STAT1 Ablation in CD11c+ Cells Protects Mice from Obesity-Induced Insulin Resistance

Abstract

Background: Obesity is a global epidemic and major risk factor for insulin resistance and type 2 diabetes. Obesity is associated with low grade chronic inflammation of adipose tissue (AT). F4/80+CD11c+ macrophages/dendritic cells are increased and polarized into M1-like phenotypes in AT and may contribute to insulin resistance in mouse models of obesity. STAT1 is a transcription factor that play key roles in macrophage polarization into M1-like phenotypes. Hence, we investigated the role of CD11c+ macrophage/dendritic cell STAT1 in obesity-induced AT inflammation and insulin resistance. Methods: Mice with specific knockout of STAT1 in CD11c+ cells were generated by crossbreeding STAT1 fl/fl and CD11c-Cre mice. CD11c/STAT1 KO and littermate controls were fed either high fat diet (HFD, for 16 weeks) to induce obesity or normal diet (ND) as lean controls. We evaluated body composition, insulin sensitivity, gene expression of inflammatory markers, various immune cells and brown/beige adipogenesis markers in AT. Results: Perigonadal white AT (PWAT) and body weight were not significantly different between KO and control groups but liver weight and liver-to-body weight ratio were significantly reduced in obese KO mice (p<0.05). STAT1 KO mice on HFD exhibited improved insulin sensitivity examined by insulin tolerance test (p<0.05) and reduced expression of inflammatory markers TNFα, IFNγ, IL-12 and MCP1 in PWAT and subcutaneous AT (SAT) compared to littermate controls (p<0.05). AT immune cell analysis revealed that STAT1 ablation caused a decrease in M1-like proinflammatory polarization and increase in M2-like polarization of F4/80+ macrophages, reduced number of total CD3+ T cells and CD8+T cells in PWAT. In addition, brown/beige adipogenesis markers UCP1, CIDEA and Prdm16 also upregulated (p<0.05) in SAT of obese KO mice. Conclusion: Our results show the critical role of macrophage/dendritic cell STAT1 in obesity-induced AT inflammation and insulin resistance. Disclosure A. Kalathookunnel Antony: None. X.D. Perrard: None. Z. Lian: None. J. Perrard: None. L. Hennighausen: None. C.W. Smith: None. C.M. Ballantyne: Research Support; Self; Abbott, Amarin Corporation, Amgen Inc., Esperion Therapeutics, Ionis Pharmaceuticals, Inc., Novartis Pharmaceuticals Corporation, Pfizer Inc., Regeneron Pharmaceuticals, Inc., Roche Diagnostics Corporation, Sanofi. Consultant; Self; Abbott, Amarin Corporation, Amgen Inc., AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Esperion Therapeutics, Ionis Pharmaceuticals, Inc., Matinas BioPharma, Merck & Co., Inc., Novartis Pharmaceuticals Corporation, Novo Nordisk Inc., Pfizer Inc., Regeneron Pharmaceuticals, Inc., Roche Diagnostics Corporation, Sanofi. H. Wu: None.