Bioactive products against obesity: inhibitors of insulin signaling
Metabolic Syndrome Group
Insulin signaling is essential in the control of blood glucose. Obese people are prone to develop abnormalities in this pathway, giving rise to insulin resistance and, ultimately, diabetes1 . The study of insulin signaling pathway is, therefore, of special interest for our groups. Besides, some recent studies show that moderate inhibition of the main kinase in charge of transmitting insulin signals (the so-called PI3K) have surprising beneficial effects in obesity development2,3.
Thus, finding new bioactive products which moderately inhibit PI3K or its pathway constitute a very attractive goal. Our group has set up at IMDEA Food a screening platform already used before for monitoring insulin pathway activity4 , insulin binding triggers PI3K activation and a chain of reactions ending in the exclusion of the transcription factor FOXO from the nucleus. We have generated a cell line expressing FOXO fused with a green fluorescent protein called GFP. This way, we can monitor FOXO subcellular localization by confocal microscopy in 384 well plates, so that compunds inhibiting the insulin pathway will present more FOXO-GFP in their nucleus.
At present, there is a compound with PI3K inhibitory activity approved for its use on humans: miltefosine, used for the treatment of leishmaniosis due to its ability to affect the binding of the parasite to the plasma membrane of its target cells5 . Besides, ellagic acid, enriched in the pomegranate and some other red fruits, has also been described before as a PI3K inhibitor6 .
These compounds serve as controls for our first tests of the insulin platform, and both are good candidates for anti-obesity agents on humans, since thay are already approved for other uses. With our system, we have been able to check that, in effect, miltefosine and ellagic acid induce nuclear translocation of FOXO-GFP that is: they inhibit insulin signaling. At present, we are validating these effects using different cellular approaches, and designing diets enriched in these compounds to treat obese mice and check their anti-obesity effects.