Activation of Peroxisome Proliferator–Activated Receptor (PPAR)δ Promotes Reversal of Multiple Metabolic Abnormalities, Reduces Oxidative Stress, and Increases Fatty Acid Oxidation in Moderately Obese Men

• Published in: Diabetes (New York, N.Y.) Vol. 57; no. 2; pp. 332 - 339
• Main Authors: Risérus, Ulf, Sprecher, Dennis, Johnson, Tony, Olson, Eric, Hirschberg, Sandra, Liu, Aixue, Fang, Zeke, Hegde, Priti, Richards, Duncan, Sarov-Blat, Leli, Strum, Jay C., Basu, Samar, Cheeseman, Jane, Fielding, Barbara A., Humphreys, Sandy M., Danoff, Theodore, Moore, Niall R., Murgatroyd, Peter, O'Rahilly, Stephen, Sutton, Pauline, Willson, Tim, Hassall, David, Frayn, Keith N., Karpe, Fredrik
• Format: Journal Article
• Language: English
• Published: Alexandria, VA American Diabetes Association 01.02.2008
• Subjects: Adolescent; Adult; Apolipoproteins B - blood; Apolipoproteins B - drug effects; Biological and medical sciences; Care and treatment; Cholesterol, HDL - blood; Cholesterol, HDL - drug effects; Diabetes. Impaired glucose tolerance; Double-Blind Method; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Fat metabolism; Fatty Acids - metabolism; Fibric acids; Genetic aspects; Humans; Magnetic Resonance Imaging; Male; Medical sciences; MEDICIN; MEDICINE; Metabolic diseases; Metabolic syndrome X; Middle Aged; Obesity; Obesity - physiopathology; Oxidation-Reduction; Oxidative stress; Oxidative Stress - physiology; Peroxisomes; Physiological aspects; Placebos; PPAR delta - agonists; PPAR delta - physiology; Thiazoles - pharmacology; Triglycerides - blood; Endocrinopathy; Human; Obesity; Oxidative stress; Diabetes mellitus; Nutrition disorder; Lipids; Oxidation; Fatty acids; Nutritional status; Peroxisome proliferator activated receptor
• ISSN: 0012-1797; 1939-327X; 1939-327X
• DOI: 10.2337/db07-1318

Activation of Peroxisome Proliferator–Activated Receptor (PPAR)δ Promotes Reversal of Multiple Metabolic Abnormalities, Reduces Oxidative Stress, and Increases Fatty Acid Oxidation in Moderately Obese Men Ulf Risérus 1 , Dennis Sprecher 2 , Tony Johnson 2 , Eric Olson 2 , Sandra Hirschberg 2 , Aixue Liu 3 , Zeke Fang 4 , Priti Hegde 5 , Duncan Richards 6 , Leli Sarov-Blat 5 , Jay C. Strum 5 , Samar Basu 7 , Jane Cheeseman 1 , Barbara A. Fielding 1 , Sandy M. Humphreys 1 , Theodore Danoff 3 , Niall R. Moore 8 , Peter Murgatroyd 9 , Stephen O'Rahilly 10 , Pauline Sutton 1 , Tim Willson 11 , David Hassall 12 , Keith N. Frayn 1 and Fredrik Karpe 1 1 Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, U.K 2 Cardiovascular and Urogenital Center for Excellence in Drug Discovery, GlaxoSmithKline, King of Prussia, Pennsylvania 3 Human Target Validation, Cardiovascular and Urogenital Center for Excellence in Drug Discovery, GlaxoSmithKline, King of Prussia, Pennsylvania 4 Statistics, GlaxoSmithKline, King of Prussia, Pennsylvania 5 Clinical Pharmacology and Discovery Medicine/Cardiovascular and Urogenital (CPDM CVU) Unit, GlaxoSmithKline, King of Prussia, Pennsylvania 6 Addenbrooke's Centre for Clinical Investigation (ACCI) Unit, GlaxoSmithKline, Cambridge, U.K 7 Department of Public Health, University of Uppsala, Uppsala, Sweden 8 Department of Radiology, Churchill Hospital, University of Oxford, Oxford, U.K 9 Wellcome Trust Clinical Research Facility, Addenbrooke's Hospital, Cambridge, U.K 10 Department of Clinical Biochemistry and Medicine, University of Cambridge, Cambridge, U.K 11 GlaxoSmithKline, Research Triangle Park, North Carolina 12 GlaxoSmithKline, Stevenage, U.K Address correspondence and reprint requests to Dr. F. Karpe, Churchill Hospital, Oxford OX3 7LJ, U.K. E-mail: fredrik.karpe{at}ocdem.ox.ac.uk Abstract OBJECTIVE— Pharmacological use of peroxisome proliferator–activated receptor (PPAR)δ agonists and transgenic overexpression of PPARδ in mice suggest amelioration of features of the metabolic syndrome through enhanced fat oxidation in skeletal muscle. We hypothesize a similar mechanism operates in humans. RESEARCH DESIGN AND METHODS— The PPARδ agonist (10 mg o.d. GW501516), a comparator PPARα agonist (20 μg o.d. GW590735), and placebo were given in a double-blind, randomized, three-parallel group, 2-week study to six healthy moderately overweight subjects in each group. Metabolic evaluation was made before and after treatment including liver fat quantification, fasting blood samples, a 6-h meal tolerance test with stable isotope fatty acids, skeletal muscle biopsy for gene expression, and urinary isoprostanes for global oxidative stress. RESULTS— Treatment with GW501516 showed statistically significant reductions in fasting plasma triglycerides (−30%), apolipoprotein B (−26%), LDL cholesterol (−23%), and insulin (−11%), whereas HDL cholesterol was unchanged. A 20% reduction in liver fat content ( P < 0.05) and 30% reduction in urinary isoprostanes ( P = 0.01) were also observed. Except for a lowering of triglycerides (−30%, P < 0.05), none of these changes were observed in response to GW590735. The relative proportion of exhaled CO 2 directly originating from the fat content of the meal was increased ( P < 0.05) in response to GW501516, and skeletal muscle expression of carnitine palmitoyl-transferase 1b ( CPT1b ) was also significantly increased. CONCLUSIONS— The PPARδ agonist GW501516 reverses multiple abnormalities associated with the metabolic syndrome without increasing oxidative stress. The effect is probably caused by increased fat oxidation in skeletal muscle. Apo, apolipoprotein AST, aspartate aminotransferase AUC, area under the curve γGT, γ-glutamyltransferase LCM, laser capture microdissection LPL, lipoprotein lipase MRI, magnetic resonance imaging NEFA, nonesterified fatty acid TTR, tracer-to-tracee ratio Footnotes Published ahead of print at http://diabetes.diabetesjournals.org on 16 November 2007. DOI: 10.2337/db07-1318. U.R. and D.S. contributed equally to this work. Additional information for this article can be found in an online appendix at http://dx.doi.org/10.2337/db07-1318 . The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Accepted November 10, 2007. Received September 14, 2007. DIABETES