Abstract
Peroxisome proliferator-activated receptor-α (PPARα) is a dietary lipid sensor, whose activation results in hypolipidemic effects. In this study, we investigated whether PPARα activation affects energy metabolism in white adipose tissue (WAT). Activation of PPARα by its agonist (bezafibrate) markedly reduced adiposity in KK mice fed a high-fat diet. In 3T3-L1 adipocytes, addition of GW7647, a highly specific PPARα agonist, during adipocyte differentiation enhanced glycerol-3-phosphate dehydrogenase activity, insulin-stimulated glucose uptake, and adipogenic gene expression. However, triglyceride accumulation was not increased by PPARα activation. PPARα activation induced expression of target genes involved in FA oxidation and stimulated FA oxidation. In WAT of KK mice treated with bezafibrate, both adipogenic and FA oxidation-related genes were significantly upregulated. These changes in mRNA expression were not observed in PPARα-deficient mice. Bezafibrate treatment enhanced FA oxidation in isolated adipocytes, suppressing adipocyte hypertrophy. Chromatin immunoprecipitation (ChIP) assay revealed that PPARα was recruited to promoter regions of both adipogenic and FA oxidation-related genes in the presence of GW7647 in 3T3-L1 adipocytes. These findings indicate that the activation of PPARα affects energy metabolism in adipocytes, and PPARα activation in WAT may contribute to the clinical effects of fibrate drugs.
Highlights
Peroxisome proliferator-activated receptor-␣ (PPAR␣) is a dietary lipid sensor, whose activation results in hypolipidemic effects
PPARa activation promoted both adipocyte differentiation and FA oxidation in 3T3-L1 adipocytes. These effects were observed in vivo, which resulted in the enhancement of whole-body oxygen consumption and suppression of adipocyte hypertrophy. These findings indicate that the pharmacological activation of PPARa affects energy metabolism in adipocytes and that the PPARa activation in white adipose tissue (WAT) may contribute to the clinical effects of fibrate drugs
An inhibitor of mitochondrial electron transport, almost completely diminished the increase in oxygen consumption rate (OCR). These findings indicate that PPARa activation in adipocytes enhances FA oxidation and increases OCR via the induction of Peroxisome proliferator-activated receptors (PPAR) target genes related to FA oxidation, suggesting that the effects of PPARa activation contribute to the discrepancy between adipogenic activity and lipid accumulation levels induced by PPARa activation
Summary
Peroxisome proliferator-activated receptor-␣ (PPAR␣) is a dietary lipid sensor, whose activation results in hypolipidemic effects. In WAT of KK mice treated with bezafibrate, both adipogenic and FA oxidation-related genes were significantly upregulated. These changes in mRNA expression were not observed in PPAR␣-deficient mice. Chromatin immunoprecipitation (ChIP) assay revealed that PPAR␣ was recruited to promoter regions of both adipogenic and FA oxidation-related genes in the presence of GW7647 in 3T3L1 adipocytes. These findings indicate that the activation of PPAR␣ affects energy metabolism in adipocytes, and PPAR␣ activation in WAT may contribute to the clinical effects of fibrate drugs.—Goto, T., J-Y.
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