Nicotinamide Riboside and Mitochondrial Metabolism

Not Applicable

Completed

• Conditions: Obesity
• Interventions: Dietary Supplement: NR in BMI-discordant twins; Dietary Supplement: NR in BMI-concordant twins

• Registration Number: NCT03951285
• Lead Sponsor: Helsinki University Central Hospital

Brief Summary

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.

Detailed Description

Not available

Study Timeline

• Study Start: 2016-05-25
• Study First Submitted: 2019-01-10
• Study First Submitted QC: 2019-05-13
• Study First Posted: 2019-05-15
• Primary Completion: 2019-05-31
• Study Completion: 2019-05-31
• Status Verified: 2019-12
• Last Update Submitted: 2019-12-23
• Last Update Posted: 2019-12-24

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 56

Inclusion Criteria

1. BMI >18.5 kg/m2 in both members of the twin pair
2. Agreed to maintain current level of physical activity throughout the study
3. Agreed to avoid vitamin supplementation or nutritional products with vitamin B3 14 days prior to the enrolment and during the study
4. Written, informed consent to participate in the study

Exclusion Criteria

1. Unstable medical conditions as determined by the principal investigator
2. Clinically significant abnormal lab results at screening (e.g. AST and/or ALT > 2 x ULN, and/or bilirubin > 2 x ULN)
3. Subjects who have a planned surgery during the course of the trial
4. 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.
5. History of blood/bleeding disorders
6. Immunocompromised individuals such as subjects that had undergone organ transplantation or subjects diagnosed with human immunodeficiency virus (HIV)
7. Hepatitis
8. Blood donation in the previous 2 months
9. Anemia (hemoglobin <120)
10. Participation in a clinical research trial within 30 days prior to randomization
11. Allergy or sensitivity to study supplement ingredients
12. Individuals who are cognitively impaired and/or who are unable to give informed consent.
13. 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.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
NR	NR in BMI-discordant twins	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.
NR	NR in BMI-concordant twins	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.
Placebo	NR in BMI-concordant twins	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.

Primary Outcome Measures

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

Secondary Outcome Measures

Name	Time	Method
NAD+ and related metabolite levels in blood	At baseline and 5 months after supplementation	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
Skeletal muscle mitochondrial oxidative capacity	At baseline and 5 months after supplementation	Change in mitochondrial function in skeletal muscle by immunohistochemical respiratory chain enzyme analysis