CCR2 modulates inflammatory and metabolic effects of high-fat feeding
Stuart P. Weisberg, … , Rudolph L. Leibel, Anthony W. Ferrante Jr.
Stuart P. Weisberg, … , Rudolph L. Leibel, Anthony W. Ferrante Jr.
Published January 4, 2006
Citation Information: J Clin Invest. 2006;116(1):115-124. https://doi.org/10.1172/JCI24335.
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Research Article Metabolism

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.

Authors

Stuart P. Weisberg, Deborah Hunter, Reid Huber, Jacob Lemieux, Sarah Slaymaker, Kris Vaddi, Israel Charo, Rudolph L. Leibel, Anthony W. Ferrante Jr.

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Figure 3

Insulin sensitivity in obese Ccr2–/– and obese Ccr2+/+ mice.

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Insulin sensitivity in obese Ccr2–/– and obese Ccr2+/+ mice. ...
Fasting plasma insulin (A) and blood glucose concentrations (B) were measured in lean Ccr2+/+ (black bars) and Ccr2–/– (gray bars) mice and mice of both genotypes made obese following 20 weeks of high-fat diet feeding. There were no significant genotype-dependent differences in fasting glucose or insulin concentrations in lean animals. However, fasting glucose and insulin concentrations were lower in obese Ccr2–/– compared with obese Ccr2+/+ mice despite similar degrees of adiposity (insulin: P < 0.005; glucose: P < 10–4). (C) HOMA-IR values (expressed as IU-mg/dl) were significantly lower (P < 10–4) among obese Ccr2–/– than obese Ccr2+/+ mice. (D) A plot of HOMA-IR values against body mass among all Ccr2–/– (gray squares) and Ccr2+/+ (black circles) mice reveals that the relationship between insulin sensitivity and body mass differs between mice dependent upon Ccr2 genotype. **P < 0.01 compared with wild type. Values are expressed as mean ± SD.