Peptides and Energy: What the Research Says

Searches that pair peptides with "energy" usually collapse three very different research questions into one word. This page separates them, then walks through the compounds that actually have published work attached, labels the strength of that evidence, and states plainly where the literature is thin or absent. Nothing here ranks compounds, and nothing here is guidance for personal use.

What "energy" means in the published literature

Studies use the word in at least three non-interchangeable ways:

• Subjective fatigue — questionnaire or scale scores reported by participants. This is the meaning closest to everyday usage, and it is the endpoint least often used in the peptide literature.
• Whole-body energy expenditure and substrate use — calorimetry measurements of how many calories are burned and whether fat or carbohydrate is oxidised. This is a metabolic measurement, not a feeling.
• Cellular bioenergetics — mitochondrial function, oxidative stress markers, and the availability of cofactors such as NAD+. A 2020 review in Biochemical Society Transactions described NAD+ as an essential redox metabolite and co-substrate and framed it as an anti-cancer and anti-ageing therapeutic target (PMID 32573651).

A compound can move one of these measures without moving the others. Increased fat oxidation does not mean a person felt more alert; improved mitochondrial markers in rodent tissue do not mean a human reported less fatigue. Keeping the three categories apart is the single most useful habit when reading claims in this area.

Mitochondrial-derived peptides: MOTS-c

MOTS-c is a short peptide encoded within mitochondrial DNA, which is why it appears in discussions of cellular energy more often than any other peptide. The published work, however, has largely used disease models rather than fatigue endpoints.

A 2022 paper in Pharmacological Research reported that the mitochondrial-derived peptide MOTS-c relieved hyperglycemia and insulin resistance in gestational diabetes mellitus (PMID 34798268). A separate 2024 study in Advanced Science reported that MOTS-c suppressed ovarian cancer progression by attenuating USP7-mediated LARS1 deubiquitination (PMID 39321430). Both are mechanistic investigations of metabolic and oncologic biology; neither was framed as a study of tiredness, exercise capacity or energy expenditure in healthy people.

Evidence label: preclinical and mechanistic. Readers looking for human fatigue outcomes will not find them in these two papers, and no human trial of MOTS-c for energy appears in the verified literature summarised here.

NAD+ precursors: the largest body of "energy" research

Nicotinamide mononucleotide (NMN), nicotinamide riboside (NR) and niacin are not peptides — they are vitamin B3 derivatives — but they dominate the cellular-energy conversation and are frequently grouped with peptides in consumer discussion. The rationale is the co-substrate role described in the 2020 NAD+ review (PMID 32573651).

Animal work

One of the most-cited animal studies, published in Cell Metabolism in 2016, reported that long-term administration of nicotinamide mononucleotide mitigated age-associated physiological decline in mice (PMID 28068222). The study examined aged rodents rather than humans, and "physiological decline" is a composite of measures, not a fatigue score.

Other animal and mechanistic work has mapped NAD+ biology onto specific organs. A 2023 paper in Nature Communications reported that NAD+ repletion with niacin counteracted cancer cachexia (PMID 37012289), a wasting syndrome in which weakness and exhaustion are prominent features. A 2025 paper in the Journal of Hepatology reported that ACMSD inhibition — a means of raising NAD+ through the de novo pathway — corrected fibrosis, inflammation and DNA damage in MASLD/MASH models (PMID 39181211). A 2024 study in Acta Pharmacologica Sinica reported that Macrod1 suppressed diabetic cardiomyopathy via the PARP1-NAD+-SIRT3 pathway (PMID 38459256). And a 2021 paper in the Journal of Neuroinflammation reported that NAD+ improved cognitive function and reduced neuroinflammation by ameliorating mitochondrial damage and decreasing ROS production in chronic cerebral hypoperfusion models through the Sirt1/PGC-1α pathway (PMID 34530866).

These papers share a pattern worth noticing: researchers targeted a disease process in an animal or cell model and measured tissue-level outcomes. None measured self-reported energy in people.

Human trials

Two randomised human studies in the verified set tested NAD+ precursors in patient populations. The NICE randomized clinical trial, published in Nature Communications in 2024, evaluated nicotinamide riboside for peripheral artery disease (PMID 38871717). A randomized crossover clinical trial published in JCI Insight in 2023 examined coenzyme Q10 and nicotinamide riboside in chronic kidney disease (PMID 37159264).

Both recruited people with a specific diagnosis, which limits how far the findings extend to healthy adults who describe themselves as tired. A 2024 systematic review in the American Journal of Physiology — Endocrinology and Metabolism evaluated the safety and effectiveness of NAD in different clinical conditions (PMID 37971292), and is the most useful single entry point for anyone wanting the breadth of the human record rather than a single trial.

Evidence label: mixed. Animal data are extensive and consistent in direction; human randomised data exist but sit in defined clinical populations, as the trials themselves show (PMID 38871717, PMID 37159264).

Incretin analogues and measured energy expenditure

Weight-loss peptides enter the energy conversation from a different direction: weight loss normally triggers metabolic adaptation, a drop in energy expenditure greater than body-size change alone would predict. A 2025 study in Cell Metabolism reported that tirzepatide did not impact metabolic adaptation in people with obesity but increased fat oxidation (PMID 40203836).

That is a calorimetry finding about fuel selection and expenditure, not a finding about subjective vitality. The study did not report that participants felt more energetic, and it should not be read that way.

Evidence label: human, but a narrow endpoint.

Evidence quality at a glance

Safety and tolerability: What Studies Report

Safety information in this area comes mainly from the NAD+ literature. The 2024 systematic review in the American Journal of Physiology — Endocrinology and Metabolism was designed specifically to evaluate the safety as well as the effectiveness of NAD in different clinical conditions (PMID 37971292), and is the appropriate source to consult for pooled tolerability findings rather than any single trial.

Randomised trials contribute controlled safety observations within their own populations: the NICE trial studied nicotinamide riboside in people with peripheral artery disease (PMID 38871717), and the crossover trial studied coenzyme Q10 and nicotinamide riboside in chronic kidney disease (PMID 37159264). Safety data collected in people with vascular or kidney disease do not automatically describe what happens in other groups.

For MOTS-c, the verified papers here were preclinical (PMID 39321430, PMID 34798268), so no human tolerability profile can be drawn from them. Absence of reported harm in animal work is not evidence of human safety.

Where the literature is thin

• Few fatigue endpoints. The studies summarised here measured glucose handling, tissue pathology, cognition in a disease model, walking-related disease status or calorimetry — for example fat oxidation in the tirzepatide study (PMID 40203836) — rather than self-rated energy in healthy adults.
• Species gap. The most striking longevity-adjacent result was obtained in mice (PMID 28068222), and mouse NAD+ metabolism differs from human metabolism.
• No head-to-head comparisons. Nothing in this set compared a mitochondrial-derived peptide against an NAD+ precursor, so any ranking would be invented rather than measured.
• Population mismatch. Human randomised data came from people with peripheral artery disease (PMID 38871717) and chronic kidney disease (PMID 37159264).

Regulatory context

MOTS-c is not an approved drug and is distributed in research settings as a research-use-only material; research-use-only labelling means a substance has not been evaluated for human administration. Tirzepatide is an approved prescription medicine for specific indications, and the calorimetry study cited above examined it in people with obesity (PMID 40203836). Nicotinamide riboside and nicotinamide mononucleotide occupy a separate regulatory category from peptide drugs, and their status differs by jurisdiction.

Reading claims about peptides and energy

Three questions separate a supportable statement from an unsupportable one. First, which definition of energy did the study use? Second, was the model human, and if so, which population — the crossover trial, for instance, enrolled people with chronic kidney disease (PMID 37159264). Third, was the energy-related outcome a primary measure or an incidental observation? A claim that survives all three is rare in this field.

This page is for educational purposes only and is not medical advice; consult a licensed physician about any health concern, symptom of fatigue, or any substance discussed here.

References

• Tirzepatide did not impact metabolic adaptation in people with obesity, but increased fat oxidation (Cell Metabolism, 2025)
• Evaluation of safety and effectiveness of NAD in different clinical conditions: a systematic review (American Journal of Physiology. Endocrinology and Metabolism, 2024)
• Long-Term Administration of Nicotinamide Mononucleotide Mitigates Age-Associated Physiological Decline in Mice (Cell Metabolism, 2016)
• NAD(+) repletion with niacin counteracts cancer cachexia (Nature Communications, 2023)
• ACMSD inhibition corrects fibrosis, inflammation, and DNA damage in MASLD/MASH (Journal of Hepatology, 2025)
• Mitochondrial-Derived Peptide MOTS-c Suppresses Ovarian Cancer Progression by Attenuating USP7-Mediated LARS1 Deubiquitination (Advanced Science, 2024)
• Nicotinamide adenine dinucleotide (NAD+): essential redox metabolite, co-substrate and an anti-cancer and anti-ageing therapeutic target (Biochemical Society Transactions, 2020)
• Nicotinamide riboside for peripheral artery disease: the NICE randomized clinical trial (Nature Communications, 2024)
• Macrod1 suppresses diabetic cardiomyopathy via regulating PARP1-NAD(+)-SIRT3 pathway (Acta Pharmacologica Sinica, 2024)
• The mitochondrial-derived peptide MOTS-c relieves hyperglycemia and insulin resistance in gestational diabetes mellitus (Pharmacological Research, 2022)
• Randomized crossover clinical trial of coenzyme Q10 and nicotinamide riboside in chronic kidney disease (JCI Insight, 2023)
• NAD(+) improves cognitive function and reduces neuroinflammation by ameliorating mitochondrial damage and decreasing ROS production in chronic cerebral hypoperfusion models through Sirt1/PGC-1α pathway (Journal of Neuroinflammation, 2021)