The contrasting roles of PPARδ and PPARγ in regulating the metabolic switch between oxidation and storage of fats in white adipose tissue.

ABSTRACT

BACKGROUND: The nuclear receptors peroxisome proliferator-activated receptor γ (PPARγ) and peroxisome proliferator-activated receptor δ (PPARδ) play central roles in regulating metabolism in adipose tissue, as well as being targets for the treatment of insulin resistance. While the role of PPARγ in regulating insulin sensitivity has been well defined, research into PPARδ has been limited until recently due to a scarcity of selective PPARδ agonists. RESULTS: The metabolic effects of PPARγ and PPARδ activation have been examined in vivo in white adipose tissue from ob/ob mice and in vitro in cultured 3T3-L1 adipocytes using (1)H nuclear magnetic resonance spectroscopy and mass spectrometry metabolomics to understand the receptors' contrasting roles. These steady state measurements were supplemented with (13)C-stable isotope substrate labeling to assess fluxes, in addition to respirometry and transcriptomic microarray analysis. The metabolic effects of the receptors were readily distinguished, with PPARγ activation characterized by increased fat storage, synthesis and elongation, while PPARδ activation caused increased fatty acid ß-oxidation, tricarboxylic acid cycle rate and oxidation of extracellular branch chain amino acids. Stimulated glycolysis and increased fatty acid desaturation were common pathways for the agonists. CONCLUSIONS: PPARγ and PPARδ restore insulin sensitivity through varying mechanisms. PPARδ activation increases total oxidative metabolism in white adipose tissue, a tissue not traditionally thought of as oxidative. However, the increased metabolism of branch chain amino acids may provide a mechanism for muscle atrophy, which has been linked to activation of this nuclear receptor. PPARδ has a role as an anti-obesity target and as an anti-diabetic, and hence may target both the cause and consequences of dyslipidemia.