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 (Phis) during high-fat diet (HFD)-induced obesity.


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. eATMPhis (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(+) eATMPhis were identified after 8 weeks of HFD. MGL1(med)/CD11c(+) cells comprised approximately 65% of CD11c(+) eATMPhis. CD11c(+) eATMPhis expressed a mixed M1/M2 profile, with some M1 transcripts upregulated (IL-12p40 and IL-1beta), 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 eATMPhi subtype displayed an enhanced M2 phenotype as compared with HFD week 8. CD11c(+) subtypes downregulated IL-1beta and genes mediating antigen presentation (I-a, CD80) and upregulated the M2 hallmark Ym-1 and genes promoting oxidative metabolism (PGC-1alpha) and adipogenesis (MMP-2). MGL1(med)/CD11c(+) eATMPhis upregulated additional M2 genes (IL-13, SPHK1, CD163, LYVE-1, and PPAR-alpha). MGL1(med)/CD11c(+) ATMPhis expressing elevated PGC-1alpha, PPAR-alpha, 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(+) eATMPhi transcriptional profile and implicating PPAR activation in its elicitation.


CONCLUSIONS
These results 1) redefine the phenotypic potential of CD11c(+) eATMPhis and 2) suggest previously unappreciated phenotypic and functional commonality between murine and human ATMPhis in the development of obesity and its complications.
Shaul
Merav E
ME
Obesity and Metabolism Laboratory, Jean Mayer U.S. Department of Agriculture Human Nutrition Research Center on Aging, Tufts University, Boston, Massachusetts, USA.
Bennett
Grace
G
Strissel
Katherine J
KJ
Greenberg
Andrew S
AS
Obin
Martin S
MS
D000273:Adipose Tissue / Q000378:metabolism*; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D051940:B7-2 Antigen / Q000378:metabolism; D039521:CD11c Antigen / Q000378:metabolism*; D004041:Dietary Fats / Q000009:adverse effects*; D005434:Flow Cytometry; D007150:Immunohistochemistry; D053590:Interleukin 1 Receptor Antagonist Protein / Q000378:metabolism; D053762:Interleukin-12 Subunit p40 / Q000378:metabolism; D018793:Interleukin-13 / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000139:chemically induced* / Q000378:metabolism* / Q000503:physiopathology; D016133:Polymerase Chain Reaction; D011956:Receptors, Cell Surface / Q000378:metabolism; D000098902:CD163 Antigen
D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D051940:B7-2 Antigen; D039521:CD11c Antigen; D000098902:CD163 Antigen; D004041:Dietary Fats; D053590:Interleukin 1 Receptor Antagonist Protein; D053762:Interleukin-12 Subunit p40; D018793:Interleukin-13; D011956:Receptors, Cell Surface