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Absence of CC Chemokine Ligand 2 Does Not Limit Obesity-Associated Infiltration of Macrophages Into Adipose Tissue

¹ Department of Medicine, Division of Endocrinology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts
² Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
³ Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, Massachusetts

Address correspondence and eprint requests to Jeffrey S. Flier, Beth Israel Deaconess Medical Center, 330 Brookline Ave., Finard 202, Boston, MA 02215. E-mail: jflier{at}bidmc.harvard.edu

Abbreviations: CCL, CC chemokine ligand; CCR, CC chemokine receptor; FACS, fluorescence-activated cell sorting; HIF-1, hypoxia-inducible factor-1; IL, interleukin; iNOS, inducible nitric oxide synthase; ITT, insulin tolerance test; KRH, Krebs-Ringer HEPES; MCP, monocyte chemoattractant protein; SOCS-3, suppressor of cytokine signaling-3; TNF-, tumor necrosis factor-

Macrophage recruitment to adipose tissue in obesity contributes to enhanced adipose tissue inflammatory activity and thus may underlie obesity-associated metabolic dysfunction. Obese adipose tissue exhibits increases in CC chemokine ligand 2 (CCL2, or monocyte chemoattractant protein-1), an important macrophage-recruiting factor. We therefore hypothesized that elevated CCL2 may contribute to obesity-associated adipose tissue macrophage recruitment. Male 6-week-old CCL2^–/– and wild-type mice (n = 11–14 per group) were fed standard and high-fat diets until 34 weeks of age. At 12–16 and 25–29 weeks of age, blood was collected for plasma glucose and hormone measurements, and glucose tolerance and insulin tolerance tests were performed. Adipose tissue was collected at 34 weeks for analysis of macrophage infiltration. Surprisingly, CCL2^–/– mice on high-fat diet showed no reductions in adipose tissue macrophages. CCL2^–/– mice on standard and high-fat diet were also glucose intolerant and had mildly increased plasma glucose and decreased serum adiponectin levels compared with wild-type mice. On high-fat diet, CCL2^–/– mice also gained slightly more weight and were hyperinsulinemic compared with wild-type mice. Because macrophage levels were unchanged in CCL2^–/– mice, the phenotype appears to be caused by lack of CCL2 itself. The fact that metabolic function was altered in CCL2^–/– mice, despite no changes in adipose tissue macrophage levels, suggests that CCL2 has effects on metabolism that are independent of its macrophage-recruiting capabilities. Importantly, we conclude that CCL2 is not critical for adipose tissue macrophage recruitment. The dominant factor for recruiting macrophages in adipose tissue during obesity therefore remains to be identified.

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