AICAr, a Widely Used AMPK Activator with Important AMPK-Independent Effects: A Systematic Review

AICAr, a Widely Used AMPK Activator with Important AMPK-Independent Effects: A Systematic Review

Fifth, given the powerful therapeutic effect of AICAR in PALI, the potential effect of AICAR in other organ dysfunctions including respiratory, renal, and cardiovascular of SAP needs to be further explored. The signaling molecule 5′-AMP-activated protein kinase plays a pivotal role in metabolic adaptations. Treatment with 5-aminoimidazole-4-carboxamide-1-β-d-ribofranoside (AICAR) promotes the expression of metabolic regulators and components involved in glucose uptake, mitochondrial biogenesis, and fatty acid oxidation in skeletal muscle cells. Our aim was to determine whether AICAR-induced changes in metabolic regulators and components were more prominent in white or red muscle. Rats were treated with AICAR (1mg/g body weight/day) for 14 days, resulting in increased expression levels of nicotinamide phosphoribosyltransferase (NAMPT), peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), glucose transporter 4 proteins, and enhanced mitochondrial biogenesis. These changes were more prominent in white rather than red gastrocnemius muscle or were only observed in the white gastrocnemius.

5-Aminoimidazole-4-carboxamide ribonucleoside (AICAr) has been one of the most commonly used pharmacological modulators of AMPK activity. The majority of early studies on the role of AMPK, both in the physiological regulation of metabolism and in cancer pathogenesis, were based solely on the use of AICAr as an AMPK-activator. Even with more complex models of AMPK downregulation and knockout being introduced, AICAr remained a regular starting point for many studies focusing on AMPK biology.

We also investigated the impact of AICAR/Compound C treatment on acetyl-CoA carboxylase (ACC), the downstream target of activated AMPK in T cells. Similarly, AICAR promoted, while Compound C inhibited, phosphorylation of ACC (Ser-79) in Iono-activated CD4+ and CD8+ T cells from WT mice (Figure ​(Figure1E).1E). Using Western blot analysis, we further confirmed that AICAR enhanced, but Compound C inhibited, the phosphorylation of AMPK and ACC in T cells from WT mice, but not from KO mice (Figure ​(Figure1F).1F). Altogether, using CD4-Cre-AMPKα1fl/fl mice, our data clearly indicate a specific AMPK activation/inhibition effect of AICAR/Compound C in T cells. To verify our hypothesis, we used Nrf2 KO mice and WT mice to conduct a comparative study in an L-arginine-induced PALI model with or without AICAR treatment. We found that knockout of Nrf2 limited the ability of AICAR to reduce the severity of PALI in mice (Figures 7A–E).

Cell culture and treatment

  • Pierce protease and phosphatase inhibitor mini tablets (Lot #WD319834, Cat #A32959) were from Thermo Fisher Scientific and utilised for protein extraction.
  • Moreover, the search of the literature reveals the common use of acadesine instead of AICAr [4,6,7,8,9,10,11,12,13,14,15,16,17,18,19].
  • Collectively, our results indicate that the ability of AICAR to disrupt an interaction of a transcription factor with its DNA response element may account for the effect of AICAR on transcriptional activation.
  • The introduction of AICAR against the background of HFD in groups 4, 5, and 6 led to a significant decrease in the number of animals with an increased content of fat cells in the abdominal cavity.

Briefly, tumour samples were digested in 1 mg/ml collagenase/dispase (Roche, Indianapolis, IN). Live single cells account for 90% of the whole population and dead cells account for less than 10%. AICAR represses the MUC1 activity in EGFR-mutant lung cancer, disrupting protein–protein interactions between MUC1-CT and JAK1 and EGFR. Although a peptide blocks MUC1 signalling, metabolites targeting MUC1 are not well studied. Although there was a tendency toward a rise in total crude membrane GLUT4 protein content in RG muscles as a consequence of AICAR treatment, these data did not reach statistical significance.

Still, the present study demonstrates an activation of AMPK in liver as well as in skeletal muscle as a consequence of in vivo AICAR administration, suggesting that this enzyme system is potentially involved in the mechanism of our findings. Although it is most likely that the chemical compound AICAR exerts its effects through activation of the AMPK, it cannot be ruled out that other cellular pathways are influenced by AICAR administration. For instance, a direct inhibitory effect on fructose-1,6-bisphosphatase and thereby suppression of hepatic gluconeogenesis by ZMP (AICAR monophosphate) has previously been proposed (30,42). This result might in part be explained by the improvements in glucose and insulin homeostasis, but a possible inhibition of hepatic synthesis of fatty acids exerted by AMPK (28) is also likely. Further, a recent study has shown that acute in vivo AICAR infusion in awake obese Zucker rats suppresses plasma concentrations of triglycerides and fatty acids and decreases glycerol turnover, suggesting a potential antilipolytic effect as well as a possible reduction in hepatic lipogenesis (31). In addition, AMPK activation is known to acutely increase the rate of muscular (19,20) and hepatic (39) fatty acid oxidation.

Statistical Analysis

Following LPS stimulation, phosphorylation as well as nuclear translocation of the NFκB family member RelA (p65) also remained intact in the presence of AICAR (Fig.2B). AICAR had also no effect towards activation of three major MAPK branches by LPS, since we observed similar phosphorylation of extracellular signal-regulated kinase (ERK), p38 MAPK, and nuclear c-Jun in macrophages stimulated with LPS in the presence or absence of AICAR (Fig. 2A,B). Our aims were to determine whether AICAR-induced changes in metabolic regulators, such as NAMPT, SIRT1, and PGC-1α, and in metabolic components, such as GLUT4 and mitochondrial oxidative enzymes, differed between type I fiber-rich red gastrocnemius and type IIB fiber-rich white gastrocnemius muscles. AICAR (alternatively, acadesine) is a naturally occurring substance that regulates adenosine—a nucleoside that occurs in all cells of the body. It also activates AMP-activated protein kinase (AMPK), a protein that regulates metabolism and energy homeostasis [1, 2]. The effects of activating AMPK are extremely complex since it is involved in so many different metabolic pathways of the body.

The researchers suggest that AMPK activators are potentially useful for the treatment of conditions such as obesity, type 2 diabetes and cancer. Combining different AMPK activators in different clinical contexts might provide optimal treatment. They conclude that more research is needed to determine the precise mechanisms of action of AMPK activators and thereby optimize treatment strategies. Animals were tested in the morning after a 12-h fast and 24 h after the last AICAR injection.

Data Availability Statement

Our data suggest that an interference with NFκB DNA binding explains a unexpectedly potent and broad anti-inflammatory action of AICAR in human macrophages. Our data contrast previous observations in murine macrophages linking inhibition of inflammatory responses by ACIAR to AMPK-dependent activation of the protein deacetylase Sirt121. At the same time we corroborate findings of AMPK-independent anti-inflammatory effects in murine macrophage cell lines23,24. We show that anti-inflammatory effects of AICAR are relevant for the human innate immune system.

Then, pancreatic and liver sections were stained with hematoxylin and eosin (H&E) staining (G1120, Solarbio, Beijing, China) according to the manufacturer’s instructions. There are many circumstances that Testosteron phenylpropionat order online activate AMPK naturally, including hypoxia (low oxygen levels during exercise or at elevation), hypoglycemia (low blood sugar with exercise or fasting), the use of cellular energy during muscle contraction, and anything that disrupts energy creation within cells. For example, it increases the usage of fat for energy and causes cells to make more mitochondria (the cells’ powerhouses or energy creators). AICAR (5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside) is a substance produced naturally by the body that stimulates AMP activated protein kinase (AMPK), a protein that regulates metabolism in a variety of ways.