Dynamic, M2-Like Remodeling Phenotypes of CD11c+Adipose Tissue Macrophages During High-Fat Diet-Induced Obesity in Mice

摘要

Objective-To identify, localize, and determine M1/M2 polarization of epidydimal adipose tissue (eAT) macrophages (Os) during high-fat diet (HFD)-induced obesity.rnResearch design and methods-Male C57BL/6 mice were fed an HFD (60% fat kcal) or low-fat diet (LFD) (10% fat kcal) for 8 or 12 weeks. eATMOs (F4/80~+ cells) were characterized by in vivo fluorescent labeling, immunohistochemistry, fluorescence-activated cell sorting, and quantitative PCR.rnResults-Recruited interstitial macrophage galactose-type C-type lectin (MGL)1~+/CDllc~ and crown-like structure-associated MGLl-/CDllc~+ and MGL1~(med)/CDllc~+ eATMOs were identified after 8 weeks of HFD. MGL1~(med)/CDllc~+ cells comprised -65% of CDllc~+ eATMOs. CDllc~+ eATMOs expressed a mixed M1/M2 profile, with some Ml transcripts upregulated (IL-12p40 and IL-1β), others downregulated (iNOS, caspase-1, MCP-1, and CD86), and multiple M2 and matrix remodeling transcripts upregulated (arginase-1, IL-IRa, MMP-12, ADAM8, VEGF, and Clec-7a). At HFD week 12, each eATMO subtype displayed an enhanced M2 phenotype as compared with HFD week 8. CD11c~+ subtypes downregulated IL-1β and genes mediating antigen presentation (I-a, CD80) and upregulated the M2 hallmark Ym-1 and genes promoting oxidative metabolism (PGC-lα) and adipogenesis (MMP-2). MGL1~(med)/CD11c~+ eATMOs upregulated additional M2 genes (ILrl3, SPHK1, CD163, LYVE-1, and PPAR-α). MGL1~(med)/CD11c~+ ATM$s expressing elevated PGC-1α, PPAR-α, and Ym-1 transcripts were selectively enriched in eAT of obese mice fed pioglitazone for 6 days, confirming the M2 features of the MGL1~(med)/CD11c~+ eATMO transcriptional profile and implicating PPAR activation in its elicitation.rnConclusions-These results 1) redefine the phenotypic potential of CD11c~+ eATMOs and 2) suggest previously unappreciated phenotypic and functional commonality between murine and human ATMOs in the development of obesity and its complications.