Obesity
Conditions
Keywords
Obesity, Metabolic syndrome, Vitamin B3, Nicotinamide riboside, Mitochondrial dysfunction, Mitochondria, Adipose tissue, Skeletal muscle
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.
Interventions
DIETARY_SUPPLEMENTNR 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.
DIETARY_SUPPLEMENTNR 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.
Sponsors
University of Helsinki
University of Iowa
Finnish Institute for Health and Welfare
Göteborg University
Helsinki University Central Hospital
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
NONE
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.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
Yes
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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 - electron microscopy | At baseline and 5 months after supplementation | Change in mitochondria histology by electron microscopy evaluation of skeletal muscle |
| 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) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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 |
Other
| Measure | Time frame | Description |
|---|---|---|
| Ectopic lipid accumulation in liver and muscle (in vivo) | At baseline and 5 months after supplementation | Change in liver and skeletal muscle lipid accumulation measured with H-MRS in vivo |
| Circulating inflammation markers | At baseline and 5 months after supplementation | Change in circulating levels of IL-2, IL-5, IL-6, IL-12 and TNF-alpha will be measured by multiplex |
| Whole body insulin sensitivity | At baseline and 5 months after supplementation | Insulin sensitivity as measured by oral glucose tolerance test (OGTT)-derived indexes |
| Body weight and body composition | At baseline and 5 months after supplementation | 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 |
Outcome results
None listed