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

  1. Martin S. Obin
  1. From the Obesity and Metabolism Laboratory, Jean Mayer U.S. Department of Agriculture Human Nutrition Research Center on Aging, Tufts University, Boston, Massachusetts.
  1. Corresponding authors: Martin S. Obin, martin.obin{at}tufts.edu, or Andrew S. Greenberg, andrew.greenberg{at}tufts.edu.

Abstract

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+ 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 MGL1med/CD11c+ eATMΦs were identified after 8 weeks of HFD. MGL1med/CD11c+ cells comprised ∼65% of CD11c+ eATMΦs. CD11c+ 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+ 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). MGL1med/CD11c+ eATMΦs upregulated additional M2 genes (IL-13, SPHK1, CD163, LYVE-1, and PPAR-α). MGL1med/CD11c+ 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 MGL1med/CD11c+ eATMΦ transcriptional profile and implicating PPAR activation in its elicitation.

CONCLUSIONS These results 1) redefine the phenotypic potential of CD11c+ eATMΦs and 2) suggest previously unappreciated phenotypic and functional commonality between murine and human ATMΦs in the development of obesity and its complications.

Footnotes

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    • Received September 21, 2009.
    • Accepted February 14, 2010.

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  1. Diabetes vol. 59 no. 5 1171-1181
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