Team:BGU Israel/Project/Artificial Exercise

In order to cope with the large accumulation of fat in the liver, we looked for a remedy that will enable the body to reach high energy expenditure, thus leading to high rate of fat degradation. In our search, we learnt about the use of DNP (2,4 – dinitrophenol) as a dieting aid, in early 1930.

DNP increases the permeability of the inner mitochondrial membrane to protons, allowing them to move from the inner membrane space to the mitochondrial matrix, bypassing ATP synthase. This process weakens the coupling of the electron transport chain to the production of ATP. In an attempt to raise the pH gradient, which is negatively affected by DNP, a fast oxidation of substrates occurs while the synthesis rate of ATP stays low and oxidation energy is released as heat instead. While DNP was very effective for losing weight, it has a dangerous side effect - the heat released during the uncoupling process can cause fatal hyperthermia. The use of DNP caused numerous amounts of deaths from fever symptoms, and eventually the production of the drug was prohibited but it is still illegally used with a death toll every year.

Our goal in this project was to design a treatment that has the advantages of DNP as uncoupling factor, but with an ability to control the dangerous overheating. As DNP is a chemical molecule and as such it is very difficult to control its effect once it is in the body, we looked for a protein (which is easier to produce and control from within) that works in a similar way to that of DNP, and so we found UCP1.

Uncoupling protein 1 (UCP1) is normally found in the mitochondria of brown adipose tissue, and is used to generate heat. Its mechanism of action is very similar to that of DNP – it also works by uncoupling (as its name might suggest) the two processes needed to create ATP, but since UCP1 is a protein and not a chemical compound we had the ability to control its function and expression to our benefit. If we could make this process occur directly in the liver, where UCP1 is not naturally present, it could prove to be very useful for the fast degradation of unnecessary fat. The similarity between UCP1 and DNP also means that the end result of overheating will happen in both cases. So how could we prevent it from happening?

As depicted in figure 1, the heat produced due to the activity of UCP1 will cause temperature to rise, activating HSP70 and inducing the synthesis of a repressor. This repressor will inhibit the synthesis of UCP1, and is its concentration in the mitochondrial membrane will be decreased due to natural protein degradation, As a result, the temperature will go down and the process could start again without reaching an endangering temperature.

Click on the picture to check out the machanism