Oral Presentation ANZOS Annual Scientific Meeting 2021

Improved metabolic profile in mice receiving dual pharmacological targeting of NAD+ biosynthesis and degradation. (#35)

Jasmine Banks 1 , Eileen Ding 1 , Azrah Samsudeen 1 , Renee Amo-Appiah 1 , Lindsay Wu 1 , Lake-Ee Quek 2 , Sarah Hancock 1 , Nigel Turner 1
  1. Department of Pharmacology, School of Medical Sciences, University of New South Wales, Sydney, NSW, Australia
  2. Charles Perkins Centre, The University of Sydney, Sydney, NSW, Australia

Nicotinamide adenine dinucleotide (NAD+) plays a crucial role as the substrate for NAD+-dependent enzymes that mediate numerous fundamental cellular processes including energy metabolism, cell survival, DNA repair, inflammation, circadian rhythms and lifespan. Despite its repeated cycling in redox reactions, NAD+ levels decline with age in both rodents and humans and have also been shown to decrease with other metabolically compromised states such as obesity. Conversely, metabolically beneficial interventions such as calorie restriction and exercise are associated with increases in NAD+ levels. To date, various studies have demonstrated positive metabolic effects of replenishing declining NAD+ levels in these conditions through the provision of NAD+ precursors such as NMN or NR, or the inhibition of NAD+-consumers such as CD38. In addition to NAD+, CD38 has also been shown to degrade NMN, compromising its ability to increase NAD+in vivo. Given the promising effects of NMN administration alone, we sought to examine the effects of NMN treatment in combination with the inhibition of CD38 through the use of the compound 78c in mice. We found that the combination of NMN+78c acutely raised NAD+, NADH and NR levels across multiple tissues as well as hepatic NMN levels in mice, more so than NMN or 78c alone. When administered for eight weeks in HFD-fed mice, the most significant attenuation of weight gain and fat deposition relative to HFD controls was observed in the combined treatment group, with a more pronounced effect compared to either treatment alone. The combination of NMN+78c was also the only treatment that resulted in improved insulin sensitivity relative to HFD controls (based on an index of glucose and insulin levels during an oral glucose tolerance test). These effects of enhancing NMN treatment with inhibition of NAD+ precursor breakdown show promising therapeutic potential for metabolic conditions affecting modern society, such as obesity.