Effect of Nicotinamide Riboside on Ketosis, Fat Oxidation & Metabolic Rate

Background: At least 30% of Americans have fatty liver disease. This means that they store too much fat in the liver. At the moment lifestyle changes are the only way to treat this problem. Objective: To test how (1) a low-carbohydrate diet and (2) a supplement called nicotinamide riboside (NR) affect how a person s body uses dietary fat. Eligibility: Men aged 18 to 65 and women aged 18 to 50 who are healthy volunteers with a body mass index (height to weight ratio) of 25 or more. Adults with maturity-onset diabetes of the young type 2 (MODY2) are also needed. Design: Participants with diabetes will have 1 screening visit and a 9-day clinic stay. Healthy volunteers will have 1 screening visit and 2 clinic stays of 1 to 2 weeks each. During screening, all participants will have a physical exam with blood and urine tests. They will have their heart rhythm measured while riding a gym bike. NR is a pill taken by mouth. Only healthy volunteers will take the NR, for 14 days at a time, during 1 clinic stay. During their other stay, they will take placebos; these are pills that look like the study supplement but contain no NR. During each clinic stay, all participants will eat a normal American diet. Then they will eat a ketogenic low-carb diet for 5 days. Participants will have many tests, including: Sleeping every night and having two 24-hour stays in a special room that measures the gases their body uses and produces. Drinking a high-fat shake, then remaining seated for 5 hours while their blood and breath are monitored. Having a substance injected into the arm and remaining seated for 3 hours while their blood is measured. Wearing monitors to measure their activity levels. Another monitor will measure their blood glucose levels. Having imaging scans. ...

Study Description: This is a randomized, double-blind, placebo-controlled crossover study of adults with overweight or obesity to determine whether nicotinamide riboside supplementation increases sleeping energy expenditure and fat oxidation rate during a ketogenic diet. Objectives: Primary Aim 1: Determine whether sleeping energy expenditure increases after transitioning to a low carbohydrate ketogenic diet as compared to a baseline high carbohydrate run-in diet in men Primary Aim 2: Determine whether sleeping energy expenditure is affected by NR supplementation during a ketogenic diet in men Secondary Aim 1: Determine whether fat oxidation during sleep increases after transitioning to a low carbohydrate ketogenic diet as compared to a baseline high carbohydrate run-in diet in men Secondary Aim 2: Determine whether fat oxidation during sleep is affected by NR supplementation during a ketogenic diet from the baseline run-in diet in men Exploratory Aims: Exploratory comparison of the above endpoints between men and women without MODY2. Exploratory comparison of the above diet-related endpoints between patients with MODY2 and those obtained during the Placebo period in other participants. Several exploratory measurements are planned to help comprehensively phenotype the effects of the diets and nicotinamide riboside supplementation and are intended to be hypothesis-generating. We will assess the following: Liver TG Liver NAD, ATP, and ATP synthesis rates Daily ketosis, insulin secretion, and protein utilization Rates of ketogenesis and lipolysis Physical activity and sleep assessment Body composition assessment Fasting and postprandial blood measurements of various metabolites, hormones, cytokines, and markers of inflammation. Microbiome composition Hunger and satiety before and after meals Eating rate Chronotype and sleep quality Usual food intake Endpoints: Primary: Mean change in sleeping energy expenditure between the ketogenic diet and the baseline run-in diet Mean difference in sleeping energy expenditure between NR and placebo during the ketogenic diet Secondary: Mean change in sleeping fat oxidation rate between the ketogenic diet and the baseline run-in diet Mean difference in fat oxidation rate between NR and placebo during the ketogenic diet Exploratory: 1H magnetic resonance spectroscopy 31P magnetic resonance spectroscopy 24hr urine ketones, C-peptide, nitrogen Stable isotope infusions of 13C beta-hydroxybutyrate and 2H glycerol Daily accelerometry and wireless EEG headband DXA scans Fasting and postprandial blood concentrations of various metabolites, hormones, cytokines and inflammatory markers Blood glucose variability and mean concentration as measured by Continuous Glucose Monitoring Daily fasting glucose and beta-hydroxybutyrate concentrations by finger-prick Microbiome composition Hunger and satiety visual analogue scores Meal duration Pittsburg sleep quality index, morningness-eveningness questionnaire, and subjective sleep visual analogue scores Usual food intake as measured by Food frequency questionnaire

To investigate whether NR supplementation augments the sleeping energy expenditure and fat oxidation rate during the ketogenic diet in men and women with overweight and obesity

To measure changes in sleeping energy expenditure and fat oxidation rate after transitioning from a baseline diet to an isocaloric ketogenic diet similar to our previous study in men

To investigate whether NR supplementation augments the sleeping energy expenditure and fat oxidation rate during the ketogenic diet in men and women with overweight and obesity

Consisting of 15% protein, 35% fat, and 50% carbohydrate, matching the macronutrient composition of a typical American diet

Subjects without MODY2 will take either placebo or NR (1 g BID, 2 g per day total) supplements for 7 days during this Run-in phase

Subjects without MODY2 will take either placebo or NR (1 g BID, 2 g per day total) supplements for 7 days during this Run-in phase

Mean change in sleeping energy expenditure measured by room calorimetry from 2 days of standard run-in diet to 5 days of ketogenic diet

Mean difference in sleeping energy expenditure measured by room calorimetry during 5 days of ketogenic diet with NR supplementation or placebo

Mean change in sleeping fat oxidation measured by room calorimetry from 2 days of standard run-in diet to 5 days of ketogenic diet

Mean difference in sleeping fat oxidation measured by room calorimetry during 5 days of ketogenic diet with NR supplementation or placebo

INCLUSION CRITERIA: In order to be eligible to participate in this study, an individual must meet all of the following criteria: Meet one of the following: Adult males aged 18-65 years Pre-menopausal adult females aged 18-50 years Adult males aged 18-65 years with diagnosed maturity-onset diabetes of the young type 2 (MODY2) or pre-menopausal adult females aged 18-50 years with diagnosed MODY2 Weight stable (< +/- 5 % body weight change over past 6 months) as determined by volunteer report Body mass index (BMI) >= 25 kg/M^2 Able to cycle at a moderate rate and intensity with a HR equal to or greater than 0.3(SqrRoot) (220-age-HRest)+HRest but not exceeding 0.4(SqrRoot) (220-age-HRest)+HRest with no signs of arrhythmia EXCLUSION CRITERIA: An individual who meets any of the following criteria will be excluded from participation in this study: Taking prescription medications or other drugs or supplements that may influence energy metabolism or nutrient digestion or absorption (including, but not limited to, diet/weight loss medication or other medications at the discretion of the PI and/or study team) Indicators of liver disease; combination of both albumin < 2.8 mg/mL and bilirubin > 3 mg/Ml Individuals with significant medical comorbidities (e.g., non-MODY2 diabetes, NYHA Class >II heart failure, or CKD Stage II or worse, or American Society of Anesthesiologists Physical Status Class 3 or above) Individuals taking prescription medications to treat hypertension in participants without MODY2 Participating in a regular exercise program (> 2h/week of vigorous activity) as determined by volunteer report Positive pregnancy test (females only) Hematocrit < 40% (men only) Hematocrit <37% (women only) Caffeine consumption > 300 mg/day as determined by volunteer report Alcohol consumption > 3 drinks per day for men or > 2 drinks per day for women as determined by volunteer report Regular use of tobacco (smoking or chewing), e-cigarettes (a.k.a. vapes), nicotine patches, or illicit drugs over past 6 months as determined by volunteer report. Subjects may also be excluded based on a urine drug test. Psychological conditions as determined by volunteer report such as (but not limited to) eating disorders, depression, bipolar disorders, that would be incompatible with safe and successful participation in this study, as determined by investigators Volunteers with strict dietary concerns (e.g. vegetarian or kosher diet, food allergies) or a reported dislike of a significant fraction of the study foods Unwilling or unable to comply with or perform all study procedures (e.g. cycling or activities of daily living), or unavailability for the duration of the study, as determined by participant or investigator discretion Unwilling or unable to adhere to Lifestyle Considerations throughout study duration, as determined by participant or investigator discretion Volunteers unwilling or unable to give informed consent

Hall KD, Chen KY, Guo J, Lam YY, Leibel RL, Mayer LE, Reitman ML, Rosenbaum M, Smith SR, Walsh BT, Ravussin E. Energy expenditure and body composition changes after an isocaloric ketogenic diet in overweight and obese men. Am J Clin Nutr. 2016 Aug;104(2):324-33. doi: 10.3945/ajcn.116.133561. Epub 2016 Jul 6.