期刊
JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES
卷 69, 期 1, 页码 44-57出版社
OXFORD UNIV PRESS INC
DOI: 10.1093/gerona/glt122
关键词
Oxidative stress; Mitochondrial biogenesis; Calorie restriction; Nicotinamide phosphoribosyltransferase; Insulin signaling
资金
- National Natural Science Foundation [81100866, 81130061]
- Shanghai Municipal Education Commission Scientist Project [12ZZ078]
- National Basic Research Program of China [2009CB521902]
- Program of Shanghai Subject Chief Scientist [10XD1405300]
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 gamma coactivator-1 alpha. 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 O-2(-center dot), 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-gamma coactivator-1 alpha, 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.
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