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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 +] eATMΦs 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 +] ATMΦs 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 [ABSTRACT FROM AUTHOR]