Resveratrol ameliorates aging-related metabolic phenotypes by inhibiting cAMP phosphodiesterases.
Resveratrol, a polyphenol in red wine, has been reported as a calorie restriction mimetic with potential antiaging and antidiabetogenic properties. It is widely consumed as a nutritional supplement, but its mechanism of action remains a mystery. Here, we report that the metabolic effects of resveratrol result from competitive inhibition of cAMP-degrading phosphodiesterases, leading to elevated cAMP levels. The resulting activation of Epac1, a cAMP effector protein, increases intracellular Ca(2+) levels and activates the CamKKβ-AMPK pathway via phospholipase C and the ryanodine receptor Ca(2+)-release channel. As a consequence, resveratrol increases NAD(+) and the activity of Sirt1. Inhibiting PDE4 with rolipram reproduces all of the metabolic benefits of resveratrol, including prevention of diet-induced obesity and an increase in mitochondrial function, physical stamina, and glucose tolerance in mice. Therefore, administration of PDE4 inhibitors may also protect against and ameliorate the symptoms of metabolic diseases associated with aging.
Laboratory of Obesity and Aging Research, Genetics and Developmental Biology Center, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Sung-Jun
SJ
Park
Faiyaz
F
Ahmad
Andrew
A
Philp
Keith
K
Baar
Tishan
T
Williams
Haibin
H
Luo
Hengming
H
Ke
Holger
H
Rehmann
Ronald
R
Taussig
Alexandra L
AL
Brown
Myung K
MK
Kim
Michael A
MA
Beaven
Alex B
AB
Burgin
Vincent
V
Manganiello
Jay H
JH
Chung
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D000091162:AMP-Activated Protein Kinase Kinases; D052436:Adipose Tissue, White / Q000187:drug effects; D000375:Aging / Q000378:metabolism*; D000818:Animals; D031204:Caloric Restriction; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000737:chemistry / Q000378:metabolism; D004032:Diet; D018149:Glucose Intolerance / Q000517:prevention & control; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism; D051379:Mice; D008958:Models, Molecular; D018482:Muscle, Skeletal / Q000187:drug effects; D009243:NAD / Q000378:metabolism; D009765:Obesity / Q000517:prevention & control; D011494:Protein Kinases / Q000378:metabolism; D000077185:Resveratrol; D020889:Rolipram / Q000008:administration & dosage; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism; D015398:Signal Transduction; D056564:Sirtuin 1 / Q000378:metabolism; D013267:Stilbenes / Q000008:administration & dosage*
C482601:Epac protein, mouse; D020662:Guanine Nucleotide Exchange Factors; D019837:Ryanodine Receptor Calcium Release Channel; D013267:Stilbenes; D009243:NAD; D011494:Protein Kinases; D000091162:AMP-Activated Protein Kinase Kinases; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1; D020889:Rolipram; D000077185:Resveratrol