Please Scroll Down to See Forums Below 
floridalife
New member
thought this was really interesting
http://www.futurebodies.com/Ketone Articles.htm
Dr. Michael Colgan, Phd, CCN
Fat Loss
By Dr. Michael Colgan, Phd, CCN
© Colgan Institute, 1997
Uncoupling Principle.
Over the past 20 years, we have successfully used combinations of four principles: Wired, Brawn, Bump-and-Grind, and Modified Ancestral Diet to drop body fat (measured by underwater weighing) as low as 5% in male athletes and 7% in females. But all these methods are old hat. They have been used with varying degrees of efficiency for hundreds of years. They are so crude as to be laughable. Until the last decade, the science of fat loss was still in the Middle Ages. Now it's time to get serious. Uncoupling is serious science. Uncoupling is really the first scientific attempt to uncover the mechanisms which Nature designed into the human body to regulate body fat.
In 1992, I wrote in this magazine about the first attempts at developing an uncoupling supplement using hydroxyl citric acid from the Malabar tamarind to depress the liver enzyme malonyl coenzyme-A, in an effort to uncouple fat oxidation from the energy cycle. It works reasonably well if combined with aerobic exercise on an empty stomach. But back then we still had such huge gaps in our knowledge of body fat regulation. We didn't know what we were doing, and hydroxy citric acid got an undeserved bad rap. Now with the discovery of leptin to spur us on, science is closing in.
How Does Uncoupling Work
To grasp the idea of uncoupling we have to dip into a smidgen of biochemisty. I only have space to sketch it - but stick with me, it is the likely future of lean. The best example is brown fat. Brown adipose tissue (BAT) in your body contains a protein called thermo-genin or uncoupling protein- 1 (UCP- 1). This protein changes the atomic structure of fats and generates heat independent of normal energy metabolism. For the science buffs, UCP- 1 opens a biochemical pathway, much like a wormhole in space - no, wormholes are not science fiction - by dissipating the proton gradient across the inner membrane of the mitochondria in BAT. Fatty acids can then oxidize (be "burned" for heat) without any connection to, that is "uncoupled" from, the normal energy process of conversion of fat to adenosine triphosphate (ATP).
Is this an important mechanism of heat production by burning fat? You bet. In many small animals and in neonates, UCP- 1 is the main control of body temperature. New animal research shows that beta-3 agonists increase BAT uncoupling, thereby "burning" body fat and keeping animals lean, no matter what diet they are fed. These findings would be great confirmation of the use of ephedrine and other beta-agonists for human fat loss, except that most human adults don't have much brown fat. So BAT uncoupling is not a usual avenue for adult fat loss. That leaves unexplained at least one-third of our body heat, which is independent of respiration, and therefore must occur independent of use of ATP for energy.
New Uncoupling Mechanisms
New research offers some exciting answers. Fleury and colleagues at DNRS/Ceremod in Meudon, France, have uncovered a second uncoupling protein, UCP-2, which is widely dispersed in human muscle, immune cells and plain old white body fat. UCP-2 has heat-producing effects very similar to those of UCP- 1, effects that are independent of ATP production.
Equally important, genetic studies map UCP-2 to regions of human chromosome 11, and mouse chromosome 7, that are linked by other research to control of body fat.
Even more important, UCP-2 also maps to chromosome regions involved in regulation of insulin metabolism, confirming what we suspected all along, that insulin efficiency is a key variable in body fat control. This finding supports my long-time advice to use chromium picolinate, alpha-lipoic acid, and omega-3 essential fats in fat-loss supplements, because all three regulate insulin efficiency.
That's not all. In May, 1997, a Swiss team of researchers at the Department of Medical Chemistry at the University of Geneva reported a third uncoupling protein: UCP-3, very similar to UCP-1 and UCP-2, but occurring mainly in skeletal muscle.8 Almost simultaneously, in June, 1997, researchers at Beth Israel Medical Center and Harvard Medical School in Boston reported the same discovery of UCP-3, with the added finding that, although it is abundant in skeletal muscle, and in white body fat, UCP occurs minimally in smooth muscle of the heart or in other vital organs. Consequently, specific stimulation of UCP-3 to increased thermogenesis is unlikely to adversely affect organ function. This finding is important, especially following the FDA's recent, hasty and shamefaced withdrawal of prescription weight-loss drugs phen-fen (phenteranine feniluramine) and Redux® (dexfenflurantine) because of heart and other organ pathology.
Support for Use of Beta-Agonists
The discovery of UCP-2 and UCP-3 also supports use of beta-3 adrenergic agonists to increase thermogenesis specifically in muscle and white body fat. Researchers at the Department of Biochemistry of the University of Ottawa in Canada have just shown that rats treated with a highly specific beta-3 agonist increased their resting metabolic rate by a whopping 40-45%, by increasing uncoupled thermogenesis in white fat and brown fat. This increase in thermogenesis, independent of normal energy metabolism, completely reversed diet-induced obesity in these rats.
More important, the study also showed that the white body fat of the rats developed a host of new BAT cells from previously inactive preadipocytes.10 This induction of BAT by a beta-agonist is tremendous evidence, because we know already that BAT can be induced to grow in adult human white fat by habitual exposure to low temperatures. Eskimos living in the Arctic have a lot more BAT than you or I, and can up-regulate their body heat in response to cold in a flash.
So the quantity of BAT and UCP-1 is not fixed in adult humans. Together with UCP-2 and UCP-3, that gives us a combined uncoupling of heat production that would strip the lard off anyone, regardless of whatever food they eat. Oh, the beta-3 agonist involved: disodium (R,R)-5-[2-[[2-(3-chlorophenyl)-2-hydroxyethyl]-amino] propyl]-1,3-ben zodioxazole- 2,2-dicarboxylate. Commercial name code CL316,243. Dosage: 1.0 mg/kg bodyweight per day. Don't try this at home.
Adding to the evidence for increased uncoupling of BAT, by a beta-3 agonist, researchers at the National Institutes of Health, Diabetes Branch in Bethesda, MD, have just shown that UCP-3 uncoupling also can be boosted by the beta-3 agonist CL214,613.11 More important for supplementation, UCP-3 uncoupling is also stimulated by up-regulating thyroid function, by cold exposure, and by dietary changes.11 These findings were confirmed in November, 1997 by Lamin and colleagues at Amylin Pharmaceuticals in San Diego, CA.
All the evidence - of which I've had space only to review a smattering - points to the conclusion that uncoupling proteins in muscle and white body fat can be manipulated by supplements to dramatically reduce body fat.
Which Supplements Do The Trick?
The $64,000 question is: which supplements do you use and how much of each? I've already given the astute reader quite a few clues. Now I'll spell it out a bit more. Again I have the space only to sketch it, but I think you'll get the idea. First we have to boost fat transport into the mitochondria of muscle and other cells, because unless we can increase the free fatty acids available to mitochondria there's nothing extra to "burn" or otherwise dispose of. In scientific gobbledygook, free fatty acid transport is rate-limiting for ketogenesis.
As elegantly explained by my friend Mark McCarty, research scientist at the Nutrition 21 company in San Diego, boosting fat transport requires two strategies. First you have to increase the amount of the enzyme, carnitine palmitoyl transferase, which catalyses the transport, that is, sets the pace. As I and others have documented, supplementary 1-carnitine achieves this task very nicely, though today we use the acetylated form of carnitine.
Second, you have to increase the activity of the carnitine enzyme, which is normally held in check by another enzyme, malonyl coenzyme A. So you have to suppress malonyl coenzyme A. This we achieved in 1992 using hydroxy citric acid, following clues in the early animal work of Lowenstein in the 70s.
O.K. Now we have additional free fatty acids flowing nicely into mitochondria. Readers who have been following my articles will remember that these fatty molecules are not really "burned" for energy or for uncoupled heat production. Such descriptions are only schoolboy explanations of a complex process of controlled nuclear energy that occurs by the transfer of electrons from the energy stored in food to your flesh. What we are really talking about is loading the mitochondria with electrons until we create a surplus too big for the mitochondria to use up in generating ATP. With the discovery of UCP-2 and UCP-3, which generate heat in muscle and body fat independent of ATP synthesis, it is likely that the body normally uses these electrons which are surplus to ATP needs, to provide the one-third of human adult body heat, which, as I explained earlier, is independent of the ATP process. All we are doing with 1-carnitine and hydroxycitrate is boosting this natural process.
The next step is a bit more complicated. The surplus electron load creates an increased electrochemical proton gradient on the inner membrane of the mitochondria. Remember how I said earlier that this was the basis of the uncoupling process. Easiest way to explain it is that the electron load generates a controlled nuclear energy reaction which blows all the surplus electrons out of the mitochondria into the cytosol (body) of the cell. This process uses up the proton gradient, enabling the electrons to re-enter the mitochondria and pass via uncoupling proteins direct to carbon dioxide (C02), generating heat in the process, and completely bypassing ATP synthesis. This well-documented cycle is called reverse electron transport.
Pyruvate Enters the Picture
Sorry. I didn't make a very good stab at that, trying to simplify a ton of biochemistry. The main point is that the reverse electron transport requires other supplements to enhance the shuttling back and forth of electrons. Mark McCarty and John Gustin propose that calcium pyruvate may be just the ticket, because it is a potent precursor for some of the key chemicals involved, namely oxaloacetate and dihyroxyacetone phosphate. Right now the weight-loss effects of high dose pyruvate are unexplained, and I commend these researchers for their insight. McCarty's hypothesis certainly would explain why pyruvate alone is not much effective at fat loss. It boosts only one of the steps involved. By the way, for manufacturers concerned about paying the high patent royalties for selling pyruvate for weight loss, there is an alternative.
Biotin Can Help
High-dose biotin has been shown to stimulate pyruvate kinase activity, which may be a key chemical in pyruvate-mediated aspects of uncoupling. Of course, if I were Dan Duchaine, I would probably recommend metformin, which is more potent, but has undesirable side effects.
CoQ1O Involved?
CoQ10 may also be rate-limiting for the electron shuttle. Common CoQ10 deficiency in America is well-documented by Karl Folkers and colleagues. One effect of supplementation in such cases is enhancement of electron shuttle chemicals. As a hang-up of the shuttle at any point can cause the whole uncoupling process to collapse, CoQ10 may well be another supplement essential to fat regulation.
There are also other essential supplements involved, some of which I have noted earlier in this article. Putting them all together in the right proportions, and using them in the right way to generate increased uncoupling is a complex task. Right now experiments at the Colgan Institute and at Nutrition 21 in San Diego are close to the nub. As one of the already low body fat subjects myself, I have to eat an extra 110grams of fat per day. This 1,000 surplus calories would normally end up on my gut. So far (six weeks) I haven't gained a fatty ounce. But I'm hot all the time, so it's likely that uncoupling is on overdrive. Sure raises a few eyebrows up here in the Canadian winter when I walk around town in shirtsleeves.
Sorry guys, we can't answer any calls or letters from individuals about this supplement. But you'll see it on the market soon enough. Manufacturers with serious proposals, you know who to call.
Supplement rating: *****
http://www.futurebodies.com/Ketone Articles.htm
Dr. Michael Colgan, Phd, CCN
Fat Loss
By Dr. Michael Colgan, Phd, CCN
© Colgan Institute, 1997
Uncoupling Principle.
Over the past 20 years, we have successfully used combinations of four principles: Wired, Brawn, Bump-and-Grind, and Modified Ancestral Diet to drop body fat (measured by underwater weighing) as low as 5% in male athletes and 7% in females. But all these methods are old hat. They have been used with varying degrees of efficiency for hundreds of years. They are so crude as to be laughable. Until the last decade, the science of fat loss was still in the Middle Ages. Now it's time to get serious. Uncoupling is serious science. Uncoupling is really the first scientific attempt to uncover the mechanisms which Nature designed into the human body to regulate body fat.
In 1992, I wrote in this magazine about the first attempts at developing an uncoupling supplement using hydroxyl citric acid from the Malabar tamarind to depress the liver enzyme malonyl coenzyme-A, in an effort to uncouple fat oxidation from the energy cycle. It works reasonably well if combined with aerobic exercise on an empty stomach. But back then we still had such huge gaps in our knowledge of body fat regulation. We didn't know what we were doing, and hydroxy citric acid got an undeserved bad rap. Now with the discovery of leptin to spur us on, science is closing in.
How Does Uncoupling Work
To grasp the idea of uncoupling we have to dip into a smidgen of biochemisty. I only have space to sketch it - but stick with me, it is the likely future of lean. The best example is brown fat. Brown adipose tissue (BAT) in your body contains a protein called thermo-genin or uncoupling protein- 1 (UCP- 1). This protein changes the atomic structure of fats and generates heat independent of normal energy metabolism. For the science buffs, UCP- 1 opens a biochemical pathway, much like a wormhole in space - no, wormholes are not science fiction - by dissipating the proton gradient across the inner membrane of the mitochondria in BAT. Fatty acids can then oxidize (be "burned" for heat) without any connection to, that is "uncoupled" from, the normal energy process of conversion of fat to adenosine triphosphate (ATP).
Is this an important mechanism of heat production by burning fat? You bet. In many small animals and in neonates, UCP- 1 is the main control of body temperature. New animal research shows that beta-3 agonists increase BAT uncoupling, thereby "burning" body fat and keeping animals lean, no matter what diet they are fed. These findings would be great confirmation of the use of ephedrine and other beta-agonists for human fat loss, except that most human adults don't have much brown fat. So BAT uncoupling is not a usual avenue for adult fat loss. That leaves unexplained at least one-third of our body heat, which is independent of respiration, and therefore must occur independent of use of ATP for energy.
New Uncoupling Mechanisms
New research offers some exciting answers. Fleury and colleagues at DNRS/Ceremod in Meudon, France, have uncovered a second uncoupling protein, UCP-2, which is widely dispersed in human muscle, immune cells and plain old white body fat. UCP-2 has heat-producing effects very similar to those of UCP- 1, effects that are independent of ATP production.
Equally important, genetic studies map UCP-2 to regions of human chromosome 11, and mouse chromosome 7, that are linked by other research to control of body fat.
Even more important, UCP-2 also maps to chromosome regions involved in regulation of insulin metabolism, confirming what we suspected all along, that insulin efficiency is a key variable in body fat control. This finding supports my long-time advice to use chromium picolinate, alpha-lipoic acid, and omega-3 essential fats in fat-loss supplements, because all three regulate insulin efficiency.
That's not all. In May, 1997, a Swiss team of researchers at the Department of Medical Chemistry at the University of Geneva reported a third uncoupling protein: UCP-3, very similar to UCP-1 and UCP-2, but occurring mainly in skeletal muscle.8 Almost simultaneously, in June, 1997, researchers at Beth Israel Medical Center and Harvard Medical School in Boston reported the same discovery of UCP-3, with the added finding that, although it is abundant in skeletal muscle, and in white body fat, UCP occurs minimally in smooth muscle of the heart or in other vital organs. Consequently, specific stimulation of UCP-3 to increased thermogenesis is unlikely to adversely affect organ function. This finding is important, especially following the FDA's recent, hasty and shamefaced withdrawal of prescription weight-loss drugs phen-fen (phenteranine feniluramine) and Redux® (dexfenflurantine) because of heart and other organ pathology.
Support for Use of Beta-Agonists
The discovery of UCP-2 and UCP-3 also supports use of beta-3 adrenergic agonists to increase thermogenesis specifically in muscle and white body fat. Researchers at the Department of Biochemistry of the University of Ottawa in Canada have just shown that rats treated with a highly specific beta-3 agonist increased their resting metabolic rate by a whopping 40-45%, by increasing uncoupled thermogenesis in white fat and brown fat. This increase in thermogenesis, independent of normal energy metabolism, completely reversed diet-induced obesity in these rats.
More important, the study also showed that the white body fat of the rats developed a host of new BAT cells from previously inactive preadipocytes.10 This induction of BAT by a beta-agonist is tremendous evidence, because we know already that BAT can be induced to grow in adult human white fat by habitual exposure to low temperatures. Eskimos living in the Arctic have a lot more BAT than you or I, and can up-regulate their body heat in response to cold in a flash.
So the quantity of BAT and UCP-1 is not fixed in adult humans. Together with UCP-2 and UCP-3, that gives us a combined uncoupling of heat production that would strip the lard off anyone, regardless of whatever food they eat. Oh, the beta-3 agonist involved: disodium (R,R)-5-[2-[[2-(3-chlorophenyl)-2-hydroxyethyl]-amino] propyl]-1,3-ben zodioxazole- 2,2-dicarboxylate. Commercial name code CL316,243. Dosage: 1.0 mg/kg bodyweight per day. Don't try this at home.
Adding to the evidence for increased uncoupling of BAT, by a beta-3 agonist, researchers at the National Institutes of Health, Diabetes Branch in Bethesda, MD, have just shown that UCP-3 uncoupling also can be boosted by the beta-3 agonist CL214,613.11 More important for supplementation, UCP-3 uncoupling is also stimulated by up-regulating thyroid function, by cold exposure, and by dietary changes.11 These findings were confirmed in November, 1997 by Lamin and colleagues at Amylin Pharmaceuticals in San Diego, CA.
All the evidence - of which I've had space only to review a smattering - points to the conclusion that uncoupling proteins in muscle and white body fat can be manipulated by supplements to dramatically reduce body fat.
Which Supplements Do The Trick?
The $64,000 question is: which supplements do you use and how much of each? I've already given the astute reader quite a few clues. Now I'll spell it out a bit more. Again I have the space only to sketch it, but I think you'll get the idea. First we have to boost fat transport into the mitochondria of muscle and other cells, because unless we can increase the free fatty acids available to mitochondria there's nothing extra to "burn" or otherwise dispose of. In scientific gobbledygook, free fatty acid transport is rate-limiting for ketogenesis.
As elegantly explained by my friend Mark McCarty, research scientist at the Nutrition 21 company in San Diego, boosting fat transport requires two strategies. First you have to increase the amount of the enzyme, carnitine palmitoyl transferase, which catalyses the transport, that is, sets the pace. As I and others have documented, supplementary 1-carnitine achieves this task very nicely, though today we use the acetylated form of carnitine.
Second, you have to increase the activity of the carnitine enzyme, which is normally held in check by another enzyme, malonyl coenzyme A. So you have to suppress malonyl coenzyme A. This we achieved in 1992 using hydroxy citric acid, following clues in the early animal work of Lowenstein in the 70s.
O.K. Now we have additional free fatty acids flowing nicely into mitochondria. Readers who have been following my articles will remember that these fatty molecules are not really "burned" for energy or for uncoupled heat production. Such descriptions are only schoolboy explanations of a complex process of controlled nuclear energy that occurs by the transfer of electrons from the energy stored in food to your flesh. What we are really talking about is loading the mitochondria with electrons until we create a surplus too big for the mitochondria to use up in generating ATP. With the discovery of UCP-2 and UCP-3, which generate heat in muscle and body fat independent of ATP synthesis, it is likely that the body normally uses these electrons which are surplus to ATP needs, to provide the one-third of human adult body heat, which, as I explained earlier, is independent of the ATP process. All we are doing with 1-carnitine and hydroxycitrate is boosting this natural process.
The next step is a bit more complicated. The surplus electron load creates an increased electrochemical proton gradient on the inner membrane of the mitochondria. Remember how I said earlier that this was the basis of the uncoupling process. Easiest way to explain it is that the electron load generates a controlled nuclear energy reaction which blows all the surplus electrons out of the mitochondria into the cytosol (body) of the cell. This process uses up the proton gradient, enabling the electrons to re-enter the mitochondria and pass via uncoupling proteins direct to carbon dioxide (C02), generating heat in the process, and completely bypassing ATP synthesis. This well-documented cycle is called reverse electron transport.
Pyruvate Enters the Picture
Sorry. I didn't make a very good stab at that, trying to simplify a ton of biochemistry. The main point is that the reverse electron transport requires other supplements to enhance the shuttling back and forth of electrons. Mark McCarty and John Gustin propose that calcium pyruvate may be just the ticket, because it is a potent precursor for some of the key chemicals involved, namely oxaloacetate and dihyroxyacetone phosphate. Right now the weight-loss effects of high dose pyruvate are unexplained, and I commend these researchers for their insight. McCarty's hypothesis certainly would explain why pyruvate alone is not much effective at fat loss. It boosts only one of the steps involved. By the way, for manufacturers concerned about paying the high patent royalties for selling pyruvate for weight loss, there is an alternative.
Biotin Can Help
High-dose biotin has been shown to stimulate pyruvate kinase activity, which may be a key chemical in pyruvate-mediated aspects of uncoupling. Of course, if I were Dan Duchaine, I would probably recommend metformin, which is more potent, but has undesirable side effects.
CoQ1O Involved?
CoQ10 may also be rate-limiting for the electron shuttle. Common CoQ10 deficiency in America is well-documented by Karl Folkers and colleagues. One effect of supplementation in such cases is enhancement of electron shuttle chemicals. As a hang-up of the shuttle at any point can cause the whole uncoupling process to collapse, CoQ10 may well be another supplement essential to fat regulation.
There are also other essential supplements involved, some of which I have noted earlier in this article. Putting them all together in the right proportions, and using them in the right way to generate increased uncoupling is a complex task. Right now experiments at the Colgan Institute and at Nutrition 21 in San Diego are close to the nub. As one of the already low body fat subjects myself, I have to eat an extra 110grams of fat per day. This 1,000 surplus calories would normally end up on my gut. So far (six weeks) I haven't gained a fatty ounce. But I'm hot all the time, so it's likely that uncoupling is on overdrive. Sure raises a few eyebrows up here in the Canadian winter when I walk around town in shirtsleeves.
Sorry guys, we can't answer any calls or letters from individuals about this supplement. But you'll see it on the market soon enough. Manufacturers with serious proposals, you know who to call.
Supplement rating: *****
. Interesting read, kinda. I've never heard of the increased permiability of the mitochondrial membrane called a "wormhole" before though 
. Anything that reduces the "space-time continuum" of my bodyfat is fine with me I guess.
