Targeting NAD Metabolism to Improve Glucose Homeostasis in Obesity and Aging

University Of Pennsylvania, Philadelphia PA

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Abstract

Targeting NAD Metabolism to Improve Glucose Homeostasis in Obesity and Aging We are testing the hypothesis that nicotinamide adenine dinucleotide (NAD+) metabolism can be targeted to improve physiology in aged and obese individuals. NAD+ is a ubiquitous molecule that is required as a redox cofactor or substrate for hundreds of enzymes within the cell. It can be derived from dietary tryptophan, niacin, nicotinamide, or administered synthetic intermediates. Prolonged deficiency of all of these precursors leads to pellagra (characterized by dermatitis, diarrhea, and dementia) and eventually death. In recent years, it has become appreciated that NAD+ concentration falls in many tissues with age or obesity, and that the pathogenesis of many diseases includes a component of NAD+ depletion within the target tissue. Multiple groups, including ours, have established that high doses of precursors have therapeutic effects in rodent models of disease. However, much remains to be learned about NAD+ metabolism, even as nutraceutical formulations containing precursors are being marketed to the general public. A substantial weakness of the current literature is that most of the published studies involve systemic treatment and measurement of only distal phenotypes, such as rudimentary blood biomarkers, general health, or disease outcomes. Because of this, the molecular mechanisms and sites of action for pre-clinical and clinical studies involving NAD+ often remain obscure, even for positive outcomes, while negative outcomes remain difficult to interpret. The major focus of our work during the prior award cycles has been to develop mass-spectrometry and genetics-based models to understand the metabolism of NAD+ precursors, their effects on cellular metabolism, and critical tissues and sites of action. Here we propose to extend these studies by: 1) Characterizing the effects of changes in NAD+ availability on subcellular distribution of the co-factor and on flux through NAD-dependent steps in glucose metabolism, 2) Mapping the distribution and metabolism of emerging alternative NAD+ precursors that might have more favorable uptake or stability profiles after oral delivery, and 3) Taking advantage of our recent discovery of the mammalian mitochondrial NAD+ carrier to study the consequences of selectively manipulating that NAD+ pool in vivo in liver and skeletal muscle. Together, the proposed studies will substantially advance our understanding of both the basic biology of NAD+ metabolism and how it might ultimately be targeted to improve health and alleviate conditions associated with aging and obesity.