Abstract 677: The PPARdelta Agonist GW501516: Influence on Features of the Metabolic Syndrome

Abstract

Hypertriglyceridemia and insulin resistance in the setting of obesity, i.e. the metabolic syndrome, are thought related to ectopic fat storage and impaired regulation of fat oxidation. Rodent models suggest that increased PPARdelta function may correct these abnormalities. Design/Methods: Double-blind, randomized, 3-parallel group (n = 6 in each group), 2-week study of PPARdelta agonist ( GW501516 –10mg), PPARalpha agonist ( GW590735 –20ug) and placebo. Men with a waist > 95cm, BMI > 27, TG > 100mg/dl < 400mg/dl, and HDLc < 50 mg/dl were included. Blood lipids, fatty acids, serum insulin and liver fat content (MRI) were measured at baseline and termination of study, while oral 13 C-palmitate-labeled fat-feeding allowed post-meal examination of plasma NEFA metabolism and oxidation ( 13 CO 2 exhalation). Skeletal muscle biopsies were taken to monitor transcript regulation of fat oxidation pathways. Results: The PPARdelta group revealed reduction of LDLc, apoB and TG by 23%, 21%, and 31%, respectively and of plasma NEFA, without any deterioration of insulin and glucose homeostasis. Comparable TG reduction in PPARalpha (27%), with modest apoB reductions (−13%) were not accompanied by NEFA reductions. Hepatic fat was significantly reduced in the PPARdelta group only (p = 0.04). After the labeled fat meal, cumulative exhaled 13 CO 2 was increased (p = 0.03; enhanced fat catabolism) and accompanied by increased mRNA expression of skeletal muscle CPT1b only in the PPARδ group. Summary: Short term administration of a selective PPARdelta agonist decreased TG, apoB, LDL-C and NEFA concentrations. Increased peripheral fatty acid uptake and oxidation may partly explain these benefits.