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

Overview

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 * 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, markers of inflammation , and other circulating signaling factors. * Microbiome composition * Hunger and satiety before and after meals * Eating rate * Chronotype and sleep quality * Usual food intake * 24-h and exercise energy expenditure 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: * H 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, inflammatory markers and other circulating signaling factors * 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 * 24-h and exercise energy expenditure from respiratory chamber