elevated activation of the transcription factor, NF-κB, and increased expression of its pro-survival target genes. Finally, an obesogenic milieu increased ATM viability only when NF-κB signaling pathways were functional. Conclusions: Our data demonstrate that obesity promotes survival of inflammatory ATMs, possibly through an NF-κB-regulated mechanism.
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    • "Obesity can be categorized as a pro-inflammatory phenotype, with adipose tissue sitting at the crossroad of metabolism and immunity. Approximately 40% of the cell population in engorged adipose tissue consists of macrophages, which are activated by the abundance of necrotic adipocytes (Meijer et al., 2011; Shapiro et al., 2011; Weisberg et al., 2006). In parallel, adipocytes can release proinflammatory cytokines (Meijer et al., 2011) At the signaling level, both obesogenic and immunogenic tissues share common pathways and co-expressed molecules (Chase and Sharma, 2013), which may serve to coordinate their messages. "
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    ABSTRACT: Energy metabolism and immunity are characterized as abnormal in schizophrenia. Because these two systems are highly coordinated, we measured expression of prototypic obesogenic and immunogenic genes in freshly harvested PBMC from controls and participants with schizophrenia. We report significant increases in PPARγ, SREBP1, IL-6 and TNFα, and decreases in PPARα and C/EPBα and mRNA levels from patients with schizophrenia, with additional BMI interactions, characterizing dysregulation of genes relating to metabolic-inflammation in schizophrenia. Published by Elsevier Ireland Ltd.
    Psychiatry Research 11/2014; 225(1-2). DOI:10.1016/j.psychres.2014.11.007 · 2.47 Impact Factor
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