Obesity Potentiates T H 2 Immunopathology via Dysregulation of PPAR γ

How obesity affects immune function is not well understood. Clinically, obesity is strongly associated with severe T2 immunopathology, though the physiological, cellular, and molecular underpinnings of this association remain obscure. Here, we demonstrate that obese mice are susceptible to severe atopic dermatitis (AD), a major manifestation of T2 immunopathology and disease burden in humans. Mechanistically, we show that dysregulation of the nuclear hormone receptor (NHR) PPAR (peroxisome proliferator-activated receptor gamma) in T cells is a causal link between obesity and the increased T2 immunopathology. We find that PPAR oversees a cellular metabolic transcriptional program that restrains nuclear gene expression of the chief T2 priming and effector cytokine interleukin-4 (IL-4). Accordingly, thiazolidinediones (TZDs), potent PPAR agonists, robustly protect obese mice from T2 immunopathology. Collectively, these findings establish PPAR as a molecular link between obesity and T2 immune homeostasis and identify TZDs as novel therapeutic candidates for T2 immunopathology. Fundamentally, these findings demonstrate that shifting physiologic metabolic states can shape the tone of adaptive immune responses to modulate differential disease susceptibility.