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| Name | Class |
|---|---|
| University of Helsinki | OTHER |
| University of Iowa | OTHER |
| Finnish Institute for Health and Welfare | OTHER_GOV |
| Göteborg University |
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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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| NR | Experimental | 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 | Placebo Comparator | 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. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| NR in BMI-discordant twins | Dietary Supplement | 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. |
| 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 |
| 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 |
| 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) |
Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Kirsi H Pietiläinen, MD PhD | University of Helsinki | Principal Investigator |
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| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 24100782 | Background | 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. | |
| 26574954 |
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| ID | Term |
|---|---|
| D009765 | Obesity |
| D024821 | Metabolic Syndrome |
| D028361 | Mitochondrial Diseases |
| ID | Term |
|---|---|
| D050177 | Overweight |
| D044343 | Overnutrition |
| D009748 | Nutrition Disorders |
| D009750 | Nutritional and Metabolic Diseases |
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| ID | Term |
|---|---|
| C018613 | nicotinamide-beta-riboside |
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| OTHER |
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.
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|
| NR in BMI-concordant twins | Dietary Supplement | 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. |
|
|
| 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 |
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 |
| Background |
| 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. |
| 26760174 | Background | 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. |
| 22682224 | Background | 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. |
| 27230286 | Background | 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. |
| 29211728 | Background | 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. |
| D001835 |
| Body Weight |
| D012816 | Signs and Symptoms |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D007333 | Insulin Resistance |
| D006946 | Hyperinsulinism |
| D044882 | Glucose Metabolism Disorders |
| D008659 | Metabolic Diseases |