Clinical trial NCT03951285: Nicotinamide Riboside and Mitochondrial Metabolism
Official title: Vitamin B3 as a Novel Mitochondrial Therapy for Obesity
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Obesity
Keywords: Obesity
Metabolic syndrome
Vitamin B3
Nicotinamide riboside
Mitochondrial dysfunction
Mitochondria
Adipose tissue
Skeletal muscle
Lead sponsor: Helsinki University Central Hospital
Sponsor class: OTHER
Collaborators: name: University of Helsinki
name: University of Iowa
name: Finnish Institute for Health and Welfare
name: Göteborg University
First posted: 2019-05-15
Enrollment: 56
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Intervention 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.
Primary purpose: PREVENTION

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.


Eligibility criteria: 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.

Primary outcomes:
measure: Mitochondrial biogenesis - mitochondrial DNA quantification
timeFrame: At baseline and 5 months after supplementation
measure: Mitochondrial biogenesis - mitochondria-related mRNA expression
timeFrame: At baseline and 5 months after supplementation
measure: Mitochondrial biogenesis - electron microscopy
timeFrame: At baseline and 5 months after supplementation
Secondary outcomes:
measure: NAD+ and related metabolite levels in blood
timeFrame: At baseline and 5 months after supplementation
measure: Skeletal muscle mitochondrial oxidative capacity
timeFrame: At baseline and 5 months after supplementation
Other outcomes:
measure: Body weight and body composition
timeFrame: At baseline and 5 months after supplementation
measure: Ectopic lipid accumulation in liver and muscle (in vivo)
timeFrame: At baseline and 5 months after supplementation
measure: Whole body insulin sensitivity
timeFrame: At baseline and 5 months after supplementation
measure: Circulating inflammation markers
timeFrame: At baseline and 5 months after supplementation
Locations:
Study officials:
affiliation: University of Helsinki
name: Kirsi H Pietiläinen, MD PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.