Dynamic, M2-like remodeling phenotypes of CD11c+ adipose tissue macrophages during high-fat diet-induced obesity in mice

OBJECTIVE--To identify, localize, and determine M1/M2 polarization of epidydimal adipose tissue (eAT) macrophages (Φs) during high-fat diet (HFD)-induced obesity. RESEARCH 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, eATMΦs (F4/[80.sup.+] cells) were characterized by in vivo fluorescent labeling, immunohistochemistry, fluorescence-activated cell sorting, and quantitative PCR. RESULTS--Recruited interstitial macrophage galactose-type C-type lectin (MGL)[1.sup.+]/[CD11c.sup.-] and crown-like structure-associated [MGL1.sup.-]/[CD11c.sup.+] and [MGL1.sup.med]/[CD11c.sup.+] eATMΦs were identified after 8 weeks of HFD. [MGL1.sup.med]/[CD11c.sup.+] cells comprised ~65% of [CD11c.sup.+] eATMΦs. [CD11c.sup.+] eATΦs expressed a mixed M1/M2 profile, with some M1 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-1Ra, MMP-12, ADAM8, VEGF, and Clec-7a). At HFD week 12, each eATMΦ subtype displayed an enhanced M2 phenotype as compared with HFD week 8. [CD11c.sup.+] 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-1α) and adipogenesis (MMP-2). [MGL1.sup.med]/[CD11c.sup.+] eATMΦs upregulated additional M2 genes (IL-13, SPHK1, CD163, LYVE-1, and PPAR-α). [MGL1.sup.med]/[CD11c.sup.+] ATM(Ps 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.sup.med]/[CD11c.sup.+] eATMΦ transcriptional profile and implicating PPAR activation in its elicitation. CONCLUSIONS--These results 1) redefine the phenotypic potential of [CD11c.sup.+] eATMΦs and 2) suggest previously unappreciated phenotypic and functional commonality between murine and human ATMΦs in the development of obesity and its complications. Diabetes 59:1171-1181, 2010
Chronic inflammation is a pathogenic factor in obesity complications, in particular insulin resistance (1,2). A significant advance in our understanding of obesity-associated inflammation and insulin resistance has been recognition of [...]