Journal
CELL METABOLISM
Volume 14, Issue 4, Pages 528-536Publisher
CELL PRESS
DOI: 10.1016/j.cmet.2011.08.014
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Funding
- National Institute on Aging [AG02150]
- Ellison Medical Foundation
- Longer Life Foundation
- Washington University Nutrition Obesity Research Center [P30DK056341]
- Washington University Diabetes Research and Training Center [P60DK020579]
- Japan Research Foundation for Clinical Pharmacology
- Manpei Suzuki Diabetes Foundation
- Kanae Foundation
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Type 2 diabetes (T2D) has become epidemic in our modern lifestyle, likely due to calorie-rich diets overwhelming our adaptive metabolic pathways. One such pathway is mediated by nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in mammalian NAD(+) biosynthesis, and the NAD(+)-dependent protein deacetylase SIRT1. Here, we show that NAMPT-mediated NAD(+) biosynthesis is severely compromised in metabolic organs by high-fat diet (HFD). Strikingly, nicotinamide mononucleotide (NMN), a product of the NAMPT reaction and a key NAD(+) intermediate, ameliorates glucose intolerance by restoring NAD(+) levels in HFD-induced T2D mice. NMN also enhances hepatic insulin sensitivity and restores gene expression related to oxidative stress, inflammatory response, and circadian rhythm, partly through SIRT1 activation. Furthermore, NAD(+) and NAMPT levels show significant decreases in multiple organs during aging, and NMN improves glucose intolerance and lipid profiles in age-induced T2D mice. These findings provide critical insights into a potential nutriceutical intervention against diet- and age-induced T2D.
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