CCR2 modulates inflammatory and metabolic effects of high-fat feeding
Open accessAbstract
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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Hypertrophy leads to a multiple-fold increase in infiltration of macrophages in WAT, which promotes a pro-inflammatory and insulin resistant environment.
“Hypertrophy leads to multiple fold increase in infiltration of macrophages in WAT (55, 56), which promotes a pro-inflammatory and insulin resistant environment.”
From Metabolic impact of endogenously produced estrogens by adipose tissue in females and males across the lifespan (2025) · cites this paper as [55]
The Figure 3 section reports that adipose-tissue macrophages made up 25% of cells in obese wild-type mice versus 7.2% in lean mice, supporting a multiple-fold increase associated with obesity. The Introduction links these macrophages to adipose inflammation, but the paper does not establish hypertrophy as the cause of their accumulation; the Discussion explicitly says it cannot determine whether macrophage content and insulin resistance are causally related. Page numbers are unavailable in our copy. (LLM, conf=0.87)
Experimental — accuracy not yet measuredAdipose tissue macrophages (ATMs) comprise a significant proportion of adipose tissue cells in lean and obese states.
“Adipose tissue macrophages (ATM) have been shown to comprise a significant proportion of the cellular component of adipose tissue in both lean and obese states [60–63].”
From Macrophage polarization: an opportunity for improved outcomes in biomaterials and regenerative medicine (2012) · cites this paper as [62]
In normal rodents and humans, ATMs make up as much as 10% of cellular constituents; in obese subjects, up to 40%.
“In normal rodents and humans, ATMs make up as much as ten percent of the cellular constituents of the tissue [62]. In comparison, it has been shown that in obese subjects that number rises to as much as 40% [62].”
From Macrophage polarization: an opportunity for improved outcomes in biomaterials and regenerative medicine (2012) · cites this paper as [62]
Mediterranean diet had a marginal relationship with CRP that was not significant after adjusting for CVD risk factors.
“Although a marginal relationship between CRP concentration and the Mediterranean diet was observed, this association was no longer significant when other cardiovascular risk factors were considered in the models.”
From Dietary factors and low-grade inflammation in relation to overweight and obesity (2011) · cites this paper as [282]
The inverse association between Mediterranean diet and IL-6 was independent of known CVD risk factors and persisted in within-pair twin comparison.
“This association was independent of several known cardiovascular risk factors, and persisted when twins within pairs were compared, suggesting that the results were not confounded by shared environmental and genetic factors.”
From Dietary factors and low-grade inflammation in relation to overweight and obesity (2011) · cites this paper as [282]
Observational studies generally report inverse correlations between Mediterranean diet and inflammatory markers in healthy persons.
“Observational studies have examined the association of the Mediterranean diet with inflammatory markers in healthy persons (282,283,285) , and they generally report inverse correlations.”
From Dietary factors and low-grade inflammation in relation to overweight and obesity (2011) · cites this paper as [282]
In 345 middle-aged male twins, adherence to Mediterranean diet was inversely associated with plasma IL-6.
“In a recent study (282) investigating psychological, behavioural and biological risk factors for subclinical CVD in 345 middleaged male twins, an inverse association between adherence to the Mediterranean diet and inflammation, as measured by plasma IL-6 concentration, was noted.”
From Dietary factors and low-grade inflammation in relation to overweight and obesity (2011) · cites this paper as [282]
Ccl2 and/or Ccr2 expression is increased in obese adipose tissue.
“Ccl2 and/or Ccr2 expression is increased in obese adipose tissue (119-122)”
From Insulin sensitivity: Modulation by nutrients and inflammation (2008) · cites this paper as [120]
Knocking out Ccl2 or Ccr2, or neutralizing CCL2, reduces macrophage recruitment to adipose tissue and protects against obesity-induced insulin resistance.
“In addition, KO of Ccl2 or Ccr2 or neutralization of CCL2 leads to decreased macrophage recruitment to adipose tissue and protection from obesity-induced insulin resistance (120, 121).”
From Insulin sensitivity: Modulation by nutrients and inflammation (2008) · cites this paper as [120]
IL-6, IFN-γ, and CCL2 inhibit insulin signaling in adipocytes.
“Other factors produced by inflammatory cells have since been shown to inhibit insulin signaling in the adipocyte including IL-6, IFN-γ and CCL2 (72,73).”
From The ominous triad of adipose tissue dysfunction: inflammation, fibrosis, and impaired angiogenesis. (2017) · cites this paper as [73]
There is considerable evidence for the pathophysiological role of macrophage- and/or hypertrophic adipocyte-derived chemotactic MCP-1/CCR2 pathways in the regulation of monocyte accumulation in obese adipose tissue.
“There is considerable evidence for the pathophysiological role of macrophage-and/or hypertrophic adipocytederived chemotactic MCP-1/CCR2 pathways in the regulation of monocyte accumulation in obese AT (16,17).”
From Adipose tissue remodeling and obesity (2011) · cites this paper as [17]
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- mined by quantitative RT-PCR. To normalize expression data, we used multiple internal control genes as described by Vandesompele et al. (49). The internal control genes encoding HMG-14 (Hmg14) and ribosomal protein S3 (Rps3) were selected from our murine microarray data set for having high expres- sion and little sample-to-sample variability. For each transcript assayed, intron-spanning primers were designed using publicly available genomic contig sequences obtained through Entrez Gene (http://www.ncbi.nlm. nih.gov/entrez/query.fcgi?db=gene), the public domain primer design software Primer3 (http://frodo.wi.mit.edu/primer3/primer3_code.html), and the DNA analysis software Vector NTI Suite Version 7 (Informax Inc.). Primer sequences were as follows: Rps3 forward, 5′-ATCAGAGA- GTTGACCGCAGTTG-3′; Rps3 reverse, 5′-AATGAACCGAAGCACAC- CATAG-3′; Emr1 forward, 5′-CTTTGGCTATGGGCTTCCAGTC-3′;
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- Authors
- Weisberg, S. P., Hunter, D., Huber, R., Lemieux, J., Slaymaker, S., Vaddi, K., Charo, I., Leibel, R. L., & Jr., A. W. F.
- Affiliations
- Columbia University Irving Medical Center (US)
- Incyte (United States) (US)
- Columbia University (US)
- Gladstone Institutes (US)
- Venue
- Journal of Clinical Investigation
- Published
- 2006-01-04
- Volume
- 116
- Issue
- 1
- Pages
- 115-124
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC1307559
- OpenAlex
- W4250725029
- Cited by
- 1,497
- References
- 47
- Citations by year
- 2026: 32 · 2025: 53 · 2024: 42 · 2023: 59 · 2022: 53 · 2021: 71 · 2020: 67 · 2019: 65 · 2018: 74 · 2017: 77 · 2016: 104 · 2015: 76 · 2014: 83 · 2013: 108 · 2012: 93
- FWCI
- 43.36
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- public-domain
- Locations
- Journal of Clinical Investigation (publishedVersion, public-domain)
- PubMed Central (publishedVersion)
- Funders
- National Institutes of Health (DK066525)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK-063608, DK59960, R56DK066525, (DK066525, K08DK059960, P30DK063608, R01DK066525)
- Topics
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Disease and Adiposity
- Keywords
- CCR2, obesity, high-fat diet, adipose tissue inflammation, macrophage recruitment, insulin resistance, hepatic steatosis, glucose homeostasis, adiponectin, CCR2 knockout mice, CCR2 antagonist, metabolic inflammation
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