AICAR ameliorates high-fat diet-associated pathophysiology in mouse and ex vivo models, independent of adiponectin

The experimental results showed that AICAR suppressed growth of 22Rv1 cells in soft agar in a dose-dependent manner (Figure 2). The cell cycle analyses of AICAr-arrested cells in some studies revealed an increase in the proportion of cells in the G0/G1 phase, as would be expected from the mechanism of cell cycle arrest in response to AMPK activation and mTORC1 inhibition 23. However, in embryonic stem cells, AICAr increased the cell population at both G1 and non-cycling S phases 85. Furthermore, an arrest in the S phase has been observed in MEFs 86, cancer cell lines 94, and leukemia cells 95. To understand the mechanism responsible for proliferation arrest in response to AICAr, we have to go back to the role of endogenous AICAR in de novo purine synthesis that has been well-known to affect cell growth much before the discovery of the role of AICAr in AMPK activation. As a cell-permeable nucleotide, AICAr enters the cells through adenosine transporters 20 and becomes phosphorylated by adenosine kinase into AICAR 21.

• Following incubation for 5 days, non-invading cells were carefully removed with a cotton swab.
• We then administered the same lose dose of AICAR to established DIO mice that had been fed a HF diet for 24 weeks and exhibited insulin resistance.
• Here’s what athletes should know about AICAR and other prohibited AMP activated protein kinase activators.
• Additional analysis was performed by using the freeware program BULLFROG 7 (Zapala et al., 2002) and the Java-based statistical tool VAMPIRE (Hsiao et al, 2004).
• Whereas induction of STAT3-dependent SOCS3 mRNA by IL-6 or IL-10 was inhibited by AICAR in the presence of ABT-702 (Fig. 4A), IL-4-induced expression of the typical STAT6-dependent target gene CCL18 was unaltered (Fig. 4B).

Future Directions in AICAR Research

As a result, MSKO mice on high fat (HF) diets exhibited impaired insulin signaling in skeletal muscle, fat, and liver (Fig. S7), and developed systemic insulin resistance in glucose tolerance tests, insulin tolerance tests, and hyperinsulinemic-euglycemic clamp experiments (Fig. S8). Exercise training activates a number of transcriptional regulators as well as serine/threonine kinases in skeletal muscles that contribute to metabolic re-programming (Bassel-Duby and Olson, 2006). We and others previously identified a critical role for PPARβ/δ (henceforth referred to as PPARδ) in transcriptional regulation of skeletal muscle metabolism (Dressel et al., 2003; Luquet et al., 2003; Schuler et al., 2006; Wang et al., 2004). Over-expression of a constitutively active PPARδ (VP16-PPARδ) in skeletal muscles of transgenic mice pre-programs an increase in oxidative muscle fibers, enhancing running endurance by nearly 100% in untrained adult mice (Wang et al., 2004). One of the best understood serine/threonine kinases is AMP-activated protein kinase (AMPK), a master regulator of cellular and organismal metabolism whose function is conserved in all eukaryotes (Hardie, 2007).

A total of 100 μL Caspase-Glo® 3/7 reagent was added to each well, gently mixed contents of wells using a plate shaker at 300~500 rpm for 30 s, and then samples were incubated for 30 min at RT. Enzyme activity is directly proportional to luminescence, which was measured using a luminescence microplate reader (BioTek Instruments, Inc.). Data were normalized relative to the caspase 3/7 activity of cells treated with DMSO alone. A great deal of AICAR research has revolved around the ability of the peptide to improve sperm motility; energy metabolism, and fertilizing ability.

These results indicate that pharmacologic activation of the PPARδ genetic program in adult C57Bl/6J mice is insufficient to promote a measurable enhancement of treadmill endurance. AMPK and SIRT1 share striking similarities in nutrient sensing and regulation of energy metabolism. Recent studies have disclosed a crosstalk between these two in regulation of metabolic pathways. For instance, AMPK can be an upstream signal to increase SIRT1 activity via inducing fatty acid oxidation and increasing the agonist NAD+ levels, leading to the deacetylation and activation of PGC-1α in muscle 35.

10. Statistical Analysis

Daily for 5 weeks, whereas mice on the chow diet received only saline, because we have shown that low dose of AICAR had no effects on glucose homeostasis and insulin sensitivity in lean mice (Fig. S1). As expected, AICAR treatment did not change body weight and fat pad mass in HF-fed mice over 5 weeks (Fig. S2). We previously showed that α1AMPK is abundantly expressed in fat tissue, while the expression of α2AMPK is low in fat tissue 11. Consistent with our previous findings where the AMPK signaling pathway was down-regulated by HF diet, we found here that α1AMPK activity was also decreased in epididymal fat of DIO mice compared to that of LF chow diet fed mice (Fig. S3).

In short, AMPK ensures that the various tissues of the body do not exhaust their supply of energy 2, 3. Although AICAR did not influence nuclear RelA accumulation in response to LPS, it blocked RelA binding to cognate DNA elements of LPS-induced genes as proven by ChIP assays. This may be sufficient to prevent transcriptional activation, since NFκB activation is a critical event during LPS transcriptional responses for most of its target genes25. The major outcome of cytosolic LPS-triggered signalling, nuclear translocation of transcriptional LPS effector RelA, remained intact in AICAR-treated cells as well.

Upon intracerebral infusion memory function and long-term potentiation in hippocampal slices are reduced 67. In addition, AICAR does not improve spatial memory in mice selectively lacking functional AMPK in muscle, suggesting an indirect mechanism of action and a link between muscle and brain 22. Overexpression of PGC-1α in muscle also has been reported to lead to increased production of Fibronectin type https://www.allsocks.com.ng/understanding-trenbolone-an-overview-of-its-uses/ III domain containing 5 (FNDC5), a myokine that is released during exercise 69. Enzymatic cleavage of FNDC5 generates a peptide called irisin, which may enter the brain and induce hippocampal BDNF gene expression 70.

Pharmacological or transgenic activation of these transcription factors in muscle can mimic effects of exercise on endurance 20, cognition, adult neurogenesis 21, 22, and mood 23. Conversely, lack of functional AMPK in skeletal muscle precludes spatial memory improvement 22. As shown in Table 1, the majority of the effects of AICAr on skeletal muscles are AMPK-dependent. AICAr-induced glucose uptake in skeletal muscle was abolished in the knockout of the α 2 32,33,35 and α 3 isoforms of AMPK 34. Both AICAr and treadmill exercise increased insulin sensitivity to stimulate glucose uptake, and these effects were not observed in mice with reduced or ablated AMPK activity in skeletal muscle 68,69. However, the mechanisms of exercise- and AICAr-mediated glucose transport diverge at some point downstream of AMPK since AICAr-induced effects were absent in muscle-specific knockout of atypical PKC, and atypical PKC was not required in treadmill exercise 70.