Many individuals embark on weight loss journeys with enthusiasm, only to encounter frustrating plateaus despite their best efforts with diet and exercise. Traditional methods, such as further calorie restriction or increased physical activity, often prove insufficient to reignite fat loss. This article explores the potential role of Nicotinamide Adenine Dinucleotide (NAD+) in overcoming these challenges and achieving sustainable weight loss.
Understanding Overweight and Obesity
Overweight and obesity are defined as abnormal or excessive fat accumulation that presents a risk to health. A body mass index (BMI) over 25 is considered overweight, and over 30 is obese. The issue has grown to epidemic proportions, with over 4 million people dying each year as a result of being overweight or obese in 2017 according to the global burden of disease (1). Adiposity, particularly abdominal adiposity, is associated with an increased risk of most chronic diseases such as type 2 diabetes (T2DM), cancer, cardiovascular disease (CVD), atherosclerosis, and metabolic syndrome (2). Moreover, low-grade chronic inflammation linked to adiposity, along with adipocyte development and a change in the pattern of activity of adipokines especially, leptin and adiponectin, leads to adipose tissue (AT) dysfunction (3). Following these changes, serious disorders are generally observed, such as a decrease in mitochondrial biogenesis and an increase in oxidative stress and inflammation (4-6).
The Role of NAD+
Nicotinamide Adenine Dinucleotide (NAD+) is a coenzyme essential for cellular energy production. NAD+ and its phosphorylated and reduced forms NADH, NADP+, and NADPH, are coenzymes for hydride transfer enzymes, crucial to biological redox reactions. NAD+/NADH ratio is a basic determinant of the rate of catabolism and energy production29,30. In fed state or nutrient overload NAD+/NADH ratio falls, and a prolonged redox imbalance potentially leads to metabolic pathologies, such as diabetes31. Along these lines, extensive research demonstrates that NAD+ levels significantly decline in metabolic tissues of mice and patients with obesity32,33,34,35,36,37. NAD+ decay itself may contribute to metabolic dysfunction by distinct mechanisms, including increased oxidative stress and ROS production, disbalance in the oxidative-reductive capacity, disrupted Ca2+ homeostasis, or reduced activity of sirtuins38,39; a class of deacetylase enzymes using NAD+ as cofactor and known to influence mitochondrial function and metabolism. In recent years, NAD+ has emerged as a target for the treatment of metabolic diseases, as boosting endogenous NAD+ levels has been proven effective against diet-induced metabolic pathologies, including insulin resistance, hyperglycemia, hypertriglyceridemia and NAFLD32,33,35,36,40,41,42,43,44,45.
As we age, NAD+ levels decline, leading to slower metabolism, reduced fat-burning capacity, and increased fatigue. Improving NAD+ availability via NAD+ precursor supplementation has emerged as a potential strategy to augment tissue-specific NAD+ homeostasis and improve physiological function (28).
NAD+ Synthesis and its Importance
NAD+ is synthesised in two major pathways in the human body: de novo synthesis and salvage, the latter of which has a more effective role in maintaining levels of NAD+ in the body. The compounds that are created from the salvage pathway are called NAD+ precursors (10). Furthermore, the presence of Sirtuins, NAD + -dependent protein deacetylases (SIRT1-7), is crucial for NAD + 's biological function in humans (11). Studies have shown that NAD+ precursors and Sirtuins gene expression were significantly down-regulated in obese subjects (12-14), whereas their expression increased progressively in subjects with a weight loss programme (15).
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NAD+ and Weight Loss: The Science
NAD+ affects weight loss through its involvement in various metabolic pathways. By facilitating the breakdown of nutrients and regulating energy production, NAD+ helps maintain a balanced metabolism. This, in turn, can contribute to weight loss by ensuring the efficient utilization of stored fat and preventing excessive fat accumulation.
NAD+ is vitally important for your cells and their overall health. If you provide your cells with this important coenzyme, they will reproduce healthier and more vigorously than before. This, in turn, could lead to the reduction of aging symptoms, especially those related to appearance or mobility. In a way, NAD+ can help to revitalize or reinvigorate the cells of your body. Though it’s not the same as stopping aging outright, NAD+ therapy could help delay the onset of aging symptoms in this manner.
Impact on Fat Cells
Studies have shown that increasing NAD+ levels can have a significant impact on fat cells. NAD+ activates enzymes called sirtuins, which play a role in cellular metabolism and energy expenditure. These enzymes can promote the breakdown of fats and inhibit their storage, thus aiding in weight loss.
NAD+ has been found to enhance mitochondrial function, the powerhouse of the cell responsible for energy production. By optimizing mitochondrial activity, NAD+ can boost metabolism and promote the conversion of stored fat into energy, further supporting weight loss goals.
Boosting Metabolism
A faster metabolism can help burn calories more efficiently and contribute to weight loss. By supporting the proper functioning of metabolic enzymes, NAD+ can enhance overall metabolic rate and promote weight loss.
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NAD+ is essential for the function of mitochondria, the powerhouse of the cell responsible for generating energy. By maintaining mitochondrial health and function, NAD+ ensures that the body can efficiently convert food into energy, preventing the accumulation of excess calories as fat and supporting weight loss efforts.
Appetite Control
Appetite control is crucial when it comes to weight management. NAD+ has been found to influence appetite-regulating pathways in the brain, potentially reducing cravings and promoting a feeling of fullness. This can be beneficial for those aiming to lose weight and control their calorie intake.
NAD+ is involved in the regulation of circadian rhythms, which play a role in controlling hunger and satiety. By modulating these biological rhythms, NAD+ can help regulate appetite and prevent overeating, ultimately supporting weight loss goals.
Increasing NAD+ Levels: Natural Approaches
There are several natural ways to increase NAD+ levels. Regular exercise, especially high-intensity interval training (HIIT), has been shown to stimulate NAD+ production. Exercise not only boosts NAD+ levels but also enhances mitochondrial function, which is crucial for energy production.
A healthy diet rich in niacin, also known as vitamin B3, can support NAD+ synthesis in the body. Foods like chicken, turkey, salmon, and peanuts are excellent sources of niacin and can help maintain optimal NAD+ levels.
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Lifestyle Adjustments
Making small lifestyle tweaks also goes a long way. Practicing intermittent fasting or occasional calorie restriction can jumpstart autophagy, clearing out old cells and ramping up NAD production.
NAD+ Precursors and Supplements
In some cases, supplements can be utilized to boost NAD+ levels. Nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN) are two popular supplements that can increase NAD+ levels and potentially aid weight loss. These supplements work by providing precursors that the body can use to synthesize NAD+.
Scientific Evidence on NAD+ Precursors
Consistent with the effect of NAD+ precursor supplementation on body composition observed by Remie et al. (31), the meta-analysis showed lowering BMI at 0.19 kg/m2 and BMI decrease was higher in a dose ≥2 g and a duration of intervention >12 weeks. In another study in 2018, which was conducted to investigate dietary nicotinamide riboside (NR) supplementation in a 12-week period on the improvement of insulin sensitivity and other metabolic parameters in obese and insulin-resistant men, the results showed that NR in doses of 2 g/day had no effect on resting energy expenditure, lipolysis, lipid oxidation, or body composition (32). In a study, with the aim of determining the effect of long-term NR supplementation on increasing mitochondrial biogenesis and metabolic health on twenty monozygotic twins discordant with BMI with an increasing dose of NR (250 to 1,000 mg per day) for 5 months, NR did not improve obesity or metabolic health (33). Udin et al. (34) evaluated the effects of NAD+ supplementation in rats fed a high-fat diet. The results showed that NAD+ supplementation reduced the BMI of the rats, suggesting that NAD+ supplementation may be an effective strategy for weight loss and improving metabolic health. In another animal study on diet-induced obese rats, NA decreased visceral adipose tissue and improved adiponectin levels and lipid profile (35).
Meta-Analysis Findings
The results of a systematic review and meta-analysis showed that nicotinamide adenine dinucleotide (NAD+) precursor supplementation has an effect on lowering BMI and increasing adiponectin in humans compared with control groups. Furthermore, there was a significant relationship between doses of intervention with changes in BMI.
Pooled findings from the random-effects model indicated that body mass index (BMI) (weighted mean difference (WMD): −0.19 kg/m2, 95% confidence interval (CI): −0.29 to −0.09, p < 0.001) were significantly reduced after NAD+ precursor supplementation compared to control group. Also, Pooled findings indicated that compared to the control group, adiponectin (WMD: 1.59 μg/mL, 95% CI: 0.49 to 2.68, p = 0.004) was significantly increased after with NAD+ precursor supplementation. Furthermore, significant heterogeneity was found among the studies for adiponectin (Cochran Q test, p < 0.001, I2 = 88.3%). The findings of the subgroup also show the greater effect of NAD+ precursor supplementation on BMI decrease in a dose ≥2 g and a duration of intervention >12 weeks.
Niacin and Nicotinamide
Niacin assists in the body’s fat and sugar processing, supporting cellular health, which is essential for weight control. In fact, a study published in Cell Metabolism found that niacin effectively boosts NAD+ levels in adults. Nicotinamide, on the other hand, shows promise in metabolic function improvement through reducing fat mass and increasing lean muscle. In 2021, a study found that Nicotinamide improved weight management in mice23. When given to them, Nicotinamide increased how much energy they burned and changed their body fat composition.
D-Ribose
In addition to well-known NAD+ precursors, D-ribose is another supplement worth trying. This naturally occurring sugar doesn’t directly increase NAD+ levels like the others, but it helps the body produce ATP, which in turn supports NAD+ production.
Potential Risks and Side Effects of NAD+ Supplementation
NAD+ supplementation appears generally safe, but like any intervention, it carries some risks. Limited research is available regarding the long-term effects and safety of high-dose NAD+ supplementation. It is advisable to seek professional guidance and follow recommended dosage guidelines.
One potential risk to be aware of is the lack of regulation in the supplement industry, leading to variations in product quality and purity. Without strict oversight, there is a possibility of contamination or inaccurate labeling, which could impact the effectiveness and safety of NAD+ supplements. To mitigate this risk, it is essential to choose reputable brands that undergo third-party testing for quality assurance.
Common Side Effects
Common side effects of NAD+ supplementation may include nausea, flushing, and gastrointestinal discomfort. These side effects are generally mild and temporary but should be monitored closely. If any adverse reactions occur, it is best to discontinue use and consult a healthcare professional.
Individuals with certain medical conditions or those taking specific medications should exercise caution when considering NAD+ supplementation. Drug interactions can occur, potentially affecting the efficacy of medications or causing unexpected side effects. It is crucial to disclose all medications and health conditions to a healthcare provider before starting NAD+ supplementation to ensure safety and effectiveness.
NAD+ IV Therapy
NAD IV therapy has become a buzzword for those seeking weight loss, but it’s important to manage expectations. While NAD therapy boosts extracellular NAD levels, which can help with energy and metabolism, it shouldn’t be the sole strategy for shedding pounds.
Supplements vs. IV Therapy
When considering NAD supplements versus IV therapy, it’s important to understand their differences. NAD precursor supplements are easy to take regularly and support long-term cellular health, offering a gradual boost to NAD+ levels and metabolism over time. In contrast, NAD IV treatment provides a higher, more immediate dose of NAD+, delivering quicker effects.
NAD IV therapy can be costly, and some people experience side effects like headaches, nausea, or dizziness. So, if you’re considering NAD injections for weight loss, it’s important to remember that it should be part of a broader strategy that includes a balanced diet and regular exercise.
The Circadian Rhythm Connection
Circadian rhythms are evolutionary conserved 24-h cycles in physiology dictated by an intrinsic circadian clock. In mammals, the suprachiasmatic nucleus (SCN), a master timekeeper in the hypothalamus, receives photic cues from the retina to align internal and external time. The SCN distally synchronizes ancillary oscillators in peripheral tissues. Importantly, certain cues such as nutritional inputs effectively synchronize peripheral clocks9. Aligned synchrony between all body clocks maintains homeostasis and health, for example, by adjusting metabolic performance to daily environmental fluctuations. Conversely, persistent circadian misalignment is a cause of severe diseases, including obesity and metabolic syndrome, T2D, or cardiovascular disease, amongst others10,11,12.
At the molecular level, the circadian machinery is expressed in almost all cell types and consists of transcriptional-translational autoregulatory feedback loops. The positive loop is driven by the CLOCK:BMAL1 transcriptional activator, which rhythmically binds to E-box genomic elements, thereby activating transcription of many genes including the circadian repressors, Period (Per1-3) and Cryptochrome (Cry1-2). PER:CRY complexes directly repress CLOCK:BMAL1 leading to transcriptional silencing. A number of interlocked regulatory loops, such as the one governed by RORs/REV-ERBα to regulate Bmal1 expression, intertwine to confer complexity, redundancy, and robustness to circadian rhythms13.
A paradigmatic example is illustrated by daily rhythms in nicotinamide adenine dinucleotide (NAD+) bioavailability, imposed by circadian oscillations in the clock-controlled gene Nampt, the rate-limiting enzyme for the NAM salvage pathway to NAD+19,20. Several lines of evidence demonstrate that the molecular clock and NAD+ oscillations sustain mitochondrial function and bioenergetics, manifested in daily rhythms in respiration, fatty acid oxidation, or nutrient utilization21,22,23,24,25. Indeed, it is considered that clock-controlled NAD+ biosynthesis occupies a fundamental position connecting circadian metabolic pathways26,27,28.
NAD+ Chronotherapy: A Timed Approach
In a study, researchers aimed to characterize the metabolic consequences of rhythms in NAD+ levels. To approach this question, they used a mouse model of diet-induced obesity (DIO), which is known to present decreased, non-rhythmic levels of NAD+15,16,17, and pharmacologically recovered daily rhythms of NAD+ with a peak at the onset of the active phase. To do so, they used a daily timed intraperitoneal (IP) injection with NAD+ itself at ZT11. The study showed that obese mice with enforced NAD+ oscillations improved metabolic health, significantly lost weight, and corrected NAFLD.
Key Findings of the Chronotherapy Study
After 14 days of NAD+ chronotherapy, a significant decrease in total body weight was observed in obese treated mice (HFN) with respect to their obese non-treated littermates (HF), which was sustained after 22 days. At the end of the treatment, hepatic NAD+ content was measured by HPLC, showing the expected oscillation with a peak at ~ZT12 in control mice (CD, Fig. 1c) which is mostly disrupted in HFD-fed mice (HF, Fig. 1c, Supplementary Fig. S1e)16,21,36,46. Importantly, in the HFN group, the acrophase of NAD+ was restored to ZT12 (HFN, Fig. 1c, Supplementary Fig. S1e), hence daily rhythms in hepatic NAD+ content was reinstated in obese mice.
Circulating insulin levels were much lower in the HFN group when compared to the HF group, with a major effect during the early active phase (Fig. 1d, ZT12-18, P < 0.001 Two-way ANOVA, Tukey post-test) and a six-hour phase delay in the oscillatory pattern (Supplementary Fig. S1f). Indeed, circulating insulin in HFN mice appeared largely comparable to their control littermates.
Restoring NAD+ oscillations in obese mice significantly ameliorated glucose tolerance, specifically at ZT16. After 20 days of treatment, this improvement was also apparent at ZT4. Glucose clearance upon insulin IP injection was largely enhanced by NAD+ chronotherapy.
Obese mice treated with NAD+ significantly decreased hepatic neutral lipid content. This timed NAD+ therapy reduced the accumulation of carbonylated proteins in liver lysates to normal levels and augmented mitochondrial biogenesis.
Other Potential Benefits of NAD+ Therapy
Beyond weight loss, NAD+ therapy may offer a range of other potential benefits:
Boosted Cognition
One of the potential major benefits you might experience from NAD+ therapy is improved cognitive function, specifically memory recall, boosted concentration, and mental clarity.
Reduced Pain and Discomfort
NAD+ has a major benefit in that it reduces pain and inflammation. NAD+ may reduce discomfort and alleviate pain at the same time. NAD+ is the key coenzyme that proteins called sirtuins need to function properly. Sirtuins, in turn, regulate the inflammatory response throughout your body.
Improved Energy
NAD+ may be able to assist with the production of new ATP. In doing so, NAD+ therapy could help to boost your energy levels and reduce any feelings of fatigue or exhaustion.
Better Athletic Performance
NAD+ may enhance athletic performance to some degree. NAD+ is a major coenzyme needed for muscle development. Therefore, if you want to build muscle efficiently and effectively, NAD+ could help supercharge your efforts (at least when combined with a solid workout regimen and a good diet).
Reversed Signs of Aging
NAD+ therapy may help reverse some of the signs of aging, including the appearance of skin wrinkles and aging spots and difficulty moving or low mobility.