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Journal of the American College of Nutrition, Vol. 28, No. 2, 184-195 (2009)
Published by the American College of Nutrition

Activation of PPAR {gamma} and {alpha} by Punicic Acid Ameliorates Glucose Tolerance and Suppresses Obesity-Related Inflammation

Raquel Hontecillas, DVM, PhD, Marianne O'Shea, PhD, Alexandra Einerhand, PhD, Margaret Diguardo, BA and Josep Bassaganya-Riera, DVM, PhD

Laboratory of Nutritional Immunology & Molecular Nutrition, Virginia Bioinformatics Institute, Virginia Tech (R.H., J.B.-R.)
Nutrition Therapeutics Inc (M.D.), Blacksburg, Virginia
Lipid Nutrition BV (M.O., A.E.), Channahon, Illinois

Address reprint requests to: Josep Bassaganya-Riera, Laboratory of Nutritional Immunology & Molecular Nutrition, Virginia Bioinformatics Institute, Virginia Tech, 1 Washington Street, Blacksburg, VA 24061. E-mail: jbassaga{at}vt.edu

Objective: Peroxisome proliferator-activated receptor {gamma} (PPAR {gamma}) is the molecular target for thiazolidinediones (TZDs), a class of synthetic antidiabetic agents. However, the naturally occurring agonists of PPARs remain largely unknown. Punicic acid (PUA) is a conjugated linolenic acid isomer found in pomegrante. The objective of this study was to test the hypothesis that PUA activates PPAR {gamma} and thereby ameliorates glucose homeostasis and obesity-related inflammation.

Methods: The ability of PUA to modulate PPAR reporter activity was determined in 3T3-L1 pre-adipocytes. A cell-free assay was used to measure PUA's binding to the ligand-binding domain (LBD) of human PPAR {gamma}. The preventive actions of PUA were investigated using genetically obese db/db mice and a model of diet-induced obesity in PPAR {gamma}-expressing and tissue-specific PPAR {gamma} null mice. Expression of PPAR {alpha}, {gamma}, PPAR-responsive genes and TNF-{alpha} was measured in tissues controlling glucose homeostasis.

Results: PUA caused a dose-dependent increase PPAR {alpha} and {gamma} reporter activity in 3T3-L1 cells and bound although weakly to the LBD of human PPAR {gamma}. Dietary PUA decreased fasting plasma glucose concentrations, improved the glucose-normalizing ability, suppressed NF-{kappa}B activation, TNF-{alpha} expression and upregulated PPAR {alpha}- and {gamma}-responsive genes in skeletal muscle and adipose tissue. Loss of PPAR {gamma} impaired the ability of dietary PUA to improve glucose homeostasis and suppress inflammation.

Conclusions: Our studies demonstrate that PUA binds and robustly activates PPAR {gamma}, increases PPAR {gamma}-responsive gene expression and the loss of PPAR {gamma} in immune cells impairs its ability to ameliorate diabetes and inflammation.

Key words: punicic acid, TNF-{alpha}, obesity, inflammation, PPAR alpha, PPAR gamma

Abbreviations: CLA = conjugated linoleic acid • LBD = ligand-binding domain • PPAR = peroxisome proliferator-activated receptor • PUA = punicic acid • WAT = white adipose tissue






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