Obesity Potentiates TH2 Immunopathology Via Dysregulation of PPARg

Clinically, obesity is strongly associated with severe TH2 immunopathology, though the physiological, cellular, and molecular underpinnings of this association remain obscure. We demonstrate that obese mice are susceptible to severe atopic dermatitis (AD), a major manifestation of TH2 immunopathology and disease burden in humans. Mechanistically, we show that dysregulation of the nuclear hormone receptor peroxisome proliferator-activated receptor gamma (PPARg) in T cells is a causal link between obesity and the increased TH2 immunopathology. We find that PPARg directly controls a cellular metabolic transcriptional program that restrains nuclear gene expression of the chief TH2 effector cytokines interleukin-4 (IL-4) and interleukin-13 (IL-13). Accordingly, thiazolidinediones (TZDs), potent PPARg agonists, robustly protect obese mice from TH2 immunopathology. Collectively, these findings establish PPARg as a molecular link between obesity and TH2 immune homeostasis and identify TZDs as novel therapeutic candidates for TH2 immunopathology. ChIP-seq experiments were conducted multiple times, but only one replicate was used for this publication. Input was used for background subtraction. Single end sequencing yielded 13.23M 100bp reads. Bowtie 2 was used for alignment with mm10. Peak calling, motif analyses, and other data analysis were performed using HOMER, a software suite for ChIP-seq analysis. The methods are freely available at http://biowhat.ucsd.edu/homer/. Only tags that mapped uniquely to the genome were considered for further analysis.