Nicotinamide mononucleotide, a key NAD+ intermediate, treats the pathophysiology of diet- and age-induced diabetes in mice

By Jun Yoshino, K. Mills, Myeong Jin Yoon, S. Imai. Cell Metabolism, 2011

1,291 citations recorded by the source corpus.

Summary Type 2 diabetes (T2D) has become an 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.

Subfields: Geriatrics and Gerontology, Physiology

View Paper: https://www.semanticscholar.org/paper/ad1933ff180e637a37cb648bab75a986a511b89f

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Geriatrics and Gerontology

1. Johan Auwerx
2. D. Sinclair
3. E. Verdin
4. L. Guarente
5. S. Imai
6. Joseph A. Baur
7. C. Cantó
8. R. Houtkooper

In Physiology

1. E. Verdin
2. D. Sinclair
3. Johan Auwerx
4. S. Imai
5. Joseph A. Baur
6. L. Guarente
7. Jun Yoshino
8. C. Cantó

Citations in the corpus

• NAD+ metabolism: pathophysiologic mechanisms and therapeutic potential (2020, background): “Furthermore, NMN alienates glucose intolerance and lipid profiles by recovering NAD levels in age induced T2D mouse model.(337) Conversely, overexpression of Nmnat3 in mouse can effectively increase NAD levels in a variety of tissues and prevent aging-related insulin resistance caused by diet.”
• Declining NAD+ Induces a Pseudohypoxic State Disrupting Nuclear-Mitochondrial Communication during Aging (2013, background): “C for 1 week with NMN, a precursor to NAD that increases NAD levels in vivo (Yoshino et al., 2011), reversed the decline in VHL and accumulation of HIF-1a (Figures 7E and 7F); reduced lactate levels; and increased ATP, COX activity, and mitochondrially encoded OXPHOS transcripts (Figures 7G–7I and S”
• SIRT1 and other sirtuins in Metabolism (2013, background): “More recently, supplementation with NAD precursors has been shown to restore NAD+ levels and prevent diet- or aging-induced diabetes in wild type mice [113,114].”
• Sirtuins as regulators of metabolism and healthspan (2012, background): “In addition, treatment with another NAD + precursor, nicotinamide mononucleotide, activates SIRT1 and improves glucose tolerance in mic”
• The NAD+/sirtuin pathway modulates longevity through activation of mitochondrial UPR and FOXO signaling (2013, background): “In line with the hypothesis that PARP proteins are major NAD consumers, NAD levels were robustly decreased in older mice (Figure S1B), confirming recent data (Braidy et al., 2011; Yoshino et al., 2011).”
• Sirt1 extends life span and delays aging in mice through the regulation of Nk2 homeobox 1 in the DMH and LH. (2013, methodology): “Metabolic parameters were measured using an Oxymax indirect calorimetry system (Columbus Instruments), as described previously (Yoshino et al., 2011).”
• The Mitochondrial Basis of Aging (2016, background): “Levels of NAD appears to decline in tissues as they age (Mouchiroud et al., 2013; Yoshino et al., 2011).”
• NAD+ intermediates: The biology and therapeutic potential of NMN and NR (2017, positive): “NMN improves high-fat-diet-induced glucose intolerance and dyslipidemia (Yoshino et al., 2011), skeletal muscle mitochondrial oxidative metabolism (Gomes et al., 2013), and endothelial function (de Picciotto et al., 2016) better in aged mice than young mice.”
• Therapeutic potential of NAD-boosting molecules: the in vivo evidence (2018, neutral): “…the inhibition of NAD+-consuming enzymes such as PARPs (Bai et al., 2011; Gariani et al., 2017) and CD38 (Barbosa et al., 2007), the inhibition of nicotinamide N-methyltransferase (Kraus et al., 2014) and supplementation with NAD+ precursors, NR (Cantó et al., 2012) or NMN (Yoshino et al., 2011).”
• Mitochondrial Dysfunction Induces Senescence with a Distinct Secretory Phenotype (2015, background): “Notably, NAD+ declines with age in several tissues (Braidy et al., 2011; Gomes et al., 2013; Stein and Imai, 2014; Yoshino et al., 2011), linking NAD to both senescence and aging.”