Activation of PPAR gamma and alpha by punicic acid ameliorates glucose tolerance and suppresses obesity-related inflammation.
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-kappaB 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.
Hontecillas
Raquel
R
Laboratory of Nutritional Immunology & Molecular Nutrition, Virginia Bioinformatics Institute, Virginia Tech, 1 Washington Street, Blacksburg, VA 24061, USA.
O'Shea
Marianne
M
Einerhand
Alexandra
A
Diguardo
Margaret
M
Bassaganya-Riera
Josep
J
D016475:3T3 Cells; D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology / Q000627:therapeutic use; D001786:Blood Glucose / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D015870:Gene Expression; D018149:Glucose Intolerance / Q000188:drug therapy*; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology / Q000627:therapeutic use; D008042:Linolenic Acids / Q000494:pharmacology / Q000627:therapeutic use*; D029561:Lythraceae / Q000737:chemistry*; D051379:Mice; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D009765:Obesity / Q000188:drug therapy* / Q000378:metabolism; D047493:PPAR alpha / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D047495:PPAR gamma / Q000819:agonists / Q000378:metabolism; D008517:Phytotherapy; D010938:Plant Oils / Q000494:pharmacology / Q000627:therapeutic use*; D012639:Seeds; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D000893:Anti-Inflammatory Agents; D001786:Blood Glucose; D007004:Hypoglycemic Agents; D008042:Linolenic Acids; D016328:NF-kappa B; D047493:PPAR alpha; D047495:PPAR gamma; D010938:Plant Oils; D014409:Tumor Necrosis Factor-alpha; C519714:punicic acid