Submitted to: Diabetes
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 2/20/2010
Publication Date: 5/20/2010
Citation: Shaul, M.E., Bennett, G., Strissell, K.J., Greenberg, A.S., Obin, M. 2010. Dynamic M2-like remodeling phenotypes of CD11c+ adipose tissue macrophages during high fat diet-induced obesity in mice. Diabetes. 59(5):1171-1181. Interpretive Summary: Obesity is a major cause of insulin resistance and contributes to development of type 2 diabetes. Adipose tissue expansion during obesity has been shown to trigger inflammatory pathways through the infiltration and accumulation of immune cells such as macrophages into the visceral adipose tissues. Signals between inflammatory adipose tissue macrophages (ATM's) and fat cells (adipocytes) impair insulin sensitivity in adipocytes and influence adipocyte cell death. The aim of this study was to identify, localize and determine the effects of high fat diet (HFD)on the indicators of obesity in mice. Results showed that HFD induced the production of many indicators that have been shown to promote fat tissue expansion and remodeling. The results suggest the involvement of previously unappreciated physiological indicators in the development of obesity and its complications.
Technical Abstract: Chronic inflammation is a pathogenic factor in obesity complications, in particular insulin resistance (IR). A significant advance in our understanding of obesity-associated inflammation and insulin resistance has been the recognition of the underlying role of adipose tissue macrophages (ATM's). The aim of this study was to identify, localize and determine M1/M2 polarization of epidydimal adipose tissue (eAT) macrophages (eATMF) during high fat diet (HFD)-induced obesity. Male C57BL/6 mice were fed HFD (60% fat kcal) or low fat diet (LFD, 10% fat kcal) for 8 or 12 weeks. eATMFs (F4/80+ cells) were characterized by in vivo PKH26 labeling, immunohistochemistry, FACS and quantitative PCR. Results showed that recruited (PKH26-negative) interstitial MGL1+/CD11c' and CLS-associated MGL1'/CD11c+ and MGL1med/CD11c+ eATMF subtypes were identified after 8 weeks of HFD. MGL1med/CD11c+ cells comprised ~65% of CD11c+ eATMFs. CD11c+ eATMFs expressed a mixed M1/M2 profile, with some M1 genes upregulated (IL-12p40, IL-1ß), others downregulated (iNOS, caspase-1, MCP-1, CD86), and multiple M2 and matrix remodeling genes upregulated (arginase-1, IL-1Ra, MMP-12, ADAM8, VEGF, Clec-7a). At HFD week 12, each eATMF subtype displayed an enhanced M2 phenotype as compared with HFD week 8. CD11c+ subtypes downregulated IL-1ß and genes mediating antigen presentation, (I-a, CD80) and upregulated the M2 hallmark Ym-1 and genes promoting oxidative metabolism (PGC-1a) and adipogenesis (MMP2). MGL1med/CD11c+ eATMFs upregulated additional M2 genes (IL-13, SPHK1, CD163, LYVE-1, PPAR-a). MGL1med/CD11c+ ATMFs expressing elevated PGC-1a, PPAR-a 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+ eATMF transcritptional profile and implicating PPAR activation in its elicitation. In conclusion, these results 1) redefine the phenotypic potential of CD11c+ eATMFs and 2) suggest previously unappreciated phenotypic and functional commonality between murine and human ATMFs in the development of obesity and its complications.