Biology subjects

Kim, L.-J.

Publications and source records attributed to Kim, L.-J..

3 recordsLinked to original sources

bioRxiv2020

Nicotinamide mononucleotide (NMN) de-amidation by the gut microbiome and evidence for indirect upregulation of the NAD+ metabolome

Oral administration of nicotinamide mononucleotide (NMN) is a prominent strategy to elevate nicotinamide adenine dinucleotide (NAD+) levels to treat age-related pathologies, where it is assumed to be directly incorporated into the NAD+ metabolome through the canonical recycling pathway. During oral delivery, NMN is exposed to the gut microbiome, which can modify the NAD+ metabolome through enzyme activities that are not present in mammals. Here, we show that orally delivered NMN can undergo direct deamidation and incorporation in mammalian tissue via the de novo pathway, and that this deamidation is reduced in animals treated with antibiotics to ablate the gut microbiome. Further, we show that antibiotics treatment increases the overall availability of NAD+ metabolites in the gut epithelium, with one possibility that the gut microbiome could be in competition with the host for dietary NAD+ precursors. Together, these data highlight previously undescribed interactions between orally delivered NMN and the gut microbiome.

biochemistry↗

bioRxiv2020

EXERCISE-INDUCED BENEFITS ON GLUCOSE HANDLING IN A MODEL OF DIET-INDUCED OBESITY ARE REDUCED BY CONCURRENT NICOTINAMIDE MONONUCLEOTIDE

ABSTRACTObjective Almost 40% of adults worldwide are classified as overweight or obese. Exercise is a beneficial intervention in obesity, partly due to increases in mitochondrial activity, with a potential role for the concomitant increase in nicotinamide adenine dinucleotide (NAD+). Recent studies have shown that increasing NAD+ levels through pharmacological supplementation with precursors such as nicotinamide mononucleotide (NMN) improved metabolic health in high fat diet (HFD) fed mice. We examined the combined effects of NMN and treadmill exercise on the metabolic dysregulation in HFD-induced obesity.Methods Five-week old female C57BL/6J mice were exposed to control diet or HFD. Mice fed HFD were treated with NMN in drinking water (400mg/kg; HNMN), treadmill exercise (HEx) or combined NMN and exercise (HNEx).Results Unexpectedly, NMN administration impaired several aspects of exercise-induced benefits in HFD mice, including glucose tolerance, glucose stimulated insulin secretion from islets and reduced hepatic triglyceride accumulation. Mechanistically, HNEx mice displayed increased antioxidant and reduced prooxidant gene expression in both islets and muscle, suggesting that altered redox status is associated with the loss of exercise-induced health benefits with NMN co-treatment.Conclusion Our data show that NMN treatment blocks the beneficial metabolic effects of exercise in a mouse model of diet-induced obesity in association with disturbances in redox metabolism.HighlightsNMN dampened exercise-induced benefits on glucose handling in diet-induced obesity.NMN administration in exercise enhanced ratio of antioxidants to prooxidants.We suggest NMN administration may not be beneficial when NAD+ levels are replete.Competing Interest StatementL.E.W. is an inventor on patents licensed to Metro Biotech NSW and to Jumpstart Fertility, and has received sponsored research funding from both companies. He is an advisor and shareholder in EdenRoc Sciences (Metro Biotech NSW, Metro Biotech, Liberty Biosecurity), Life Biosciences LLC and its daughter companies (Jumpstart Fertility, Continuum Biosciences, Senolytic Therapeutics, Selphagy, Animal Biosciences, Iduna) and in Intravital Pty Ltd. L.E.W. provides consulting work for Life Biosciences.View Full Text

physiology↗

bioRxiv2019

NAD+ repletion rescues female fertility during reproductive ageing

Female infertility is a common and devastating condition with life-long health, emotional and social consequences. There is currently no pharmacological therapy for preserving oocyte quality during aging, which is the strongest risk factor for infertility. This leads to an age dependent decline in natural conception and IVF success rates (1). Here, we show that this is due in part to declining levels of the metabolic cofactor nicotinamide adenine dinucleotide (NAD+), and that restoring NAD+ levels with its metabolic precursor nicotinamide mononucleotide (NMN) rejuvenates oocyte quality and quantity in aged animals, leading to improved fertility. These benefits extend to the developing embryo, where NMN supplementation in embryo culture media following IVF enhances blastocyst formation in older mice. The NAD+ dependent deacylase SIRT2 is sufficient, but not essential, to recapitulate the benefits of in vivo NMN treatment, and transgenic overexpression of SIRT2 maintains oocyte spindle assembly, accurate chromosome segregation, decreased oxidative stress and overall fertility with ageing. Pharmacological elevation of NAD+ may be an effective, non-invasive strategy for restoring and maintaining female fertility during ageing, and for improving the success of IVF.

developmental biology↗