I have been reading alot lately on uncouplers and there effects. First I should say I have never used DNP so I cant comment on that.
First before I get in to my ideas let me give a little explanation of my understaing (possibly flawed understanding) of cellular energy balance so that you can see where I am coming from.
fats can be oxidized for energy in one of two ways. in the mitochonria or in peroxisomes. in fact the peroxisomes are better at it than the mitochondria. the mitochondria can only oxidize short chain fats where as the peroxisome can oxidise all types. Under normal conditions CPT is the rate limiting substance in fat oxidation. CPT-I transports the acyl-fat in to the mitochondria and CPT frees it inside so that it can be oxidized. so normally it would be advantageous to optimize CPT. CPT is primarly deactivated by malynol-CoA(the bad kind). this compund is created by ACC working on acytal-CoA(the good kind). ACC is deactivated by AMPK(AMP mediated protein kinase) as well as glucogon. Its activated by citrate build up and insulin. as AMPKs name sugest its controlled by AMP. more specifically the AMP/ATP ratio, which signals the energy balance of the cell.
so in say normal resting conditions if energy levels become low then AMPK goes in to action and deactivates ACC allowing CPT to do its thing and create about 140 ATP mulecules.
next scenario is exercise. when we exercise we inhibit CPT in two ways. first we get low ATP so AMPK goes to work but there is a problem. first glucose is being burned creating citrate build up so that gets ACC going, so AMPKs job is harder. second even if AMPK deactivates ACC, CPT is deactivated by the pH change in the cell so its kind of moot anyway. This is the reason low intensity exercise burns a higher % of fat than high intensity exercise. (Note I did not say low intensity was a better from just that cal for cal it burns more fat; high intensity has all sorts of other benifits like NE release 3 hours post exercise). oh and ACC is the compund hydroxycitric acid is supposed to block.
now on to uncouplers. sorry for all of that but its kind of necesary as uncouplers kind of create a strange environment thats sort of like exrecise and again sort of not. So uncouplers halt ATP production in mitochondria creating an artificail ATP shortage which is what activates AMPK. good news there. it also sets forth a cascade of reactions that prevents glucose metabolism to a certain extent so citrates are not built up. Another plus. Problem being with the mitochondria not working well this increase in CPT is not going to do much. it most certainly optimizes everything for when the mitochondria are working but what percentage of time that is when someone is tacking an uncoupler is unknown to me (anyone know?).
so to get our ATP the cell will resort to using the peroxisomes more. peroxisomes are another organelle in the cellular matrix
. they are very important for fat oxidation. they can do alpha,beta, and omega oxidation where as the mitochondria mostly do beta but can do alpha if required. peroxisomal pathway is very different than mitochondrial one. first it does not involve any of the above compunds. accept for acyl-CoA so that becomes very important. peroxisomal oxidation can also acept free fatty acids as a base molecule they don't need to be cleaved like they are for mitochondrial oxidation. peroxisomes help make cholesterol for steroid formation and also make some very special fats that are needed by the brain for nerve insulation (its a component of mylin).
this is where PPAR receptors come in. these are nuclear receptors (ie. they re in the nucleus not on the membrane or in the cytosol). there are good and bad ones. the one I am most concerned about here is PPARalpha. PPAR and PXR receptors are also known as peroxisome proliferators. as the name sugests they cause they cell to make more peroxisomes. Just like exercise causes more mitohondria to be created (as well as larger mitochondria, thats an interesting topic in and of itself as 3-thia fatty acids create mega-mitochindria that are super big, several fold larger than normal). Anyway, so PPAR is the first area of importance. now for the stack.
PPARalpha ligands: this would include fibrate drugs. sesamin
if one could buy it (see my previous post on sesamin
and episesamin). fish oils, as EPA is a ligand for PPARalpha.
Next up is a strange concoction i know but there are reasons. first is pantothenic acid
. pantothenates are requied for CoA formation. Next is carnitine and lastly NAC
(n-actyal-cystine). first being that uncoupler use can deplete CoA pool and thus it could be rate limiting as its needed for transport in to the perosisomes. so thats where pantothenic acid
comes in. people tolerate very large doses of this so I dont see why a large dose is not warented; plus its cheap. next up being the carnitine the expensize ingredient. and we might need lost of it i dont know for sure. before everyone jumps all over me for this one let me explain. I know carnitine is not rate limiting for fat oxidation. lots of studies confirm this. the problem being the carnitine pool. because ACC is going to be out of comision CPT production will go through the roof and the carnitine pool will become acytylated. thats no good! we need base carnitine as it interfeeres with pantothenate kinase which can be a rate limiting step in CoA formation. finally NAC
. NAC is included for a couple of reasons. one it is one of the few antioxidants that operate inside the mitochondria so it might help there. Additionally, in one study they induced peroxisomal disorder with valpuric acid in rats and a single shot of the above combo aliviated the problem.
So there you hve it. outside of the normal stuff I think it would be wise to stack these compunds with an uncoupler. another one might be pyruvate. I say this as some people who take DNP recomend it and it does effect the carnitine pool and might spare some carnitine. But I could not find any direct studies on it so I left it out.
As far as diet goes I would stick with a chaloric deficiet and keep the carbs low and keep insulin low.
So what do you guys think? any problems in my reasoning?
There are a couple areas where this could be imporoved. first peroxisomes as there name sugests produce alot of H2O2 (hydrogen peroxide) so if someone knows a way to buffer this it also might be a good idea I just dont know how the cell handles HO2, yet.
oh and just one more interesting tid bit. in my reading I found a couple of other uncouplers that are kind of interesting. The first being asprin. I did not know that was an uncoupler. The other being cashew nut oil. aspardic acid in cashew nut oil to be specific. this ones kind of interesting as its a quick acting uncoupler. Its very strong but is deactivated quickly by the body. a fast acting uncoupler might have some uses I dont really know though.