Obesity dysregulates PPARg-associated mitochondrial metabolism to drive immunopathology

Identification: Bapat, Sagar


Obesity dysregulates PPARg-associated mitochondrial metabolism to drive immunopathology
Sagar P. Bapat1,2, Sihao Liu2, Yuqiong Liang1, Ronald M. Evans2, and Ye Zheng1 1Immunobiology and Microbial Pathogenesis Laboratory, 2Gene Expression Laboratory, The Salk Institute for Biological Studies, La Jolla, CA 92037
Little is known about how pro-obesity diets affect immune function. Clinical and epidemiological studies have demonstrated a significant association between obesity and Type 2 helper T cell (Th2)-driven immunopathology, though the physiological, cellular, and molecular underpinnings remain poorly defined. Here we demonstrate that obese mice are susceptible to severe atopic dermatitis, a major manifestation of Th2 immunopathology and disease burden in humans. This increased immunopathology is due to dysregulated function of the nuclear hormone receptor peroxisome proliferator-activated receptor gamma (PPARg) within Th2 cells that can be restored with PPARg-agonist treatment. Mechanistically, we find that PPARg directly controls a mitochondrial metabolic transcriptional program reliant on induction of pyruvate dehydrogenase kinase, isoenzyme 4 (PDK4). PDK4 upregulation induces a coordinated mitochondrial energy substrate switch from glucose to fatty acids that in turn decreases interleukin-4 (IL-4) and interleukin-13 (IL-13) expression, the chief Th2 effector cytokines. Disruption of this circuit increases IL-4 and IL-13 expression, while direct PPARg-agonist treatment restores IL-4 and IL-13 levels. These findings establish PPARg as a molecular link between obesity and Th2 immunopathology, demonstrate the role of mitochondrial metabolism in regulating nuclear gene expression, and implicate PPARg-agonists as a potent treatment against Th2-driven disease.


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