- 12-09-2005, 04:06 PM
Hepatothermic therapy of obesity: rationale and an inventory of resources.
Pantox Laboratories, San Diego, California 92109, USA.
Hepatothermic therapy (HT) of obesity is rooted in the observation that the liver has substantial capacities for both fatty acid oxidation and for thermogenesis. When hepatic fatty acid oxidation is optimized, the newly available free energy may be able to drive hepatic thermogenesis, such that respiratory quotient declines while basal metabolic rate increases, a circumstance evidently favorable for fat loss. Effective implementation of HT may require activation of carnitine palmitoyl transferase-1 (rate-limiting for fatty acid beta-oxidation), an increase in mitochondrial oxaloacetate production (required for optimal Krebs cycle activity), and up-regulation of hepatic thermogenic pathways. The possible utility of various natural agents and drugs for achieving these objectives is discussed. Potential components of HT regimens include EPA-rich fish oil, sesamin, hydroxycitrate, pantethine, L-carnitine, pyruvate, aspartate, chromium, coenzyme Q10, green tea polyphenols, conjugated linoleic acids, DHEA derivatives, cilostazol, diazoxide, and fibrate drugs. Aerobic exercise training and very-low-fat, low-glycemic-index, high-protein or vegan food choices may help to establish the hormonal environment conducive to effective HT. High-dose biotin and/or metformin may help to prevent an excessive increase in hepatic glucose output. Since many of the agents contemplated as components of HT regimens are nutritional or food-derived compounds likely to be health protective, HT is envisioned as an on-going lifestyle rather than as a temporary 'quick fix'. Initial clinical efforts to evaluate the potential of HT are now in progress. Copyright 2001 Harcourt Publishers Ltd.
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.
High mitochondrial redox potential may promote induction and activation of UCP2 in hepatocytes during hepatothermic therapy.
NutriGuard Research, 1051 Hermes Avenue, Encinitas, CA 92024, USA. firstname.lastname@example.org
Although uncoupling protein-1 is a key mediator of thermogenesis in activated brown fat, the more recently characterized uncoupling proteins-2 and -3 do not appear to influence basal metabolism, but rather may function to diminish excessive mitochondrial superoxide production when mitochondrial redox potential is high. Under these circumstances, superoxide within the mitochondrial matrix directly activates uncoupling protein-2 (UCP2), and may also promote induction of this protein. Normal healthy hepatocytes do not express UCP2, but this protein is induced in hepatocytes that are steatotic or that are treated with agents that boost superoxide production. It is proposed that induction and activation of UCP2 may play a role in the thermogenesis evoked by hepatothermic therapy, a strategy designed to decrease body fat by maximizing hepatic fatty acid oxidation. Under these conditions, high mitochondrial redox potential would be expected, and induction of UCP2's uncoupling activity would represent a homeostatically appropriate antioxidant response.
Seems like very interesting diet strategy, im doing alot of research on the subject before i try it. some supplemental agent i may use:
diet suggest using drugs like metaformin, and glucose disposale drugs.
Im just wondering what do you guys think of such diet?!
- 12-09-2005, 04:08 PM
The rationale of hepatothermic therapy (HT) is to optimize your liver’s capacity for partial or total fat burning (ketogenesis and fatty acid oxidation) and for thermogenic (heat-releasing) mechanisms fueled selectively by this fat burning. Thus, HT is a strategy for enabling the liver to efficiently convert body fat to ketone bodies, carbon dioxide, and heat. This is achieved both with special natural supplements which help to unlock the liver’s substantial fat burning capacity, as well as lifestyle measures - exercise and appropriate food choices - that establish the proper hormonal environment (less insulin, more glucagon) for hepatic fat burning. For best results, HT must incorporate the following three strategies:
1. Morning Aerobic Exercise
The morning is the best time of day for fat burning, because your body has begun to adapt to fat burning during your overnight fast.
Don’t eat breakfast before your workout, but drink two cups of strong coffee (if you aren’t caffeine intolerant) - this will help mobilize stored fat. If you eat before working out, you will do a great job of burning the carbohydrate you just ingested - rather than stored fat!
Do a moderate intensity workout (50-60% VO2max) in which you support your own weight (i.e. brisk walking, jog-walking, stair-climbing, elliptical gliders); if knee problems make this difficult, use a stationary bike. If you are exercising at the right moderate intensity, you should be able to carry on a normal conversation at the same time; high intensity exercise burns primarily stored carbohydrate rather than fat.
After you’ve had a chance to improve your muscle tone and cardiovascular fitness, gradually increase the length of your exercise to at least 40 minutes per session.
Work out at least five times weekly. (Once you reach your target weight, you may be able to reduce your exercise frequency a bit, but don’t exercise less than three times a week.)
Prolonged moderate-intensity exercise suppresses insulin, boosts glucagon, mobilizes fat, and thus is ideal for fat burning; increased capacity for fat burning will persist for several hours after exercise if you don’t raise insulin by ingesting carbohydrate
After morning exercise, you can prolong the accelerated fat burning by either not eating breakfast (you probably won’t be hungry) or by eating a low-carb protein snack as breakfast
If morning exercise is simply unfeasible, exercise on an empty stomach at some other time of the day - HT regimens with noontime or after-work exercise have worked well for many people, provided that they don’t eat for at least 2 hours prior to the exercise.
The people who get the best results with HT are usually those who do the most exercise! Exercise is crucial to the success of HT.
2. Proper Food Choices: Very Low Fat/Low Glycemic Index
Food choices in HT are intended to keep daily insulin secretion relatively low and support glucagon production (thus aiding fat burning),while minimizing fat intake.
Avoid fatty foods - fat should be no more than 15% of daily calories. No fatty meats, dairy products, or egg yolks. Minimize the use of oils in cooking, scan the labels of convenience foods for fat content, and be very sparing in your consumption of avocados and olives.
A moderate daily intake of nuts or nut butters (no more than one ounce daily) is permissible, in light of evidence that these foods are markedly protective for vascular health. (Avoid nut butters that have added hydrogenated oils.)
A very-low-fat diet, especially if accompanied by regular exercise, tends to decrease your daily insulin production by improving your body’s sensitivity to insulin - and of course also puts less new fat in your fat cells.
The starchy foods in your regular diet should have a relatively low glycemic index (that is, they should increase blood sugar gradually and moderately, to avoid excessive insulin secretion)
Pasta, rice (preferably brown parboiled), beans, corn (whole corn or popcorn), bulgur wheat, barley, “old-fashioned” (not instant) oatmeal, and whole fruit are recommendable. Avoid wheat flour products (excepting pasta, sourdough and whole-wheat pita bread), baked potatoes, and sugar-loaded soft drinks (diet sodas are okay); these foods trigger vigorous insulin secretion.
Beans - particularly home-cooked beans - have an especially low glycemic index and are great for weight control.
Eat foods in a physically intact natural form when feasible - the glycemic index of whole-kernel grains is lower than that of flours.
A table of glycemic indices - such as you can find in the popular book The Glucose Revolution - can help you choose appropriate starchy foods.
Vegetables, vegetable juices, and whole fruit are strongly recommended - they are great for your long-term health as well as for weight control. Whole fruit is the best dessert or snack. These foods are rich in potassium, crucial for the health of your vasculature and bones.
With respect to protein intake, it probably isn’t crucial to regulate this aspect of your diet. However, certain strategies in this regard can help you to minimize your daily insulin secretion and/or better control your appetite. (See Protein Options for Leanness.)
Vinegar can lower the glycemic index of a meal. Use vinegar as a salad dressing; you can also add a tablespoon of vinegar to fruit juices consumed with meals.
Alcoholic beverages, in moderation (1 or 2 drinks in the evening), are permissible, and indeed may benefit your health if you can drink responsibly. However, alcohol in excess will bring fat burning to a halt. Women who drink moderately are less likely to gain weight than
Eat enough to satisfy your hunger - no calorie counting! Eat enough carbohydrate with your evening meal so that subsequent morning exercise will be comfortable. But use your common sense and your self-restraint - gluttony will sabotage any weight-loss program!
3. HT Supplementation
HT supplementation is crucial for optimal results, and requires hydroxycitrate (HCA), carnitine, and precursors of the crucial metabolite oxaloacetate (i.e. pyruvate, aspartate) -
These supplements help to unlock the liver’s thermogenic and fat-burning
The volume of supplementation required with HT is high. If
Take supplements prior to morning exercise and before bedtime. Optionally, for the most rapid benefit, you can take a third dose either in mid-afternoon or, if you decide to skip breakfast, in mid-morning.
If you exercise at some other time of day, take the “mid-afternoon” dose of the supplements prior to the exercise session.
Since hydroxycitrate is not efficiently absorbed, many people initially experience loose stools when using these supplements; you can reduce your dose temporarily if this becomes a significant problem.
Optional supplementation: Certain supplements taken with meals may also aid HT. In particular, fish oil enriched in the essential fatty acid EPA should further boost your liver’s fat burning capacity.
Remember that HT supplementation won’t work well to achieve fat loss without the exercise training and proper dietary choices, which are needed to promote the proper hormonal environment for fat burning.
Note that HT supplementation does not involve drugs or even herbs - just nutrients, natural metabolites and food factors, all of which appear to be health-protective.
HT supplementation is not recommended for pregnant women, who should not attempt to lose weight except as instructed by their doctors.
Fat Loss vs.Weight Loss: Note that in the first few weeks of HT, lean mass tends to increase while body fat decreases. That means that body fat will decrease faster than body weight, and your initial rate of weight loss may not be impressive. After a month or more of HT, lean mass begins to decline as well, and weight loss tends to catch up with fat loss. So don’t obsess about your scale weight when beginning HT. To evaluate your progress on HT, it is best to have your body composition assessed periodically (by a personal trainer or physician) so that you can quantify your fat loss.
A caution to diabetics: When using HT, monitor your blood sugar control as instructed by your doctor, and modify your medication usage as needed, with your doctor’s assistance.
That’s all there is to it! No drugs, no semi-starvation, no calorie-counting. Nothing but exercise, health-protective food choices, and safe, natural supplements. Remember:
- 12-09-2005, 04:15 PM
Pyruvate and hydroxycitrate/carnitine may synergize to promote reverse electron transport in hepatocyte mitochondria, effectively 'uncoupling' the oxidation of fatty acids.
McCarty MF, Gustin JC.
NutriGuard Research, Encinitas, CA 92024, USA.
In a recent pilot study, joint administration of pyruvate, hydroxycitrate (HCA), and carnitine to obese subjects was associated with a remarkable rate of body-fat loss and thermogenesis, strongly suggestive of uncoupled fatty-acid oxidation. Hepatocytes possess an uncoupling mechanism--reverse electron transport--that enables fasting ketogenesis to proceed independent of respiratory control. Electrons entering the respiratory chain at the coenzyme Q (CoQ) level via FAD-dependent acyl coA dehydrogenase, can be driven 'up' the chain by the electrochemical proton gradient to reduce NAD+; if these electrons are then shuttled to the cytoplasm, returning to the respiratory chain at the CoQ level, the net result is heat generation at the expense of the proton gradient, enabling the uncoupled flow of electrons to oxygen. Pyruvate's bariatric utility may stem from its ability to catalyze the rapid transport of high-energy electrons from mitochondria to the cytoplasm, thus stimulating electron shuttle mechanisms. By enabling rapid mitochondrial uptake of fatty acids and thus disinhibiting hepatocyte ketogenesis, HCA/carnitine should initiate reverse electron transport: concurrent amplification of electron shuttle mechanisms by pyruvate can be expected to accelerate this reverse electron transport, thereby decreasing the electrochemical proton gradient. As a result, hepatocytes may be able to convert fatty acids to CO2 and heat with little net generation of ATP. These considerations suggest that it may be feasible to render hepatocytes functionally equivalent to activated brown fat, such that stored fat can be selectively oxidized in the absence of caloric restriction. Other measures which enhance the efficiency of hepatocyte electron shuttle mechanisms may increase the efficacy of this strategy.
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