Pro-Inflammatory Macrophages Increase in Skeletal Muscle of High Fat-Fed Mice and Correlate with Metabolic Risk Markers in Humans

Objective: In obesity, immune cells infiltrate adipose tissue. Skeletal muscle is the major tissue of insulin-dependent glucose disposal, and indices of muscle inflammation arise during obesity, but whether and which immune cells increase in muscle remain unclear. Methods: Immune cell presence in quadriceps muscle of wild type mice fed high-fat diet (HFD) was studied for 3 days to 10 weeks, in CCL2-KO mice fed HFD for 1 week, and in human muscle. Leukocyte presence was assessed by gene expression of lineage markers, cyto/chemokines and receptors; immunohistochemistry; and flow cytometry. Results: After 1 week HFD, concomitantly with glucose intolerance, muscle gene expression of Ly6b, Emr1 (F4/80), Tnf, Ccl2, and Ccr2 rose, as did pro- and anti-inflammatory markers Itgax (CD11c) and Mgl2. CD11c1 proinflammatory macrophages in muscle increased by 76%. After 10 weeks HFD, macrophages in muscle increased by 47%. Quadriceps from CCL2- KO mice on HFD did not gain macrophages and maintained insulin sensitivity. Muscle of obese, glucose- intolerant humans showed elevated CD68 (macrophage marker) and ITGAX, correlating with poor glucose disposal and adiposity. Conclusion: Mouse and human skeletal muscles gain a distinct population of inflammatory macrophages upon HFD or obesity, linked to insulin resistance in humans and CCL2 availability in mice.