Pro‐Inflammatory macrophages increase in skeletal muscle of high fat‐Fed mice and correlate with metabolic risk markers in humans

Abstract

Objective: In obesity, immune cells infiltrate adipose tissue. Skeletal muscle is the major tissue of insulindependent 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 1 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.

The initiation of metabolic inflammation in childhood obesity

“…Inflammation is observed in a range of tissues involved in nutrient control. For example, proinflammatory macrophage signatures are observed in sites that include adipose tissue, gut (93), liver (94), pancreas (95), muscle (96), and CNS (18,97). Animal models suggest that short-term HFD feeding leads to acute proinflammatory signals in the hypothalamus without significant leukocyte activation in other tissues that may be largely reversible (65).…”

Functional crosstalk of PGC-1 coactivators and inflammation in skeletal muscle pathophysiology

“…M1 macrophage polarization thus seems to be associated with muscle insulin resistance while M2 polarization is linked to muscle insulin sensitivity. Accordingly, an accumulation of M1 macrophages in obese rodents and humans has been described and pro-inflammatory macrophage markers within skeletal muscle correlate with poor glycemic control in diabetic patients whereas anti-inflammatory markers correlate with improved parameters in this setting [315,316]. .…”

Palmitoleate Reverses High Fat-induced Proinflammatory Macrophage Polarization via AMP-activated Protein Kinase (AMPK)

“…Overnutrition and obesity lead to a systemic low-grade inflammation (2) characterized by elevated numbers of immune cells, predominantly macrophages, in metabolic tissues such as skeletal muscle, adipose, and liver (3)(4)(5)(6)(7)(8)(9). Tissue macrophage infiltration and proliferation have been associated with the appearance of peripheral insulin resistance (2,4).…”