CCR2 modulates inflammatory and metabolic effects of high-fat feeding

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.

Role of CC Chemokine Receptor 2 in Bone Marrow Cells in the Recruitment of Macrophages into Obese Adipose Tissue

“…We found that CCR2 Ϫ/Ϫ mice have significantly lower blood glucose levels than CCR2 ϩ/ϩ mice 20 weeks after the high fat diet feeding (280.25 Ϯ 29.09 mg/dl versus 193.33 Ϯ 15.62 mg/dl; p Ͻ 0.05). These observations are consistent with the previous report on reduced macrophage infiltration in CCR2 Ϫ/Ϫ mice fed a high fat diet during the course of obesity (8).…”

“…There is considerable evidence for the pathophysiologic role of the MCP-1/CCR2 pathway in macrophage infiltration into obese adipose tissue. For instance, Weisberg et al (8) reported the attenuation of macrophage accumulation and inflammatory changes in the adipose tissue from mice lacking CCR-2 (CCR2 Ϫ/Ϫ mice) during a high fat diet. Moreover, two previous studies with transgenic mice overexpressing MCP-1 in the adipose tissue and/or MCP-1-deficient mice (MCP-1 Ϫ/Ϫ mice) showed that MCP-1 plays a role in the recruitment of macrophages into obese adipose tissue (9,10).…”

β-Arrestin-1 Protein Represses Diet-induced Obesity

“…Paraffin embedding, sectioning, and hematoxylin and eosin staining were performed according to standard protocols. Macrophages in the epididymal fat pads were visualized by anti-F4/80 antibody (eBioscience) immunostaining and quantified as described previously (13).…”

Keratinocyte-derived Chemokine in Obesity

“…These studies have led to contradicting results with several publications showing that MCP-1 and CCR2 are important for ATM recruitment and the subsequent development of IR (3)(4)(5), whereas others show no involvement of this chemokine and its receptor in these processes (6 -8). Furthermore, the studies that claim a role for MCP-1 and CCR2 in ATM recruitment and IR show that deficiency of the ligand or the receptor did not result in normalization of ATM content, indicating that other factors also participate in ATM recruitment.…”