Mice given injections containing a peptide that molecular scientists call Compound 14 lose fat, and possibly also gain more endurance capacity. Researchers at the University of Southampton in England write about this in Chemistry & Biology. Compound 14 works by boosting the concentration of Aicar, a substance chemical cyclists are familiar with.
In-vitro study
The full name of Aicar [structural formula on the right] is 5-aminoimidazole-4-carboxamide ribonucleotide, but scientists also call it ZMP. Through animal studies researchers discovered that Aicar in combination with PPAR-delta agonists dramatically boosts endurance capacity and calorie burning, and after that Aicar was picked up as a doping substance and entered the market.
Aicar activates the energy sensor AMPK, and makes cells think that they’re not getting much energy. As a reaction the cells activate enzymes that generate energy, but also enzymes like heme oxygenase, which protects against aggressive molecules. Doctors are studying whether administering Aicar during heart operations can reduce the chance of damage to the heart muscle.
Doping hunters got wind of cyclists using Aicar in 2009 and in 2011 the WADA put it on its list. So far there are reliable doping tests for Aicar: it’s difficult to develop a test because the body makes Aicar itself. One of the functions of the substance is that it is an intermediary product in the biosynthesis of purine [structural formula shown above]. Purine is a building block of nucleic acids, of which DNA is made.
The enzyme ATIC – in full aminoimidazole carboxamide ribonucleotide transformylase – plays a key role in the conversion of Aicar into purine. In 2012 researchers at the University of Southampton reported that they had discovered a small molecule that deactivates ATIC. [Chembiochem. 2012 Jul 23;13(11):1628-34.] When this happens the concentration of Aicar increases. The researchers called the molecule Compound 14. The structural formula is shown above.
In their new study, which was published recently in Chemistry & Biology, The researchers exposed cells to Aicar, Compound 14 and the glucose blocker 2-DG. The figure below shows that the cells started to use more oxygen, but emitted less lactic acid. So the cells started to use more energy and probably burned more fats too.
Animal study
The researchers gave the mice daily injections in their gut containing 50 mg Compound 14 per kg bodyweight. The human equivalent of this dose is about 300-500 mg. Other mice were given injections containing no active ingredients.
The researchers had given some of the mice a standard diet [Chow], so their weight was normal. Others had been fattened on a high-fat diet [High-Fat]. The figure below shows that Compound 14 caused weight loss in both groups.
The animals’ insulin level went down and their insulin sensitivity increased.
Conclusion
“Our current results suggest that there is much potential for Compound 14 as a treatment for diabetes as, unlike current antidiabetic drugs, this compound could improve glucose handling as well as reduce the body weight of obese diabetic patients”, the researchers wrote.
