Peroxisome proliferator-activated receptor (PPAR) α is one of the master regulators of lipid metabolism and the major target of fibrates, a class of drugs improving dyslipidemia in metabolic syndromes. To understand the tissue-specific roles of PPARα and the coordination among multiple organs, we employed newly generated mouse models enabling doxycycline-inducible overexpression of PPARα specifically in liver, adipose or the insulin-producing pancreatic β-cells. Titrated by doxycycline dose, a moderate elevation of PPARα proteins in liver activated the transcription of its target genes. In mice with diet-induced obesity, hepatic overexpression of PPARα significantly reduced steatosis and improved systemic insulin sensitivity. Surprisingly, systemic triglyceride clearance was dramatically impaired, associated with a trend towards faster VLDL secretion. PPARα overexpression in adipose tissues had a marginal effect on systemic insulin sensitivity. However, inflammation was markedly ameliorated in white but not brown fat pads. Pancreatic β-cell-specific overexpression of PPARα resulted in a significant decrease in glucose-stimulated insulin secretion, suggesting a negative impact of PPARα induction on β-cell function. Taken together, our findings reveal the differential actions of enhanced PPARα on local tissues and whole-body metabolism and call for caution to the potential adverse effects from fibrate treatment. Further dissection of PPARα signaling with our mouse models may facilitate the discovery of novel therapeutic targets with high efficacy and specificity.

Disclosure

R. Ye: None. P.E. Scherer: None.

Funding

National Institutes of Health (R01DK55758, R01DK099110, P01-DK088761-01); JDRF (17-2012-36); Novo Nordisk Foundation (to P.E.S.)

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