AICAR: Scientific Overview, Benefits, Side Effects, and More in Preclinical Studies

AICAR is a well-studied compound in preclinical research due to its role in activating AMPK, a known energy regulator at the cellular level. Scientists have explored its potential in models of insulin resistance, cardiovascular health, inflammation, and even cancer. 

Although AICAR studies present intriguing results, this compound is not approved for human use and remains limited to research purposes only.

What is AICAR?

AICAR is not a peptide and is classified as an analog of adenosine monophosphate (AMP). Due to its ability to mimic AMP, AICAR is believed to activate AMP-activated protein kinase (AMPK). The latter is a master regulator of cellular energy balance.

Since AICAR is also identified as an AMPK activator, it is often categorized as an AMPK agonist or “exercise mimetic.” This feature is only applied in the context of laboratory studies.

How AICAR Works: Scientific Mechanisms

AMPK Activation

Inside the cell, AICAR is converted into ZMP (AICAR monophosphate), a compound that closely resembles AMP. This structural similarity allows ZMP to bind and activate AMPK. 

Once activated, the AMPK is expected to initiate a range of energy-conserving processes designed to restore cellular balance. This action makes AICAR a potential key player in metabolic regulation.

Metabolic Shifts

The activation of AMPK by AICAR can lead to significant metabolic adjustments. Research shows that AICAR may enhance glucose uptake and promote fatty acid oxidation. These effects both increase the energy availability of the cell.

At the same time, AMPK activation could encourage mitochondrial biogenesis. This means that AICAR may help the cell expand its capacity for energy production.

Tissue-Specific Effects

The possible impact of AICAR and AMPK activation varies depending on the tissue:

• Muscle tissue: AICAR has been shown to increase glucose utilization and support endurance-related adaptations. As such, this research peptide becomes a valuable tool in research related to exercise physiology. [1]
• Cardiac tissue: In heart studies, AICAR has demonstrated protective effects during ischemia. The latter is a condition where oxygen and blood flow are restricted. [2]
• Liver and fat tissue: AICAR may also influence lipid metabolism and enhance insulin sensitivity. This effect offers insights into how energy regulation and metabolic balance are maintained. [3] 

Preclinical Benefits of AICAR (Animal & Lab Studies)

AICAR and Insulin Resistance

In mouse studies, AICAR administration reduced inflammation in adipose (fat) tissue. This is a key contributor to insulin resistance. Even at low doses, AICAR has been demonstrated to improve glucose homeostasis and insulin sensitivity. These actions were observed without affecting the body weight of the research models. [4]

Exercise-Mimicking Properties

One striking preclinical finding is that AICAR can mimic endurance exercise. In rodents, repeated administration increases the levels of GLUT-4 receptors on muscle cells. Such adaptations closely resemble the long-term advantages of aerobic exercise training. [5]

AICAR and Cancer Research

It is believed that AMPK has a complex role in cancer biology. The enzyme can sometimes slow tumor progression. At other times, AMPK may support cancer survival depending on the cellular context. [6]

In laboratory studies, prolonged AMPK activation by AICAR often leads to cancer death. This is primarily due to the slowing of cancer cells’ metabolism, making them vulnerable to stress. [7]

Anti-Inflammatory Properties

Similar to other AMPK activators, AICAR shows promise in reducing inflammation at the cellular level. In mouse models of colitis, the research peptide reduced immune overactivation. This is observed when AICAR suppresses NF-κB signaling in macrophages and reduces pro-inflammatory cytokines (TH1 and TH17 types). [8]

Cardiovascular Study

Inflammation is a known driver of several cardiovascular diseases. As a result, AICAR has been investigated for its protective effects in preclinical heart and cardiovascular models. In rabbits with induced atherosclerosis, AICAR reduced vascular smooth muscle proliferation. This process is linked to both artery narrowing and stent failure. [9]

Fertility Potential

Studies in a wide variety of animal models suggest that AICAR may improve sperm motility and fertilizing ability. This effect appears to be linked to enhanced metabolism in sperm cells. This is where AICAR regulates key enzymes responsible for energy production. [10]

IMPORTANT: The mentioned potential effects of AICAR are limited to laboratory settings and preclinical studies. More trials are needed to verify AICAR’s positive effect on humans. The AICAR is not approved for human consumption.

Potential Side Effects Observed in Preclinical Studies

Although AICAR shows promising effects in some contexts, some preclinical studies also report risks related to AICAR administration:

• Hypoglycemia: AICAR can produce a strong effect on innate glucose uptake. As such, research models may experience lowered blood sugar levels.
• Cardiac alterations: Prolonged exposure to AICAR has been linked to changes in heart rhythm or cardiac stress. 
• Interference with cell growth: Overactivation of AMPK may suppress anabolic pathways necessary for normal tissue development

Legal Status & Research Context

• Regulatory status: AICAR is not approved for medical or dietary use by the FDA.
• Research only use: This investigative peptide is restricted to laboratory and preclinical settings.
• Anti-doping regulations: The World Anti-Doping Agency (WADA) lists AICAR as a prohibited substance. This is due to its potential performance-enhancing properties.

Comparison with Other Peptides & AMPK Activators

• Metformin: This is a clinically approved AMPK activator widely used for type 2 diabetes. However, it is less potent in direct AMPK stimulation compared to AICAR.
• GW501516 (Cardarine): Cardarine is another research compound that is often compared to AICAR. However, it activates PPARδ rather than AMPK.
• Natural Activators: Exercise, caloric restriction, and compounds such as resveratrol can also modulate AMPK activity within a physiological context.

Compared with these, AICAR remains a valuable laboratory tool. Although it still has limitations that prevent clinical applications.

Future Directions in Research

Current and future studies are focused on:

• Developing AICAR analogs with improved bioavailability and reduced side effects.
• Exploring synergistic effects with other metabolic regulators.
• Investigating long-term AMPK activation outcomes in various tissues.
• Expanded cancer-related research, where AICAR demonstrates both pro- and anti-tumor effects depending on context. 

Conclusion

Many researchers consider AICAR as a cornerstone compound in AMPK-related studies. The research peptide offers a deeper understanding of cellular metabolism, endurance, and disease pathways. While findings from preclinical studies are promising, AICAR still possesses certain limitations that prevent its advancement to clinical use.

For now, AICAR remains an essential experimental tool that continues to influence several studies on metabolism and energy regulation.

FAQ Section

Is AICAR approved for human use?

No. AICAR is only available as a research chemical. Thus, it is not approved for human use.

Why is AICAR banned in sports?

In several preclinical models, AICAR is shown to enhance endurance and strength. WADA prohibits this research peptide as a potential performance-enhancing agent.

What makes AICAR important in research?

It is one of the most studied AMPK activators and has contributed significantly to understanding metabolism, exercise adaptation, and disease mechanisms.

References

1. de Laat, M. A., Robinson, M. A., Gruntmeir, K. J., Liu, Y., Soma, L. R., & Lacombe, V. A. (2015). AICAR administration affects glucose metabolism by upregulating the novel glucose transporter, GLUT8, in equine skeletal muscle. The Veterinary Journal, 205(3), 381–386. https://doi.org/10.1016/j.tvjl.2015.05.018 
2. Paiva, M. A., Rutter-Locher, Z., Gonçalves, L. M., Providência, L. A., Davidson, S. M., Yellon, D. M., & Mocanu, M. M. (2011). Enhancing AMPK activation during ischemia protects the diabetic heart against reperfusion injury. American Journal of Physiology-Heart and Circulatory Physiology, 300(6), H2123–H2134. https://doi.org/10.1152/ajpheart.00707.2010 
3. Rodríguez-Calvo, R., Vázquez-Carrera, M., Masana, L., & Neumann, D. (2015). AICAR Protects against High Palmitate/High Insulin-Induced Intramyocellular Lipid Accumulation and Insulin Resistance in HL-1 Cardiac Cells by Inducing PPAR-Target Gene Expression. PPAR Research, 2015, 1–12. https://doi.org/10.1155/2015/785783 
4. Yang, Z., Wang, X., He, Y., Qi, L., Yu, L., Xue, B., & Shi, H. (2012). The Full Capacity of AICAR to Reduce Obesity-Induced Inflammation and Insulin Resistance Requires Myeloid SIRT1. PLoS ONE, 7(11), e49935. https://doi.org/10.1371/journal.pone.0049935 
5. Jessen, N., Pold, R., Buhl, E. S., Jensen, L. S., Schmitz, O., & Lund, S. (2003). Effects of AICAR and exercise on insulin-stimulated glucose uptake, signaling, and GLUT-4 content in rat muscles. Journal of Applied Physiology, 94(4), 1373–1379. https://doi.org/10.1152/japplphysiol.00250.2002 
6. Faubert, B., Vincent, E. E., Poffenberger, M. C., & Jones, R. G. (2015). The AMP-activated protein kinase (AMPK) and cancer: Many faces of a metabolic regulator. Cancer Letters, 356(2), 165–170. https://doi.org/10.1016/j.canlet.2014.01.018 
7. AICAR inhibits cancer cell growth and triggers cell-type distinct effects on OXPHOS biogenesis, oxidative stress, and Akt activation. (2011). Biochimica et Biophysica Acta (BBA) – Bioenergetics, 1807(6), 707–718. https://doi.org/10.1016/j.bbabio.2010.12.00 
8. Bai, A., Yong, M., Ma, A. G., Ma, Y., Weiss, C. R., Guan, Q., Bernstein, C. N., & Peng, Z. (2010). Novel Anti-Inflammatory Action of 5-Aminoimidazole-4-carboxamide Ribonucleoside with Protective Effect in Dextran Sulfate Sodium-Induced Acute and Chronic Colitis. Journal of Pharmacology and Experimental Therapeutics, 333(3), 717–725. https://doi.org/10.1124/jpet.109.164954 
9. Igata, M., Motoshima, H., Tsuruzoe, K., Kojima, K., Matsumura, T., Kondo, T., Taguchi, T., Nakamaru, K., Yano, M., Kukidome, D., Matsumoto, K., Toyonaga, T., Asano, T., Nishikawa, T., & Araki, E. (2005). Adenosine Monophosphate-Activated Protein Kinase Suppresses Vascular Smooth Muscle Cell Proliferation Through the Inhibition of Cell Cycle Progression. Circulation Research, 97(8), 837–844. https://doi.org/10.1161/01.res.0000185823.73556.06 
10. Paweena Thuwanut, Comizzoli, P., Kamthorn Pruksananonda, Kaywalee Chatdarong, & Nucharin Songsasen. (2019). Activation of adenosine monophosphate–activated protein kinase (AMPK) enhances energy metabolism, motility, and fertilizing ability of cryopreserved spermatozoa in the domestic cat model. 36(7), 1401–1412. https://doi.org/10.1007/s10815-019-01470-5