AMPK: Potential Therapeutic Target for Alzheimer’s Disease Bentham Science

PGC-1α is not only a major stimulator of mitochondrial biogenesis but also promotes type II to type I fiber type conversion (Lee et al., 2006), along with other factors such as calcineurin (Naya et al., 2000). Our data and these lines of evidence further support the notion that AMPK and PGC-1α are centrally important regulators of metabolic and contractile performance of mammalian skeletal muscle. However, the finding that AICAR treatment increases mitochondrial biogenesis, but may not necessarily change fiber type suggests that these processes may commonly occur in tandem but not be regulated by the same physiological stimuli. AMPK plays a critical role in mediating AICAR-induced increases in mitochondrial protein abundance (Jùrgensen et al., 2007).

Importantly, AMPK directly phosphorylates PGC-1α (Jäger et al., 2007) which may result in SIRT1-mediated deacetylation and activation of PGC-1α (Cantó et al., 2009) and thus link cellular energy status, mitochondrial biogenesis, and ROS handling. Much like in adipose tissue, the presence of 5-amino-1MQ in muscle promotes the production of the GLUT4 receptor and boosts the inefficiency of metabolism leading to increased energy burn. Recent research in mice, however, suggests that inhibiting NNMT in any way, including with 5-amino-1MQ, may actually boost muscle repair by stimulating stem cells. More recent evidence suggests that the benefit of 5-amino-1MQ may extend beyond its ability to downregulate NNMT and thus increase inefficient metabolism and GLUT4 expression.

AMPK activities and ZMP concentration in tissues.

Researchers and clinicians are increasingly turning to this peptide to help prevent or battle the effects of diabetes, auto-immune disorders, and other inflammatory conditions. Yet, such high doses have shown an increased risk of kidney toxicity, which has led to discontinuation of the therapy in some subjects, despite the beneficial effects of the peptide on certain hematological parameters. Researchers are actively exploring the potential benefits of AICAR administration, including fat burning, inflammation reduction, and endurance optimization. AICAR is currently being examined as a therapeutic agent in a range of contexts, including diabetes, alcohol-induced fatty liver, and kidney cancer [4, 5, 6].

  • It remains to be seen whether 5-amino-1MQ, by reducing NNMT function, will have any effect on the various cancers mentioned.
  • As a proof-of-principle for translating our rodent data to human pathophysiology, we investigated whether AICAR could reduce inflammation and manipulate leucocyte phenotypes in omental WAT explants taken from obese patients undergoing gastric bypass surgery.
  • Plasmids containing a 733-bp fragment localized entirely within intron 1 of the rat Npy gene were used to generate probes for Npy heteronuclear RNA (hnRNA), a sensitive indicator of gene transcription (27).
  • Some peptides target insulin resistance and blood sugar levels, others directly target adipose tissue and the inflammation it causes, and still others target growth hormone deficiency.
  • To the extent that references a product that is also a prescription medication, does not does not offer medical diagnosis or treatment advice.
  • This decrease in effect of a therapeutic over time is referred to as tachyphylaxis and may, in some cases, necessitate a drug holiday to help restore effects.

Improvements in insulin sensitivity, lipid metabolism, energy balance, and inflammatory symptoms have also been shown in scientific studies using AICAR. According to research, AICAR is a small peptide that significantly functions in energy balance and metabolic pathways. Additionally, it improves insulin-related muscle cell activity by controlling insulin receptors, as per scientific studies. Similarly to AMP, the peptide 5-aminoimidazole-4-carboxamide-1—D-ribofuranoside (AICAR) is also known as ZMP.

What Is AICAR?

Fifteen hours later, epididymal fat pads from each group were extracted, and adipocytes were isolated for analysis of palmitate oxidation (3) or protein expression by Western blotting. For in vivo glucose and NEFA determination, animals were injected with either saline or AICAR, and blood samples from the saphenous vein were collected at various time points. An 8 h time course was chosen for in vivo studies to avoid the effects of circadian rhythm on lipolytic rate (21). Glucose concentration was determined by the glucose oxidase method using a commercially available kit from Sigma. What makes 5-Amino-1MQ one of the best peptides for energy is that it increases the production of another compound called NNMT.

  • Importantly, in this study, we now also demonstrate that AICAR-mediated protection against kidney disease is independent of adiponectin.
  • The levels of p-AMPK as well as p-ACC were significantly increased with the incubation of 10−8m DEX for 3–24 h in hypothalamic organotypic cultures (Fig. 3, A and B).
  • The current thinking is that AICAR or a similar molecule could slow cancer cell metabolism and make those cells more susceptible to environmental insults and thus less resistant to standard chemotherapy5.
  • The oxidation of HE in a superoxide generating system was performed by spectrofluorimetry, essentially according to the method described by Zhao, et al [23] with slight modifications.

Quantitative proteomic analyses revealed 57 proteins significantly less abundant on nuclei-enriched fractions from AICAR-fed cells, this effect being compensated by overexpression of KAP123 for 15 of them. After 3 weeks, a decline was already indicated (data not shown), but the decline in blood pressure level was clearly more evident after 6 weeks of AICAR administration. Accordingly, insulin levels were also decreased early during AICAR exposure (i.e., after 2–4 weeks; data not shown) and further diminished after 7 weeks.

Rev-erb-α modulates skeletal muscle oxidative capacity by regulating mitochondrial biogenesis and autophagy

The development of exercise science and molecular techniques has increased our understanding of the molecular pathways responsive to exercise. Knowledge of these molecular targets has led to the development of chemical interventions that can mimic the beneficial effects of exercise without requiring actual muscle activity. This review focuses on the concept of ‘exercise pills’ and how they mimic the effects produced by physical exercise including oxidative fiber-type transformation, mitochondrial biogenesis, increased fat oxidation, angiogenesis, and improvement of exercise capacity. We also review candidate exercise pills, and contrast the beneficial effects and molecular mechanisms between physical exercise and exercise pills. As a central metabolic regulator that reacts to an increase in AMP/ATP ratio, AMPK restricts growth and proliferation in response to energetic or nutritional stress.

MOTS-c works at the level of mitochondria to help these energy factories of the body make better use of raw materials. Research in rats shows that MOTS-c increases exercise capacity and reduces metabolic stress[22]. Cardarine increase energy expenditure by increasing the amount of energy available to cells. Research in mice shows that Cardarine increases exercise capacity, allowing mice to run a full 100 minutes longer with Cardarine than without[16]. Unfortunately, the declines in GH as well as the inflammation caused by fat deposition that both come with obesity tend to make motivation difficult to muster.

Authors’ original file for figure 9

Like AMPK, SIRT1 also regulates inflammatory signaling in various cells [11], [16], [17]. Recent studies directly linked SIRT1’s anti-inflammatory effects in adipocytes and macrophages to improved insulin sensitivity [18], [19], [20]. We have recently shown that α1AMPK activation mimics the effect of SIRT1 on deacetylation of NF-κB, and the full capacity of AMPK to deacetylate NF-κB and inhibit its signaling requires SIRT1 [11]. These observations raise another interesting question as to whether macrophage SIRT1 is required for the protective effects of AICAR against obesity-induced inflammation and insulin resistance. Sedentary lifestyles, limited physical exercise, and prolonged inactivity undoubtedly increase chronic diseases, including obesity, type 2 diabetes, and cardiovascular diseases. It is widely acknowledged that exercise induces a number of physiological adaptations that have beneficial effects in the prevention and treatment of these chronic metabolic diseases.

Gene expression from the c-erbA Rev-ErbA genomic locus

The serum-free medium was composed of 75% Earle’s MEM, 25% HBSS, 25 U/ml penicillin/streptomycin (Invitrogen), 1 mml-glutamine, and 5.5 mm glucose. Cultures were maintained in the standard medium for 15 d until the slices became thin enough to perform in situ hybridization, and the medium was changed to a defined serum-free medium for an additional 2 d before subjecting slices to different experimental conditions. The standard medium was changed three times a week, and the serum-free medium was changed every 24 h. An interesting question is why cyclo-CRVLIR was not identified as a hit from the primary screening process, and there are a number of viable explanations. In the SICLOPPS system, it is possible that some of the expressed cyclic peptides may be toxic to the bacterial cells and affect their growth.