CCR2 modulates inflammatory and metabolic effect of high-fat feeding

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: 13.77). 02/2006; 116(1):115-24. DOI: 10.1172/JCI24335
Source: PubMed

ABSTRACT 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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    • "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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    • "M1 macrophages aggregate around necrotic adipocytes in inflamed tissue, forming 'crown-like structures', and produce substantial amounts of pro-inflammatory cytokines such as IL6 and TNFa (Lumeng et al. 2007, Wentworth et al. 2010), contributing directly to local and systemic inflammation and insulin resistance. Blockade of inflammatory monocyte and macrophage trafficking into adipose protects mice from obesity-induced inflammation and loss of insulin sensitivity (Arkan et al. 2005, Weisberg et al. 2006) and, similarly, selective depletion of M1 macrophages in obese animal models reduces WAT inflammation without affecting diet-induced obesity (Patsouris et al. 2008). Of course, separation of macrophages into these defined M1/M2 phenotypes has its limitations; in vivo, they exhibit plasticity across the entire spectrum of activation states encompassed by the M1 and M2 nomenclature. "
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    • "In animal studies, prevention of macrophage recruitment in the adipose tissue has a positive impact on whole body insulin resistance [9] [31] [32]. Skewing liver macrophage activation towards an alternative M2 phenotype through PPARd activation may be similarly effective [95]. "
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