Targeting NAD Metabolism to Improve Glucose Homeostasis in Obesity and Aging We will test the hypothesis that nicotinamide adenine dinucleotide (NAD) metabolism can be targeted to improve physiology in aged or obese individuals. NAD is a ubiquitous molecule that is required as a redox cofactor or substrate fo hundreds of enzymes within the cell. It is derived from a number of dietary compounds, including tryptophan and vitamin B3, and prolonged deficiency in all of these precursors leads to Pellagra, and then death. It was recently shown that NAD levels fall substantially in the tissues of aged or obese mice. We hypothesize that this limits the activity of NAD-dependent enzymes, such as the deacetylase SIRT1, which has strong protective effects against diabetes and other age-related diseases. Consistent with this, administration of the NA precursors nicotinamide mononucleotide (NMN) or nicotinamide riboside (NR) increases SIRT1 activity and ameliorates insulin resistance in aged or obese animals. We have created a strain of mice that allows tissue-specific overexpression of Nicotinamide phosphoribosyltransferase (Nampt), the enzyme that produces NMN. A complementary strain of mice that allows tissue-specific deletion of Nampt has been created by the Leo lab (University Libre de Bruxelles), and generously provided to us for the generation of animals with muscle-specific loss of function. Our preliminary data show that Nampt targeted to skeletal muscle significantly enhances NAD levels, and causes no overt phenotype in young, healthy mice.
Specific Aim 1 is to test whether restoration of NAD levels in liver and muscles of aged or obese mice can rescue organ dysfunction, and whether NAD depletion is sufficient to induce dysfunction in young, healthy animals. In addition, there is strong evidence that NAD promotes insulin secretion in a SIRT1-dependent manner, but the details are somewhat controversial. It has been proposed that an extracellular form of Nampt mediates this effect by producing NMN in the circulation, which is then taken up by pancreatic beta cells to enhance NAD levels. However, the assertion that extracellular Nampt participates in NAD production, and even the existence of extracellular NMN, have been challenged.
Specific Aim 2 is to determine how insulin secretion is regulated by NAD metabolism. Together, these studies will reveal fundamental details of how NAD metabolism influences physiology, and are likely to point the way to novel therapeutic approaches for the treatment or prevention of diabetes and other age-related diseases.

Public Health Relevance

I propose testing the feasibility of manipulating NAD levels as a therapeutic approach for diabetes and other age-related diseases. Nicotinamide adenine dinucleotide (NAD) has long been considered a ubiquitous cofactor that plays only a passive role in the cell. However, recent studies have revealed that its concentration is highly dynamic, and may be a crucial point of control for sirtuins, a class of enzymes with potent antidiabetic effects. Moreover, NAD concentration is reduced in (type II) diabetic mice, and increased by caloric restriction, which completely cures the disease in mice and monkeys.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK098656-02
Application #
8731882
Study Section
Integrative Physiology of Obesity and Diabetes Study Section (IPOD)
Program Officer
Laughlin, Maren R
Project Start
2013-09-10
Project End
2018-06-30
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
2
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Pennsylvania
Department
Physiology
Type
Schools of Medicine
DUNS #
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Davila, Antonio; Liu, Ling; Chellappa, Karthikeyani et al. (2018) Nicotinamide adenine dinucleotide is transported into mammalian mitochondria. Elife 7:
Yoshino, Jun; Baur, Joseph A; Imai, Shin-Ichiro (2018) NAD+ Intermediates: The Biology and Therapeutic Potential of NMN and NR. Cell Metab 27:513-528
Sims, Carrie A; Guan, Yuxia; Mukherjee, Sarmistha et al. (2018) Nicotinamide mononucleotide preserves mitochondrial function and increases survival in hemorrhagic shock. JCI Insight 3:
Liu, Ling; Su, Xiaoyang; Quinn 3rd, William J et al. (2018) Quantitative Analysis of NAD Synthesis-Breakdown Fluxes. Cell Metab 27:1067-1080.e5
Mitchell, Sarah J; Bernier, Michel; Aon, Miguel A et al. (2018) Nicotinamide Improves Aspects of Healthspan, but Not Lifespan, in Mice. Cell Metab 27:667-676.e4
Krishnaiah, Saikumari Y; Wu, Gang; Altman, Brian J et al. (2017) Clock Regulation of Metabolites Reveals Coupling between Transcription and Metabolism. Cell Metab 25:961-974.e4
Mukherjee, Sarmistha; Chellappa, Karthikeyani; Moffitt, Andrea et al. (2017) Nicotinamide adenine dinucleotide biosynthesis promotes liver regeneration. Hepatology 65:616-630
Frederick, David W; Trefely, Sophie; Buas, Alexia et al. (2017) Stable isotope labeling by essential nutrients in cell culture (SILEC) for accurate measurement of nicotinamide adenine dinucleotide metabolism. Analyst 142:4431-4437
Angelin, Alessia; Gil-de-Gómez, Luis; Dahiya, Satinder et al. (2017) Foxp3 Reprograms T Cell Metabolism to Function in Low-Glucose, High-Lactate Environments. Cell Metab 25:1282-1293.e7
Moon, Lily; Frederick, David W; Baur, Joseph A et al. (2017) Imaging Redox State in Mouse Muscles of Different Ages. Adv Exp Med Biol 977:51-57

Showing the most recent 10 out of 20 publications