NR and metabolic syndrome: how NAD precursors affect metabolism

Revolution in the Approach to Metabolic Disorders

Metabolic syndrome is one of the greatest health problems of the modern world. It is characterized by the presence of at least three out of five risk factors: abdominal obesity, high blood pressure, elevated fasting glucose levels, high triglyceride levels, and low HDL cholesterol levels. In an era of increasing prevalence of metabolic diseases, scientists are intensively searching for effective therapeutic strategies. One of the most promising research directions is the use of NAD+ precursors, particularly nicotinamide riboside (NR).

 

What is Nicotinamide Riboside (NR)?

Nicotinamide riboside, or NR for short, is a natural form of vitamin B3 that plays a key role as a precursor to nicotinamide adenine dinucleotide (NAD+). This compound occurs naturally in food products such as cow's milk and breast milk, making it a safe dietary component. NR stands out for its unique ability to effectively increase NAD+ levels in cells without causing unwanted side effects that accompany other forms of vitamin B3, such as nicotinic acid (NA).

NAD+ - Central Regulator of Cellular Metabolism

NAD+ is a coenzyme essential for the proper functioning of energy metabolism in our cells. It participates in key metabolic processes, including glycolysis, β-oxidation of fatty acids, and oxidative phosphorylation in mitochondria. Moreover, NAD+ serves as a substrate for enzyme families of tremendous metabolic importance:

Sirtuins - Guardians of Metabolism

Sirtuins (SIRT1-7) are a family of NAD+-dependent enzymes that regulate a wide range of cellular processes through protein deacetylation. Particularly important for metabolism are SIRT1, SIRT3, and SIRT6, which protect against the development of obesity, insulin resistance, and type 2 diabetes. SIRT1 plays a crucial role in regulating insulin sensitivity and lipid metabolism in the liver, while SIRT3 operates primarily in mitochondria, supporting energy production and protecting against oxidative stress.

PARP - DNA Repair Enzymes

Poly(ADP-ribose) polymerases, or PARP, are another family of enzymes that use NAD+ to repair DNA damage and regulate cellular stress responses. In the context of metabolic syndrome, excessive PARP activity can lead to depletion of NAD+ reserves, which negatively affects mitochondrial function and promotes the development of metabolic disorders.

NAD+ Decline in Metabolic Syndrome

One of the characteristic phenomena observed in metabolic syndrome is the progressive decline of NAD+ levels in tissues. This phenomenon intensifies with age and under conditions of obesity and sedentary lifestyle. Low NAD+ levels result in:

NR in the Fight Against Metabolic Syndrome - Scientific Evidence

Studies on Animal Models

Numerous studies on mice have provided impressive evidence for the effectiveness of NR supplementation in counteracting metabolic syndrome:

Clinical Studies in Humans

Although human studies are still limited, initial results are promising:

Study on Identical Twins: In a groundbreaking study published in Science Advances, 20 pairs of identical twins differing in BMI received gradually increasing doses of NR (250-1000 mg/day) for 5 months. NR supplementation led to:

• Increased NAD+ levels in the body
• Increase in the number of mitochondria in muscles
• Improvement in muscle satellite cell differentiation
• Beneficial changes in gut microbiota composition

 

Interestingly, despite these positive effects at the cellular level, the study did not show significant improvement in metabolic parameters such as obesity or insulin sensitivity. This suggests that longer supplementation periods or higher doses are needed to achieve measurable clinical benefits.

Safety and Pharmacokinetics: Multiple studies have confirmed the safety and good tolerability of NR in humans. Supplementation effectively increases NAD+ levels in circulation, and one study also observed a reduction in blood pressure and arterial stiffness in older adults.

Mechanisms of NR Action

NR Metabolism in the Body

After consumption, NR is rapidly absorbed and metabolized. In cells, it is phosphorylated by nicotinamide riboside kinases (NRK1 and NRK2) to nicotinamide mononucleotide (NMN), which is then converted to NAD+ by NMN adenylyl transferases (NMNAT). NRK1 is found mainly in the liver and kidneys, while NRK2 is more active in muscles, including cardiac muscle.

Impact on Adipose Tissue

In obesity, adipose tissue becomes dysfunctional, exhibiting increased inflammation and impaired NAD+/sirtuin signaling. NR supplementation can restore proper NAD+ levels in adipocytes, leading to:

Gut Microbiota and NR

A fascinating discovery is the interaction between NR and gut microbiota. NR is metabolized in the intestines to nicotinamide and nicotinic acid, which affects microbiota composition. In turn, microbiota modulates the effects of NR on the body. The twin study showed that NR supplementation increases the presence of beneficial bacteria such as Faecalibacterium prausnitzii, which may contribute to improved metabolic health.

Epigenetic Regulation

NR demonstrates the ability to modulate epigenetic control of gene expression through effects on DNA methylation in muscles and adipose tissue. This mechanism may have long-term consequences for metabolic health and may explain some of the effects observed in long-term studies.

NR vs. Other NAD+ Precursors

There are several compounds that can serve as NAD+ precursors:

• Nicotinamide (NAM): The most common form of vitamin B3, but in high doses it can inhibit sirtuin activity.
• Nicotinic Acid (NA): Effectively increases NAD+, but activates the GPR109A receptor, causing characteristic "flushing".
• Nicotinamide Mononucleotide (NMN): A direct product of NR metabolism, but its presence in the diet is limited, and oral bioavailability is subject to debate.
• Nicotinamide Riboside (NR): Distinguished by a favorable safety profile, lack of GPR109A activation, and effective NAD+ elevation in multiple tissues.

Importantly, studies on NRK1-deficient mice showed that NR deficiencies cannot be compensated by nicotinamide supplementation, suggesting that different NAD+ precursors are not always interchangeable.

Therapeutic Perspectives and Challenges

 

Clinical Potential

Growing evidence suggests that NR may become a valuable therapeutic strategy in the treatment of metabolic syndrome and related disorders. Particularly promising seems to be the use of NR in:

• Preventing the progression of prediabetes to type 2 diabetes
• Treatment of non-alcoholic fatty liver disease (NAFLD)
• Supporting weight loss and improving body composition
• Improving cardiovascular function
• Delaying metabolism-related aging processes

Open Questions

Despite promising results, many questions remain unanswered:

• Optimal Dosing: Most human studies used doses of 250-1000 mg/day, but it is not clear whether these are optimal doses.
• Duration of Therapy: Some metabolic effects may require long-term supplementation to become clinically significant.
• Interactions with Other Therapies: Studies on combining NR with other interventions (e.g., sirtuin activators, caloric restriction, exercise) may provide synergistic benefits.
• Individual Response: Not all people may respond to NR in the same way, which requires identification of predictive biomarkers.

Availability and Safety

NR is currently available as a dietary supplement under trade names such as Niagen or Tru Niagen. This compound has obtained GRAS (Generally Recognized As Safe) status in the USA and is considered safe at recommended doses. Long-term safety studies have not shown significant adverse effects, making NR an attractive option for people seeking metabolic support.

Practical Implications and Lifestyle

It is worth emphasizing that NR supplementation should not be treated as a substitute for a healthy lifestyle. The best results can be achieved by combining supplementation with:

• Balanced Diet: Rich in natural NAD+ precursors (vegetables, meat, dairy products) and antioxidants.
• Regular Physical Activity: Exercise itself increases NAD+ levels and sirtuin activity.
• Caloric Restriction or Intermittent Fasting: These strategies work synergistically with NR supplementation in activating longevity-related pathways.
• Adequate Sleep: Sleep affects NAD+ metabolism and mitochondrial function.

Summary

Nicotinamide riboside represents a fascinating advance in our understanding and therapeutic possibilities in the context of metabolic syndrome. As a natural NAD+ precursor, NR offers a promising strategy for improving cellular metabolism, mitochondrial function, and insulin sensitivity. Although early clinical studies have not yet shown dramatic effects on metabolic parameters in humans, cellular mechanisms suggest significant therapeutic potential.

As our understanding of NAD+ metabolism deepens and new clinical trials provide more data, NR may become an important element of intervention in metabolic diseases and aging processes. For patients and clinicians considering NR supplementation, it is crucial to follow the latest research and consult with medical professionals to determine appropriate application in the context of individual health needs.