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

作者：Shaul Merav E; Bennett Grace; Strissel Katherine J; Greenberg Andrew S; Obin Martin S^*

来源：Diabetes, 2010, 59(5): 1171-1181.

DOI：10.2337/db09-1402

OBJECTIVE To identify, localize, and determine M1/M2 polarization of epidydimal adipose tissue (eAT) macrophages (Phi(S)) 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. eATM Phi(S) (F4/80(+) 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(+)/CD11c(-) and crown-like structure-associated MGL1(-)/CD11c(+) and MGL1(med)/CD11c(+) eATM Phi(S) were identified after 8 weeks of HFD. MGL1(med)/CD11c(+) cells comprised similar to 65% of CD11c(+) eATM Phi(S). CD11c(+) eATM Phi(S) expressed a mixed M1/M2 profile, with some M1 transcripts upregulated (IL-12p40 and IL-1 beta), 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 eATM Phi subtype displayed an enhanced M2 phenotype as compared with HFD week 8. CD11c(+) subtypes downregulated IL-1 beta and genes mediating antigen presentation (I-a, CD80) and upregulated the M2 hallmark Ym-1 and genes promoting oxidative metabolism (PGC-1 alpha) and adipogenesis (MMP-2). MGL1(med)/CD11c(+) eATM Phi(S) upregulated additional M2 genes (IL-13, SPHK1, CD163, LYVE-1, and PPAR-alpha). MGL1(med)/CD11c(+) ATM Phi(S) expressing elevated PGC-1 alpha, PPAR-alpha, and Ym-1 transcripts were selectively enriched in eAT of obese mice fed pioglitazone for 6 (lays, confirming the M2 features of the MGL1(med)/CD11c(+) eATM Phi transcriptional profile and implicating PPAR activation in its elicitation.
CONCLUSIONS These results 1) redefine the phenotypic potential of CD11c(+) eATM Phi(S) and 2) suggest previously unappreciated phenotypic and functional commonality between murine and human ATM Phi(S) in the development of obesity and its complications. Diabetes 59:1171-1181, 2010

• 出版日期2010-5