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 . CD11c + 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.