Nicotinamide phosphoribosyltransferase is required for the calorie restriction-mediated improvements in oxidative stress, mitochondrial biogenesis, and metabolic adaptation.
Calorie restriction (CR) is one of the most reproducible treatments for weight loss and slowing aging. However, how CR induces these metabolic alterations is not fully understood. In this work, we studied whether nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme for nicotinamide adenine dinucleotide biosynthesis, plays a role in CR-induced beneficial metabolic effects using a specific inhibitor of NAMPT (FK866). CR upregulated NAMPT mRNA and protein levels in rat skeletal muscle and white adipose tissue. Inhibition of NAMPT activity by FK866 in rats did not affect the SIRT1 upregulation by CR but suppressed the CR-induced SIRT1 activity and deacetylation of Forkhead box protein O1/peroxisome proliferator-activated receptor γ coactivator-1α. Inhibition of NAMPT activity by FK866 also attenuated the CR-induced SIRT3 activity, evidenced by deacetylation of superoxide dismutase-2. Furthermore, FK866 not only weakened the CR-induced decrease of oxidative stress (dichlorofluorescin signal, superoxide , and malondialdehyde levels), but also greatly attenuated the CR-induced improvements of antioxidative activity (total superoxide dismutase, glutathione, and glutathione/oxidized glutathione ratio) and mitochondrial biogenesis (mRNA levels of nuclear respiratory factor 1, cytochrome c oxidase IV, peroxisome proliferator-activated receptor-γ coactivator-1α, and transcription factor A, mitochondrial and citrate synthase activity). At last, FK866 blocked the CR-induced insulin sensitizing, Akt signaling activation, and endothelial nitric oxide synthase phosphorylation. Collectively, our data provide the first evidence that the CR-induced beneficial effects in oxidative stress, mitochondrial biogenesis, and metabolic adaptation require NAMPT.
Department of Pharmacology, Second Military Medical University, Room 506, 325 Guo He Road, Yangpu District, Shanghai 200433, China. cymiao@smmu.edu.cn or pwang@smmu.edu.cn.
Jie
J
Song
Sen-Fang
SF
Ke
Can-Can
CC
Zhou
Sai-Long
SL
Zhang
Yun-Feng
YF
Guan
Tian-Ying
TY
Xu
Chun-Quan
CQ
Sheng
Pei
P
Wang
Chao-Yu
CY
Miao
D000375:Aging / Q000235:genetics; D000818:Animals; D015153:Blotting, Western; D031204:Caloric Restriction; D004195:Disease Models, Animal; D018507:Gene Expression Regulation, Developmental; D008297:Male; D063269:Mitochondrial Turnover / Q000235:genetics*; D054409:Nicotinamide Phosphoribosyltransferase / Q000096:biosynthesis / Q000235:genetics*; D018384:Oxidative Stress / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction; D015431:Weight Loss / Q000502:physiology*
D012333:RNA, Messenger; D054409:Nicotinamide Phosphoribosyltransferase
Calorie restriction; Insulin signaling.; Mitochondrial biogenesis; Nicotinamide phosphoribosyltransferase; Oxidative stress