Nicotinamide Riboside and Mitochondrial Metabolism

Study Overview
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Brief Summary
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Vitamin B3 has recently been found to be a potent modifier of energy metabolism, especially the function of mitochondria. Mitochondria power up all cells in our bodies, by generating fuel, ATP, for cellular functions. In previous studies, it has been discovered that mitochondrial biogenesis and oxidative metabolism in adipose tissue is severely impaired in obesity, already at a young adult age. Here the investigators describe a proposal where they use nicotinamide riboside (NR), a form of vitamin B3 naturally found in milk, to activate dysfunctional mitochondria, in particular the SIRT/NAD+ pathway, and to rescue signs of obesity-related diseases. The investigators use a unique human study design: monozygotic twins either discordant or concordant for obesity, to examine the effects of NR on mitochondrial function in muscle, adipose tissue and the metabolism of the whole body. The upcoming upcoming results are important for understanding the links between mitochondrial dysfunction and chronic metabolic diseases in humans, as well as for clarifying mechanisms of the novel nutritional therapeutic approaches.

Official Title
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Vitamin B3 as a Novel Mitochondrial Therapy for Obesity

Conditions
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Obesity

Intervention / Treatment
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* Dietary Supplement: NR in BMI-discordant twins
* Dietary Supplement: NR in BMI-concordant twins


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: BMI >18.5 kg/m2 in both members of the twin pair Agreed to maintain current level of physical activity throughout the study Agreed to avoid vitamin supplementation or nutritional products with vitamin B3 14 days prior to the enrolment and during the study Written, informed consent to participate in the study Exclusion Criteria: Unstable medical conditions as determined by the principal investigator Clinically significant abnormal lab results at screening (e.g. AST and/or ALT > 2 x ULN, and/or bilirubin > 2 x ULN) Subjects who have a planned surgery during the course of the trial History of or a current diagnosis of any cancer (except for successfully treated basal cell carcinoma diagnosed less than 5 years prior to screening). Subjects with cancer in full remission more than 5 years after diagnosis are acceptable. History of blood/bleeding disorders Immunocompromised individuals such as subjects that had undergone organ transplantation or subjects diagnosed with human immunodeficiency virus (HIV) Hepatitis Blood donation in the previous 2 months Anemia (hemoglobin <120) Participation in a clinical research trial within 30 days prior to randomization Allergy or sensitivity to study supplement ingredients Individuals who are cognitively impaired and/or who are unable to give informed consent. Any other condition, which in the principal investigator's opinion may adversely affect the subject's ability to complete the study or its measures or which may have posed significant risk to the subject.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Study with two interventions in healthy monozygotic twin pairs. In the first intervention, both members of BMI-discordant monozygotic twins are treated with Nicotinamide Riboside (NR). With this unique model, the investigators obtain the information on how beneficial NR is in two different BMI classes (obese and leaner) with an identical genomic background. In the second intervention, monozygotic twins concordant for body weight are selected and randomized to treatment. One member of the twin pair is treated with NR while the other co-twin gets placebo. With the twin set-up, the investigators can detect a significant treatment effect, and the heritability of NR treatment can be estimated as well.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: NR<br>One intervention includes healthy BMI-discordant monozygotic twin pairs, which both are treated with NR. With this unique model, the investigators obtain the information on how beneficial NR is in two different BMI classes (obese and leaner) with an identical genomic background. The final dose for NR will be 1 g/day. The daily NR dose is gradually escalated by 250 mg/week so that the full dose of 1 g/day is reached in one month. The intervention time with the full NR dose is 4 months, total intervention time 5 months. At the end of the study, the daily dose will be decreased by 250 mg/week rate. | Dietary Supplement: NR in BMI-discordant twins<br>* Water-soluble form of vitamin B3, nicotinamide riboside (NR) is used in this study. The NR product name is Niagen, produced by ChromaDex. NR does not cause the known side effects (vasodilation and flushing) of another vitamin B3, niacin.<br>* Other names: Nicotinamide riboside;Dietary Supplement: NR in BMI-concordant twins<br>* Water-soluble form of vitamin B3, nicotinamide riboside (NR) is used in this study. The NR product name is Niagen, produced by ChromaDex. NR does not cause the known side effects (vasodilation and flushing) of another vitamin B3, niacin.<br>* Other names: Niagen;|
| Placebo Comparator: Placebo<br>The second intervention includes monozygotic twins concordant for body weight. It's randomized which member of the twin pair is treated with NR while the other co-twin gets placebo. The final dose for placebo will be 1 g/day. The daily placebo dose is gradually escalated by 250 mg/week so that the full dose of 1 g/day is reached in one month. The intervention time with the full placebo dose is 4 months, total intervention time 5 months. At the end of the study, the daily dose will be decreased by 250 mg/week rate. | Dietary Supplement: NR in BMI-concordant twins<br>* Water-soluble form of vitamin B3, nicotinamide riboside (NR) is used in this study. The NR product name is Niagen, produced by ChromaDex. NR does not cause the known side effects (vasodilation and flushing) of another vitamin B3, niacin.<br>* Other names: Niagen;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mitochondrial biogenesis - mitochondrial DNA quantification | Change in amount of mitochondrial DNA in skeletal muscle and adipose tissue (mtDNA quantification) | At baseline and 5 months after supplementation | 
| Mitochondrial biogenesis - mitochondria-related mRNA expression | Change in mitochondria-related mRNA expression in skeletal muscle and adipose tissue (qPCR) | At baseline and 5 months after supplementation | 
| Mitochondrial biogenesis - electron microscopy | Change in mitochondria histology by electron microscopy evaluation of skeletal muscle | At baseline and 5 months after supplementation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| NAD+ and related metabolite levels in blood | Change in levels of NAD+ and related metabolites such as: NADP+, nicotinic acid adenine dinucleotide, nicotinamide, and nicotinamide mononucleotide in blood using high performance liquid chromatography-mass spectrometry | At baseline and 5 months after supplementation | 
| Skeletal muscle mitochondrial oxidative capacity | Change in mitochondrial function in skeletal muscle by immunohistochemical respiratory chain enzyme analysis | At baseline and 5 months after supplementation | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Obesity, Metabolic syndrome, Vitamin B3, Nicotinamide riboside, Mitochondrial dysfunction, Mitochondria, Adipose tissue, Skeletal muscle