The contrasting roles of PPARĪ“ and PPARĪ³ in regulating the metabolic switch between oxidation and storage of fats in white adipose tissue.
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BACKGROUND: The nuclear receptors peroxisome proliferator-activated receptor Ī³ (PPARĪ³) and peroxisome proliferator-activated receptor Ī“ (PPARĪ“) play central roles in regulating metabolism in adipose tissue, as well as being targets for the treatment of insulin resistance. While the role of PPARĪ³ in regulating insulin sensitivity has been well defined, research into PPARĪ“ has been limited until recently due to a scarcity of selective PPARĪ“ agonists. RESULTS: The metabolic effects of PPARĪ³ and PPARĪ“ 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 PPARĪ³ activation characterized by increased fat storage, synthesis and elongation, while PPARĪ“ activation caused increased fatty acid Ī²-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: PPARĪ³ and PPARĪ“ restore insulin sensitivity through varying mechanisms. PPARĪ“ 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. PPARĪ“ has a role as an anti-obesity target and as an anti-diabetic, and hence may target both the cause and consequences of dyslipidemia.
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1474-760X
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Biotechnology and Biological Sciences Research Council (BB/H013539/1)
Wellcome Trust (078652/Z/05/Z)