Nicotinamide Riboside and Mitochondrial Metabolism (VitaPower)

Vitamin B3 as a Novel Mitochondrial Therapy for Obesity

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.

Study Overview

• Status: Completed
• Conditions: Obesity
• Intervention / Treatment: Dietary supplement: NR in BMI-discordant twins; Dietary supplement: NR in BMI-concordant twins

• Study Type: Interventional
• Enrollment (Actual): 56
• Phase: Not Applicable

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: PREVENTION
• Allocation: NON_RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: NR; 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; 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.; Other Names: Niagen; Nicotinamide riboside; Dietary supplement: NR in BMI-concordant twins; 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.; Other Names: Niagen
PLACEBO_COMPARATOR: Placebo; 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; 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.; Other Names: Niagen

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Body weight and body composition	Change in body weight as well as fat mass and fat free mass measured with bioimpedance and DEXA scanning, fat distribution by magnetic resonance imaging	At baseline and 5 months after supplementation
Ectopic lipid accumulation in liver and muscle (in vivo)	Change in liver and skeletal muscle lipid accumulation measured with H-MRS in vivo	At baseline and 5 months after supplementation
Whole body insulin sensitivity	Insulin sensitivity as measured by oral glucose tolerance test (OGTT)-derived indexes	At baseline and 5 months after supplementation
Circulating inflammation markers	Change in circulating levels of IL-2, IL-5, IL-6, IL-12 and TNF-alpha will be measured by multiplex	At baseline and 5 months after supplementation

Collaborators and Investigators

• Sponsor: Helsinki University Central Hospital
• Collaborators: Göteborg University; University of Iowa; University of Helsinki; Finnish Institute for Health and Welfare
• Investigators: Principal Investigator: Kirsi H Pietiläinen, MD PhD, University of Helsinki

Publications and helpful links

General Publications

• Naukkarinen J, Heinonen S, Hakkarainen A, Lundbom J, Vuolteenaho K, Saarinen L, Hautaniemi S, Rodriguez A, Fruhbeck G, Pajunen P, Hyotylainen T, Oresic M, Moilanen E, Suomalainen A, Lundbom N, Kaprio J, Rissanen A, Pietilainen KH. Characterising metabolically healthy obesity in weight-discordant monozygotic twins. Diabetologia. 2014 Jan;57(1):167-76. doi: 10.1007/s00125-013-3066-y. Epub 2013 Oct 8.
• Jukarainen S, Heinonen S, Ramo JT, Rinnankoski-Tuikka R, Rappou E, Tummers M, Muniandy M, Hakkarainen A, Lundbom J, Lundbom N, Kaprio J, Rissanen A, Pirinen E, Pietilainen KH. Obesity Is Associated With Low NAD(+)/SIRT Pathway Expression in Adipose Tissue of BMI-Discordant Monozygotic Twins. J Clin Endocrinol Metab. 2016 Jan;101(1):275-83. doi: 10.1210/jc.2015-3095. Epub 2015 Nov 17.
• Rappou E, Jukarainen S, Rinnankoski-Tuikka R, Kaye S, Heinonen S, Hakkarainen A, Lundbom J, Lundbom N, Saunavaara V, Rissanen A, Virtanen KA, Pirinen E, Pietilainen KH. Weight Loss Is Associated With Increased NAD(+)/SIRT1 Expression But Reduced PARP Activity in White Adipose Tissue. J Clin Endocrinol Metab. 2016 Mar;101(3):1263-73. doi: 10.1210/jc.2015-3054. Epub 2016 Jan 13.
• Canto C, Houtkooper RH, Pirinen E, Youn DY, Oosterveer MH, Cen Y, Fernandez-Marcos PJ, Yamamoto H, Andreux PA, Cettour-Rose P, Gademann K, Rinsch C, Schoonjans K, Sauve AA, Auwerx J. The NAD(+) precursor nicotinamide riboside enhances oxidative metabolism and protects against high-fat diet-induced obesity. Cell Metab. 2012 Jun 6;15(6):838-47. doi: 10.1016/j.cmet.2012.04.022.
• Trammell SA, Weidemann BJ, Chadda A, Yorek MS, Holmes A, Coppey LJ, Obrosov A, Kardon RH, Yorek MA, Brenner C. Nicotinamide Riboside Opposes Type 2 Diabetes and Neuropathy in Mice. Sci Rep. 2016 May 27;6:26933. doi: 10.1038/srep26933.
• Airhart SE, Shireman LM, Risler LJ, Anderson GD, Nagana Gowda GA, Raftery D, Tian R, Shen DD, O'Brien KD. An open-label, non-randomized study of the pharmacokinetics of the nutritional supplement nicotinamide riboside (NR) and its effects on blood NAD+ levels in healthy volunteers. PLoS One. 2017 Dec 6;12(12):e0186459. doi: 10.1371/journal.pone.0186459. eCollection 2017.

Study record dates

Study Major Dates

• Study Start (ACTUAL): May 25, 2016
• Primary Completion (ACTUAL): May 31, 2019
• Study Completion (ACTUAL): May 31, 2019

Study Registration Dates

• First Submitted: January 10, 2019
• First Submitted That Met QC Criteria: May 13, 2019
• First Posted (ACTUAL): May 15, 2019

Study Record Updates

• Last Update Posted (ACTUAL): December 24, 2019
• Last Update Submitted That Met QC Criteria: December 23, 2019
• Last Verified: December 1, 2019

More Information

Terms related to this study

• Keywords: Obesity; Metabolic syndrome; Mitochondrial dysfunction; Mitochondria; Adipose tissue; Skeletal muscle; Nicotinamide riboside; Vitamin B3
• Additional Relevant MeSH Terms: Overnutrition; Nutrition Disorders; Overweight; Body Weight; Obesity; Physiological Effects of Drugs; Micronutrients; Vitamins; Vitamin B Complex; Niacinamide
• Other Study ID Numbers: NRtwins_0001

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No