Upcoming M-1-T Cycle

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    Now to complete my shameless post whoring, I'll start my M-1-T @ 20mg daily soon as well. I'm also running the anarchy stack, Guggulbolic Extreme, and UCP-1

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    Now to complete my shameless post whoring, I'll start my stack soon as well. I'm also running the anarchy stack, Guggulbolic Extreme, and UCP-1
    Honestly, although you may not care, I think the Guggulbolic and the anarchy stack are rather redundant, if not outright unnecessary for an M-1-T cycle. I also question the uncoupler stacking as well, but, eh, who am I to dictate to others about their cycles; not to mention hijack others threads to do so. Apologies, but you might want to do at least a little more thinking before you dive in.
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    Originally posted by Method


    Honestly, although you may not care, I think the Guggulbolic and the anarchy stack are rather redundant, if not outright unnecessary for an M-1-T cycle.
    how do you figure Guggulsterones and the anarchy stack to be redundant? As i understand it Guggulsterones stimulate the thyroid gland. R-ALA is a nutrient partitioner and also a strong antioxidant. alcar transports fats into the mitochondria, and in the mitochondria these fats are converted to an energy source. CLA works by increasing AA and glucose transport into the muscle cells via insulin stimulated pathways, and therefore in hypocaloric diets acts as an anti-catabolic. CLA also keeps blood glucose levels more stable. In essence preventing preventing high blood glucose or hypoglycaemia after a carb meal.
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    Originally posted by Method


    Honestly, although you may not care, I think the Guggulbolic and the anarchy stack are rather redundant, if not outright unnecessary for an M-1-T cycle. I also question the uncoupler stacking as well, but, eh, who am I to dictate to others about their cycles; not to mention hijack others threads to do so. Apologies, but you might want to do at least a little more thinking before you dive in.

    Originally posted by goldylight


    how do you figure Guggulsterones and the anarchy stack to be redundant? As i understand it Guggulsterones stimulate the thyroid gland. R-ALA is a nutrient partitioner and also a strong antioxidant. alcar transports fats into the mitochondria, and in the mitochondria these fats are converted to an energy source. CLA works by increasing AA and glucose transport into the muscle cells via insulin stimulated pathways, and therefore in hypocaloric diets acts as an anti-catabolic. CLA also keeps blood glucose levels more stable. In essence preventing preventing high blood glucose or hypoglycaemia after a carb meal.
    Well goldylight basically spelled that one out for me, for the most part. I do realize your point that cutting with M1T alone should be good, but these all work through different mechanisms that have different benefits.

    Why would you question uncoupler stacking exactly? And how would a strong anti-oxident be redundant when using an uncoupler, not to mention glucose control? Are the many benefits of ALCAR and Green Tea somehow magically not present with an AS cycle? This is news to me.

    I think what you may mean is that you would not spend the $$ to combine all of these together, if M1T will give benefits alone for cutting. I can respect that viewpoint, but don't insult my intelligence by insinuating I haven't thought about this at all. I will concede that this is certainly not the most cost-effective stack out there, but to say it will not be efficient or certain aspects are "redundant" seems rather unfounded to me.

    The anarchy stack is a year round thing for me now, regardless of cycling. The gglesterones I got a good deal on, and I have used them in the past and do not actually expect a dramaticsynergy or outstanding results from that one compound. As for UCP-1, I have done many cycle of that and SU in the past with success. Different strokes for different folks is one thing, but if you believe that one compund will negate the effects of another here or there is som specific reason to not do this, please post it.

     

    Sorry Bobo, this can be taken to another thread if need be.
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    Now, have my responses just been moved? or have they now been completely deleted? (because I'd really rather not have to retype them...) Please feel free to delete this too once I get my answer...
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    jweave, any comments to methods questions? I also don't see why it is necessary to run all those supps _during_ a cycle seeing that M-1-T is pretty potent.
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    Originally posted by jweave23
    Now to complete my shameless post whoring, I'll start my M-1-T @ 20mg daily soon as well. I'm also running the anarchy stack, Guggulbolic Extreme, and UCP-1
    have you ever thought of using the anarchy stack with guggul and 7-keto? Was thinking of using that for my next cutting cycle.
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    Originally posted by MarcusG
    jweave, any comments to methods questions? I also don't see why it is necessary to run all those supps _during_ a cycle seeing that M-1-T is pretty potent.
    1. They aren't "necessary" by any means, as in "essential" for this cutting cycle, but then again what exactly is "necessary"? Again I think we're talking about cost-benfit here, which I understand may not be optimized with these supps taken together, but I wasn't going fot the most cost effective cycle this time around, necessarily.

    2. I'm running the anarchy stack indefinitely, for a multitude of reasons such as these from ALCAR alone, as posted in the anarchy stack thread in supps:

    Acetyl L-Carnitine

    ALC improves both Short-Term Memory and Long-Term Memory.

    ALC improves Mood [ALC improves Mood in 53% of healthy subjects].

    Acetyl L-Carnitine retards some aspects of the Aging Process in the Skin:

    ALC improves the reaction times of people afflicted with Cerebral Insufficiency.

    ALC (2-4 grams per day) improves walking distance without Pain in people afflicted with Intermittent Claudication.

    ALC prevents the age-related impairment of Eyesight (by protecting the Neurons of the Optic Nerve and the Occipital Cortex of the Brain.

    ALC enhances the ability of Macrophages to function as Phagocytes.

    ALC improves Athletic Performance [ALC given prior to Exercise increased the maximum running speed of animals].

    ALC enhances the function of Cytochrome Oxidase (an essential enzyme of the Electron Transport System (ETS).

    ALC improves the Energy metabolism of Neurons (by enhancing the transport of Medium-Chain Saturated Fatty Acids and Short-Chain Saturated Fatty Acids across the Cell Membranes of Neurons into the Mitochondria).

    ALC inhibits the damage caused by Hypoxia.
    ALC transports Lipids into the Mitochondria of Cells.

    ALC improves mood and memory in people with Age Associated Memory Impairment.

    ALC improves Mental Function where Alcohol induced cognitive Impairment exists.

    ALC increases Alertness.

    Acetyl-L-Carnitine inhibits the deterioration in Mental Function associated with Alzheimer’s Disease and slows the progression of Alzheimer’s Disease [people afflicted with Alzheimer’s Disease exhibited significantly less deterioration in Mental Function following the administration of supplemental ALC for 12 months. This finding was verified by using nuclear magnetic resonance on the subjects].

    ALC increases Alertness in people afflicted with Alzheimer's Disease - 2,500-3,000 mg per day for 3 months].
    ALC inhibits the toxicity of Amyloid-Beta Protein (ABP) to Neurons.

    ALC improves Attention Span in people afflicted with Alzheimer's Disease.

    ALC improves Short Term Memory in people afflicted with Alzheimer's Disease.

    High concentrations of ALC are naturally present in various regions of the Brain.
    ALC reverses the age-related decline that occurs in Cholinergic Receptors (i.e. the Receptors that receive Acetylcholine).

    ALC improves (eye to hand) Coordination [supplemental ALC @ 1.5 grams per day for 30 days improved eye to hand coordination in healthy, sedentary subjects by a factor of 300-400%].

    ALC improves the Interhemispheric Flow of Information across the Corpus Callosum of the Brain.

    ALC retards the decline in the number of Dopamine Receptors that occurs in tandem with the Aging Process and (more rapidly) with the onset of Parkinson's Disease.

    ALC enhances the release of Dopamine from Dopaminergic Neurons and improves the binding of Dopamine to Dopamine Receptors.

    ALC can prevent the destruction of Dopamine Receptors by MPTP (a neurotoxin capable of causing Parkinson's Disease via Dopaminergic Receptor death.

    ALC improves Attention Span and Memory in people afflicted with Down’s Syndrome.

    ALC retards the inevitable decline in the number of Glucocorticoid Receptors that occurs in tandem with the Aging Process.

    ALC enhances the recovery of people afflicted with Hemiplegia (Paralysis of one side of the body) and improves their Mood and Attention Span.

    ALC retards the age-related deterioration of the Hippocampus [research - rats].

    Acetyl-L-Carnitine (ALC) improves Learning ability [women aged 22 - 27 were supplemented with ALC for 30 days. Complex video game tests before and after supplementation concluded that supplemental ALC caused large increases in speed of Learning, speed of reaction and reduction in errors].

    ALC inhibits (and possibly reverses) the degeneration of Myelin Sheaths that occurs in tandem with the progression of the Aging Process [scientific research - hyperglycemic mice treated with ALC for 16 weeks exhibited improved nerve conduction velocity and exhibited thicker Myelin Sheaths and larger myelinated Nerve Fibers].

    ALC retards the inevitable decline in the number of Nerve Growth Factor (NGF) Receptors that occurs in tandem with the Aging Process.

    ALC stimulates and maintains the growth of new Neurons within the Brain (both independently of Nerve Growth Factor (NGF) and as a result of preserving NGF) and helps to prevent the death of existing Neurons [ALC inhibits Neuron death in the Striatal Cortex, Prefrontal Cortex and the Occipital Cortex of the Brain].

    ALC inhibits the degeneration of Neurons that is implicit in Neuropathy.

    ALC rejuvenates and increases the number of N-Methyl-D-Aspartate Receptors (NMDA Receptors) in the Brain [even a single dose of ALC increases the number of functional NMDA Receptors]:

    ALC protects the NMDA Receptors in the Brain from the natural decline that occurs in tandem with the Aging Process [research - animals].

    ALC is presently being researched as a treatment for Parkinson's Disease.

    ALC inhibits the loss of Vision, degeneration of Neurons and damage to the Retina associated with Retinopathy (including Diabetic Retinopathy).

    ALC improves the quality of Sleep and reduces the quantity of Sleep required.

    ALC improves Spatial Memory (an aspect of Short Term Memory that involves remembering one’s position in space).

    ALC inhibits the excessive release of Cortisol in response to Stress and inhibits the depletion of Luteinising Hormone Releasing Hormone (LHRH) and Testosterone that occurs as a result of excessive Stress.

    ALC improves Verbal Fluency.

    ALC enhances the function of Cytochrome Oxidase (also called Complex IV) - an essential enzyme of the Electron Transport System.

    ALC normalizes Beta-Endorphin levels.
    ALC reduces Stress-induced Cortisol release [research - animals].

    ALC prevents the depletion of Luteinising Hormone Releasing Hormone (LHRH) caused by exposure to excessive Stress.

    ALC retards the decline in the production of Nerve Growth Factor (NGF) that occurs in tandem with the Aging Process.

    ALC increases plasma Testosterone levels (via its influence on Acetylcholine neurotransmission in the Striatal Cortex of the Brain) and prevents the depletion of Testosterone caused by exposure to excessive Stress [research - rats].

    ALC increases the body's levels of circulating Thyrotrophin.

    ALC facilitates the production of Adenosine Triphosphate (ATP) [research - animals].

    ALC "shuttles" Long Chain Fatty Acids between the Cytosol and the Mitochondria of Cells.

    ALC facilitates both the release and synthesis of Acetylcholine.

    ALC's ability to increase the synthesis of Acetylcholine occurs as a result of it donating its Acetyl group towards the production of Acetylcholine.

    ALC increases the Brain's levels of Choline Acetylase (which in turn facilities the production of Acetylcholine).

    ALC enhances the release of Dopamine from Dopaminergic Neurons and improves the binding of Dopamine to Dopamine Receptors.

    References

    De Falco, F. A., et al. Effect of the chronic treatment with L-acetylcarnitine in Down’s syndrome. Clin Ther. 144:123-127, 1994.

    Bowman, B. Acetyl-carnitine and Alzheimer’s disease. Nutr Rev. 50:142-144, 1992.

    Bruno, G., et al. Acetyl-L-carnitine in Alzheimer disease: a short-term study on CSF neurotransmitters and neuropeptides. Alzheimer Dis Assoc Disord (USA). 9(3):128-131, 1995.

    Calvani, M., et al. Action of acetyl-L-carnitine in neurodegeneration and Alzheimer’s disease. Annals of the New York Academy of Sciences (USA). 663:483-486, 1993.

    Carta, A., et al. Acetyl-L-carnitine: a drug able to slow the progress of Alzheimer’s Disease? Annals of the New York Academy of Sciences (USA. 640:228-232, 1991.

    Guarnaschelli, C., et al. Pathological brain ageing: evaluation of the efficacy of a pharmacological aid. Drugs under Experimental and Clinical Research. 14(11):715-718, 1988.

    Passeri, M., et al. Acetyl-L-carnitine in the treatment of mildly demented elderly patients. International Journal of Clinical Pharmacology Research. 10(1-2):75-79, 1990.

    Pettegrew, J. W., et al. Clinical and neurochemical effects of acetyl-L-carnitine in Alzheimer’s disease. Neurobiol Aging. 16:1-4, 1995.

    Rai, G., et al. Double-blind, placebo controlled study of acetyl-L-carnitine in patients with Alzheimer’s dementia. Current Medical Research and Opinion. 11(10):638-647, 1989.

    Sano, M., et al. Double-blind parallel design pilot study of acetyl levocarnitine in patients with Alzheimer’s disease. Arch Neurol. 49:1137-1141, 1992.

    Sinforiani, E., et al. Neuropsychological changes in demented patients treated with acetyl-L-carnitine. International Journal of Clinical Pharmacology Research. 10(1-2):69-74, 1990.

    Spagnoli, A. U., et al. Long-term acetyl-l-carnitine treatment in Alzheimer’s disease. Neurology. 41(11):1726-1732, 1991.


    I won't get on the soapbox too much regarding the anarchy stack.....anyone who reads the multitude of threads regarding it, especially here at AM, will see the obvious benefits of running it long-term. I will not justify the use of it anymore, and will simply refer people to that thread here, located at http://www.anabolicminds.com/forum/s...;threadid=5553

    3. As for Guggulbolic Extreme: I have been using it for the past 5 days and just may stop until the cycle is over, or run it in between cycles of M-1-T if I decide to shorten them to several insted of one long one, which I may do.

    4. UCP-1 I happen to get good results from and am hoping that my results might be that much better if I do take it during this cycle as well. I have started M-1-T tonight, and haven't started UCP-1 yet, and again may run that inbetween shorter cycles.

    I hope that clarifies any questions as to my motivations behind this, and remember......everything is up for negotiation, lol!!

     
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    Good luck. Be careful at 20mgs. I hear this stuff is potent
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    Originally posted by goldylight


    have you ever thought of using the anarchy stack with guggul and 7-keto? Was thinking of using that for my next cutting cycle.
    I have been using the anarchy stack for a little while now, and have been using gugg for the past 5 days. I have used gugg in conjunction with 7-keto in the past and was happy with the results. Your idea is a good one, go with it IMO.
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    Originally posted by NO MERCY
    Good luck. Be careful at 20mgs. I hear this stuff is potent
    Thanks, and I'm hoping it is!!

    My new idea is either 2 3 week cycles with 1.5 weeks inbetween or 3 2week cycles with 1 week inbetween.

    Between these cycles I would run the gugg and UCP-1. Again, if someone can convince me of a better plan, please do so
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    I'm currently going to run it at 20mg a day for 30 days, then three weeks off and then 10mg a day for three weeks. It will be exactly one bottle. Of course I will probably take 8 weeks off then. But I will be stocking up while I'm off. I am on day 2 now. This **** is legit. Be prepared for the back cramps though. Mine are the worst at night.
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    I don't want to sound like a hypocrit, because I take 2g of ALCAR daily as well, but a lot of the 'benefits' you tout mean very little IMO:

    ALC improves the reaction times of people afflicted with Cerebral Insufficiency.
    Wonderful, but do you have cerebral insufficiency?

    ALC (2-4 grams per day) improves walking distance without Pain in people afflicted with Intermittent Claudication
    Cool. But are you afflicted by this?

    ALC enhances the ability of Macrophages to function as Phagocytes.
    LOL...this one gets me; do you even know what this means?

    ALC improves Athletic Performance [ALC given prior to Exercise increased the maximum running speed of animals].
    Animal study. I'm not going to completely dismiss it because 5g of ALCAR and 10g of Choline Citrate also does the same thing in humans (can't find the study, but it's out there...). Still, you need to Choline to buffer the ALCAR with, otherwise, you're not seeing these benefits, and you need HIGH-dose ALCAR for this one. I should also add that Vallini-Gannon trial of high-dose Carnitine supplementation combined with aerobic training on dieting women from the 2000 Journal of Sports Nutrition & Exercise found that it improved performance "did not significantly alter the TBM or FM of overweight women, thereby casting doubt on the efficacy of L-C supplementation for weight loss."


    ALC enhances the function of Cytochrome Oxidase (an essential enzyme of the Electron Transport System (ETS).

    ALC improves the Energy metabolism of Neurons (by enhancing the transport of Medium-Chain Saturated Fatty Acids and Short-Chain Saturated Fatty Acids across the Cell Membranes of Neurons into the Mitochondria).

    ALC transports Lipids into the Mitochondria of Cells.
    Okay, but the rate-limiting step in fat mobilization, utilization, and subsequently, oxidation at rest is still HSL, so this means very little from a dieting standpoint, although it does provide some insight into how ALCAR can improve exercise performance.


    ALC improves mood and memory in people with Age Associated Memory Impairment.

    Acetyl-L-Carnitine inhibits the deterioration in Mental Function associated with Alzheimer’s Disease and slows the progression of Alzheimer’s Disease [people afflicted with Alzheimer’s Disease exhibited significantly less deterioration in Mental Function following the administration of supplemental ALC for 12 months. This finding was verified by using nuclear magnetic resonance on the subjects].

    ALC increases Alertness in people afflicted with Alzheimer's Disease - 2,500-3,000 mg per day for 3 months].
    ALC inhibits the toxicity of Amyloid-Beta Protein (ABP) to Neurons.

    ALC improves Attention Span in people afflicted with Alzheimer's Disease.

    ALC improves Short Term Memory in people afflicted with Alzheimer's Disease.
    Same as above, none of this applies to you

    ALC improves Mental Function where Alcohol induced cognitive Impairment exists.
    This one is cool: I usually end up feeling obligated to bust some ALCAR and Silymarin extract damn-near every Saturday morning. But still, does this have any applications to dieting?

    See what I'm getting at? ALCAR is a phenominal supplement, but half of these things you've listed don't even apply to you, and about 90% of the rest won't do a damn thing for you on a diet. Now, there are some things related to dopamine and cortisol and cognitive function that will, so I would keep the ALCAR, but don't just umbrella a page of random and unrelated assertions together and then conclude its a convincing argument. But whatever, you like the anarchy stack, you say it works for you: if it's not broke, who am I to tell you to fix it. (Except the CLA portion. You're not bulking, so why even waste calories on it? It only really benefits untrained subjects and rodents, and you're neither. And, more to the point, CLA is absolutely worthless when cutting. The trans-10, cis-12 isomer only inhibits lipogenesis, it's worthless in regards to lipolysis. The 9,11 isomer will also do very little for you on a cutting cycle as well, because you're simply not operating with a caloric surplus. If I was less lazy I'd format a full rebuke, but instead, just check these out:

    Effects of CLA Supplementation During Resistance Training on Body Composition and Strength

    M. Ferreira¹, R. Kreider¹, M. Wilson¹, and A. Almada². Department of HMSE, University of Memphis¹, Memphis, TN 38152 & Experimental and Applied Sciences², Golden,
    CO 80401.

    Conjugated linoleic acids (CLA) are essential fatty acids that have been reported to possess anti-catabolic properties. Animal studies have found that CLA supplementation increases total body mass while reducing fat mass. This study investigated the effects of CLA supplementation during resistance training on markers of catabolism, body composition, and strength. In a double-blind and randomized manner, 27 experienced resistance-trained males were matchpaired according to total bodyweight and training volume and randomly assigned to supplement their diets with capsules containing either an olive oil placebo (P) or 5.6 g/day of CLA for 28 days. Fasting blood samples, total body mass, dual energy x-ray absorptiometry (DEXA) determined body composition, and 1RM bench press and leg press tests were performed on days 0 and 28 of supplementation. Data were analyzed by repeated measures ANOVA and are presented as mean ± SEM changes from day 0. No significant differences were observed in changes in total body mass (P: -0.10 ± 0.3; CLA: 0.02 ± 0.4 kg; P=0.77), DEXA scanned mass (P: 0.22 ± 0.3; CLA: 0.40 ± 0.3 kg; p=0.68), fat-free mass (P: 0.16 ± 0.2; CLA: 0.14 ± 0.2 kg; p=0.95), fat mass (P: 0.06 ± 0.1; CLA: 0.26 ± 0.2 kg; p=0.43), or percent bodyfat (P: 0.02 ± 0.2; CLA: 0.28 ± 0.3%; p=0.40). However, there was some evidence that CLA supplementation lessened changes in the ratio of blood urea nitrogen to creatinine, which is a general marker of catabolic state (P: 2.2 ± 1.0; CLA: -0.07 ± 0.9; p=0.10). Moreover, while not statistically significant, strength analysis revealed that 1RM bench press (P: -3.0 ± 2; CLA: 2.0 ± 2 kg; p=0.09), leg press (P: 7.3 ± 3; CLA: 11.9 ± 4 kg; p=0.41), and overall gains in 1RM strength (P: 4.3 ± 4; CLA: 13.9 ± 6 kg; p=0.17) were generally greater in the CLA group. Results indicate that 28 days of CLA supplementation (5.6 g/day) did not significantly alter body composition in resistance-trained males.



    Effect of conjugated linoleic acid supplementation after weight loss on appetite and food intake in overweight subjects.

    Kamphuis MM, Lejeune MP, Saris WH, Westerterp-Plantenga MS.

    1Department of Human Biology, Faculty of Health Sciences, Maastricht University, Maastricht, The Netherlands.

    OBJECTIVE:: To study the effects of 13 weeks conjugated linoleic acid (CLA) supplementation in overweight subjects on body-weight maintenance, parameters of appetite and energy intake (EI) at breakfast after weight loss. DESIGN:: This study had a double-blind, placebo-controlled randomized design. SUBJECTS:: A total of 26 men and 28 women (age 37.8+/-7.7 y; body mass index 27.8+/-1.5 kg/m(2)). INTERVENTIONS:: Subjects were first submitted to a very-low-calorie diet (VLCD; 2.1 MJ/day) for 3 weeks after which they started with the 13-week intervention period. They either received 1.8 g CLA or placebo per day or 3.6 g CLA or placebo per day. Additionally, subjects of the high dosage intervention replaced their habitual lunch by one meal of a protein-rich, low-energy supplement. EI was measured at breakfast and appetite profile after an overnight fast. RESULTS:: The mean body weight loss was 6.9+/-1.7% of their original body weight. Multiple regression analysis showed that at the end of the 13-week intervention, CLA did not have an effect on body weight regain. Feelings of fullness and satiety were increased and feelings of hunger were decreased after 13 weeks intervention by CLA compared to placebo, independent of %body weight regain. However, EI measured at breakfast was not affected by CLA. CONCLUSION:: Appetite (hunger, satiety and fullness) was favorably, dose-independently affected by a 13-week consumption of 1.8 or 3.6 g CLA/day. This did not result in a lower EI at breakfast or an improved body-weight maintenance after weight loss.European Journal of Clinical Nutrition (2003) 57, 1268-1274. doi:10.1038/sj.ejcn.1601684


    Conjugated linoleic acid supplementation in humans: effects on body composition and energy expenditure.

    Zambell KL, Keim NL, Van Loan MD, Gale B, Benito P, Kelley DS, Nelson GJ.

    U.S. Department of Agriculture/Western Human Nutrition Research Center, University of California, Davis 95616, USA.

    Recent animal studies have demonstrated that dietary conjugated linoleic acid (CLA) reduces body fat and that this decrease may be due to a change in energy expenditure. The present study examined the effect of CLA supplementation on body composition and energy expenditure in healthy, adult women. Seventeen women were fed either a CLA capsule (3 g/d) or a sunflower oil placebo for 64 d following a baseline period of 30 d. The subjects were confined to a metabolic suite for the entire 94 d study where diet and activity were controlled and held constant. Change in fat-free mass, fat mass, and percentage body fat were unaffected by CLA supplementation (0.18+/-0.43 vs. 0.09+/-0.35 kg; 0.01+/-0.64 vs. -0.19+/-0.53 kg; 0.05+/-0.62 vs. -0.67+/-0.51%, placebo vs. CLA, respectively). Likewise, body weight was not significantly different in the placebo vs. the CLA group (0.48+/-0.55 vs. -0.24+/-0.46 kg change). Energy expenditure (kcal/min), fat oxidation, and respiratory exchange ratio were measured once during the baseline period and during weeks 4 and 8 of the intervention period. At all three times, measurements were taken while resting and walking. CLA had no significant effect on energy expenditure, fat oxidation, or respiratory exchange ratio at rest or during exercise. When dietary intake was controlled, 64 d of CLA supplementation at 3 g/d had no significant effect on body composition or energy expenditure in adult women, which contrasts with previous findings in animals.


    Conjugated linoleic acid supplementation in humans: effects on fatty acid and glycerol kinetics.

    Zambell KL, Horn WF, Keim NL.

    USDA/Western Human Nutrition Research Center, Department of Exercise Science, University of California, Davis 95616, USA.

    Recent studies with mouse adipocytes have shown that dietary conjugated linoleic acid (CLA) may reduce body fat by increasing lipolysis. The present study examined the effect of CLA supplementation on fatty acid and glycerol kinetics in six healthy, adult women who were participating in a controlled metabolic ward study. These women were fed six CLA capsules per day (3.9 g/d) for 64 d following a baseline period of 30 d. The subjects were confined to a metabolic suite for the entire 94-d study, where diet and activity were controlled and held constant. The rate of appearance (Ra) of glycerol, which indicates lipolytic rates, was similar at baseline and after 4 wk of CLA supplementation at rest (1.87 +/- 0.21 and 2.00 +/- 0.39 micromol/kg/min, respectively) and during exercise (7.12 +/- 0.74 and 6.40 +/- 0.99 micromol/kg/min, respectively). Likewise, the Ra of free fatty acids (FFA) was not significantly different after 4 wk of dietary CLA at rest (2.72 +/- 0.06 and 2.74 +/- 0.12 micromol/kg/min, respectively) or during exercise (6.99 +/- 0.40 and 5.88 +/- 0.29 micromol/kg/min, respectively). CLA supplementation also had no effect on the percentage of FFA released from lipolysis that were re-esterified. The apparent rate of FFA re-esterification was 65.2 +/- 4.2% at rest and 32.1 +/- 3.44% during exercise. Four weeks of CLA supplementation had no significant effect on fatty acid or glycerol metabolism in healthy, weight-stable, adult women.

    Then there's also just the fact that CLA is a 'bastard' N-6, which means that it's going to be competing with (and kicking the ass of) your flax and fish oils for absorbption in the phospholipid membrane. Now, if you're proposing taking like 15-16g a day of the stuff as I've heard many Anarchy-guys advocate, you better be taking in a lot of flax to keep your N-3:N-6 ratios optimal for cutting. Which once again begs me to ask: why bother?

    As far as the UCP-1 goes, once again, I'd say save it until you're not running M-1-T. To explain why would, once again, take a lot of time which I'm not up to putting in. But read this, which gives a very good idea of how uncouplers act, and just think about how those sorts of conditions would affect tissue-turnover rates and protein synthesis in someone endeavoring to gain LBM.

    the article is here:

    http://www.blackwell-synergy.com/lin....00043.x/full/
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    Don't know, it works fine for me, and yes, the site is perfectly legit, it's the homepage for Blackwell Publishing Inc.

    If it really doesn't work for you, try going here, and scrolling down to article #255, then you can get it in PDF format

    http://www.blackwell-synergy.com/ser...2001&part=null
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    Originally posted by Method
    I don't want to sound like a hypocrit, because I take 2g of ALCAR daily as well, but a lot of the 'benefits' you tout mean very little IMO:



    Wonderful, but do you have cerebral insufficiency?



    Cool. But are you afflicted by this?



    LOL...this one gets me; do you even know what this means?



    Animal study. I'm not going to completely dismiss it because 5g of ALCAR and 10g of Choline Citrate also does the same thing in humans (can't find the study, but it's out there...). Still, you need to Choline to buffer the ALCAR with, otherwise, you're not seeing these benefits, and you need HIGH-dose ALCAR for this one. I should also add that Vallini-Gannon trial of high-dose Carnitine supplementation combined with aerobic training on dieting women from the 2000 Journal of Sports Nutrition & Exercise found that it improved performance "did not significantly alter the TBM or FM of overweight women, thereby casting doubt on the efficacy of L-C supplementation for weight loss."




    Okay, but the rate-limiting step in fat mobilization, utilization, and subsequently, oxidation at rest is still HSL, so this means very little from a dieting standpoint, although it does provide some insight into how ALCAR can improve exercise performance.




    Same as above, none of this applies to you



    This one is cool: I usually end up feeling obligated to bust some ALCAR and Silymarin extract damn-near every Saturday morning. But still, does this have any applications to dieting?

    See what I'm getting at? ALCAR is a phenominal supplement, but half of these things you've listed don't even apply to you, and about 90% of the rest won't do a damn thing for you on a diet. Now, there are some things related to dopamine and cortisol and cognitive function that will, so I would keep the ALCAR, but don't just umbrella a page of random and unrelated assertions together and then conclude its a convincing argument. But whatever, you like the anarchy stack, you say it works for you: if it's not broke, who am I to tell you to fix it. (Except the CLA portion. You're not bulking, so why even waste calories on it? It only really benefits untrained subjects and rodents, and you're neither. And, more to the point, CLA is absolutely worthless when cutting. The trans-10, cis-12 isomer only inhibits lipogenesis, it's worthless in regards to lipolysis. The 9,11 isomer will also do very little for you on a cutting cycle as well, because you're simply not operating with a caloric surplus. If I was less lazy I'd format a full rebuke, but instead, just check these out:

    Effects of CLA Supplementation During Resistance Training on Body Composition and Strength

    M. Ferreira¹, R. Kreider¹, M. Wilson¹, and A. Almada². Department of HMSE, University of Memphis¹, Memphis, TN 38152 & Experimental and Applied Sciences², Golden,
    CO 80401.

    Conjugated linoleic acids (CLA) are essential fatty acids that have been reported to possess anti-catabolic properties. Animal studies have found that CLA supplementation increases total body mass while reducing fat mass. This study investigated the effects of CLA supplementation during resistance training on markers of catabolism, body composition, and strength. In a double-blind and randomized manner, 27 experienced resistance-trained males were matchpaired according to total bodyweight and training volume and randomly assigned to supplement their diets with capsules containing either an olive oil placebo (P) or 5.6 g/day of CLA for 28 days. Fasting blood samples, total body mass, dual energy x-ray absorptiometry (DEXA) determined body composition, and 1RM bench press and leg press tests were performed on days 0 and 28 of supplementation. Data were analyzed by repeated measures ANOVA and are presented as mean ± SEM changes from day 0. No significant differences were observed in changes in total body mass (P: -0.10 ± 0.3; CLA: 0.02 ± 0.4 kg; P=0.77), DEXA scanned mass (P: 0.22 ± 0.3; CLA: 0.40 ± 0.3 kg; p=0.68), fat-free mass (P: 0.16 ± 0.2; CLA: 0.14 ± 0.2 kg; p=0.95), fat mass (P: 0.06 ± 0.1; CLA: 0.26 ± 0.2 kg; p=0.43), or percent bodyfat (P: 0.02 ± 0.2; CLA: 0.28 ± 0.3%; p=0.40). However, there was some evidence that CLA supplementation lessened changes in the ratio of blood urea nitrogen to creatinine, which is a general marker of catabolic state (P: 2.2 ± 1.0; CLA: -0.07 ± 0.9; p=0.10). Moreover, while not statistically significant, strength analysis revealed that 1RM bench press (P: -3.0 ± 2; CLA: 2.0 ± 2 kg; p=0.09), leg press (P: 7.3 ± 3; CLA: 11.9 ± 4 kg; p=0.41), and overall gains in 1RM strength (P: 4.3 ± 4; CLA: 13.9 ± 6 kg; p=0.17) were generally greater in the CLA group. Results indicate that 28 days of CLA supplementation (5.6 g/day) did not significantly alter body composition in resistance-trained males.



    Effect of conjugated linoleic acid supplementation after weight loss on appetite and food intake in overweight subjects.

    Kamphuis MM, Lejeune MP, Saris WH, Westerterp-Plantenga MS.

    1Department of Human Biology, Faculty of Health Sciences, Maastricht University, Maastricht, The Netherlands.

    OBJECTIVE:: To study the effects of 13 weeks conjugated linoleic acid (CLA) supplementation in overweight subjects on body-weight maintenance, parameters of appetite and energy intake (EI) at breakfast after weight loss. DESIGN:: This study had a double-blind, placebo-controlled randomized design. SUBJECTS:: A total of 26 men and 28 women (age 37.8+/-7.7 y; body mass index 27.8+/-1.5 kg/m(2)). INTERVENTIONS:: Subjects were first submitted to a very-low-calorie diet (VLCD; 2.1 MJ/day) for 3 weeks after which they started with the 13-week intervention period. They either received 1.8 g CLA or placebo per day or 3.6 g CLA or placebo per day. Additionally, subjects of the high dosage intervention replaced their habitual lunch by one meal of a protein-rich, low-energy supplement. EI was measured at breakfast and appetite profile after an overnight fast. RESULTS:: The mean body weight loss was 6.9+/-1.7% of their original body weight. Multiple regression analysis showed that at the end of the 13-week intervention, CLA did not have an effect on body weight regain. Feelings of fullness and satiety were increased and feelings of hunger were decreased after 13 weeks intervention by CLA compared to placebo, independent of %body weight regain. However, EI measured at breakfast was not affected by CLA. CONCLUSION:: Appetite (hunger, satiety and fullness) was favorably, dose-independently affected by a 13-week consumption of 1.8 or 3.6 g CLA/day. This did not result in a lower EI at breakfast or an improved body-weight maintenance after weight loss.European Journal of Clinical Nutrition (2003) 57, 1268-1274. doi:10.1038/sj.ejcn.1601684


    Conjugated linoleic acid supplementation in humans: effects on body composition and energy expenditure.

    Zambell KL, Keim NL, Van Loan MD, Gale B, Benito P, Kelley DS, Nelson GJ.

    U.S. Department of Agriculture/Western Human Nutrition Research Center, University of California, Davis 95616, USA.

    Recent animal studies have demonstrated that dietary conjugated linoleic acid (CLA) reduces body fat and that this decrease may be due to a change in energy expenditure. The present study examined the effect of CLA supplementation on body composition and energy expenditure in healthy, adult women. Seventeen women were fed either a CLA capsule (3 g/d) or a sunflower oil placebo for 64 d following a baseline period of 30 d. The subjects were confined to a metabolic suite for the entire 94 d study where diet and activity were controlled and held constant. Change in fat-free mass, fat mass, and percentage body fat were unaffected by CLA supplementation (0.18+/-0.43 vs. 0.09+/-0.35 kg; 0.01+/-0.64 vs. -0.19+/-0.53 kg; 0.05+/-0.62 vs. -0.67+/-0.51%, placebo vs. CLA, respectively). Likewise, body weight was not significantly different in the placebo vs. the CLA group (0.48+/-0.55 vs. -0.24+/-0.46 kg change). Energy expenditure (kcal/min), fat oxidation, and respiratory exchange ratio were measured once during the baseline period and during weeks 4 and 8 of the intervention period. At all three times, measurements were taken while resting and walking. CLA had no significant effect on energy expenditure, fat oxidation, or respiratory exchange ratio at rest or during exercise. When dietary intake was controlled, 64 d of CLA supplementation at 3 g/d had no significant effect on body composition or energy expenditure in adult women, which contrasts with previous findings in animals.


    Conjugated linoleic acid supplementation in humans: effects on fatty acid and glycerol kinetics.

    Zambell KL, Horn WF, Keim NL.

    USDA/Western Human Nutrition Research Center, Department of Exercise Science, University of California, Davis 95616, USA.

    Recent studies with mouse adipocytes have shown that dietary conjugated linoleic acid (CLA) may reduce body fat by increasing lipolysis. The present study examined the effect of CLA supplementation on fatty acid and glycerol kinetics in six healthy, adult women who were participating in a controlled metabolic ward study. These women were fed six CLA capsules per day (3.9 g/d) for 64 d following a baseline period of 30 d. The subjects were confined to a metabolic suite for the entire 94-d study, where diet and activity were controlled and held constant. The rate of appearance (Ra) of glycerol, which indicates lipolytic rates, was similar at baseline and after 4 wk of CLA supplementation at rest (1.87 +/- 0.21 and 2.00 +/- 0.39 micromol/kg/min, respectively) and during exercise (7.12 +/- 0.74 and 6.40 +/- 0.99 micromol/kg/min, respectively). Likewise, the Ra of free fatty acids (FFA) was not significantly different after 4 wk of dietary CLA at rest (2.72 +/- 0.06 and 2.74 +/- 0.12 micromol/kg/min, respectively) or during exercise (6.99 +/- 0.40 and 5.88 +/- 0.29 micromol/kg/min, respectively). CLA supplementation also had no effect on the percentage of FFA released from lipolysis that were re-esterified. The apparent rate of FFA re-esterification was 65.2 +/- 4.2% at rest and 32.1 +/- 3.44% during exercise. Four weeks of CLA supplementation had no significant effect on fatty acid or glycerol metabolism in healthy, weight-stable, adult women.

    Then there's also just the fact that CLA is a 'bastard' N-6, which means that it's going to be competing with (and kicking the ass of) your flax and fish oils for absorbption in the phospholipid membrane. Now, if you're proposing taking like 15-16g a day of the stuff as I've heard many Anarchy-guys advocate, you better be taking in a lot of flax to keep your N-3:N-6 ratios optimal for cutting. Which once again begs me to ask: why bother?

    As far as the UCP-1 goes, once again, I'd say save it until you're not running M-1-T. To explain why would, once again, take a lot of time which I'm not up to putting in. But read this, which gives a very good idea of how uncouplers act, and just think about how those sorts of conditions would affect tissue-turnover rates and protein synthesis in someone endeavoring to gain LBM.

    the article is here:

    http://www.blackwell-synergy.com/lin....00043.x/full/
    Ok:

    1. That was a cut and paste from the anarchy stack thread. I did not say that all specific possible beneficial functions of ALCAR will benefit me. I did not "tout" these as all specifically benefitting me, again that was a copy and paste. You are being too presumptuous with your assertions of my intentions in posting that. What I did imply, however, is that with a rap sheet that long, and several benefits admitted above by yourself even, ALCAR should provide to be only beneficial to me, regardless of androgen use. Can you say that: a) taking ALCAR while on a cycle of M1T is a harmful and/or completely and totally ineffective thing (sans cost as mentioned above, that is not the major factor for me)? b) any possible benefits I may receive from using ALCAR while on cycle will be negated?

    2. I have not "umbrella-ed a blanket of random and unrelated assertions together to conclude a convincing argument". That is your slant on it. You seem to think that list was mine, and I back and represent every statement there. What I did was present what I thought to be a compelling list of possible benefits from using ALCAR, not imply that they all have a direct effect on me. There are many other things to consider with the anarchy stack, and I will not rehash them here. If you wish to argue the benefits of the anarchy stack, please do so in the anarchy thread in the supps section.

    3. I have posted this elsewhere, but I should clarify further apparently: I do not take CLA with the anarchy stack, for some reasons you have pointed out, as well as some things Nandi at CEM has brought to light, among many others at various boards.

    4. I can't access that article about uncouplers, I get a login page? You stated: "just think about how those sorts of conditions would affect tissue-turnover rates and protein synthesis in someone endeavoring to gain LBM". My point is that I am cutting, not specifically interested in major LBM gains.If they come, great, if I simply preserve mass while cutting, good enough for me.

    5. I completely understand your motivation in presenting that I may not "need" the anarchy stack while using this, but it isn't about "need" to me. With a proper diet I don't "need" any supplements at all, do I? As metnioned before, cost was not a paramount issue for me with this run. You unfortunately spent too much time on the CLA aspect BTW, as I do not take it, sorry for not clarfying that earlier. Now....consdering I don't believe my ideas to be completely idiotic and I think we've both proven some points here: get the hell of my nuts!!

     

     
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    With that said I have to concede this:

    I think the best way to go about this would be:

    (3) 2 week cycles of M1T with 1.5 weeks off inbetween.
    Between cycles running the UCP-1 and Gugg, as well as Swole V2.
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    no nolva - clomid or oxo in btw?
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    Originally posted by goldylight
    no nolva - clomid or oxo in btw?
    Of course, yeah. I have plenty of both, probably use clomid
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    Originally posted by Method
    Don't know, it works fine for me, and yes, the site is perfectly legit, it's the homepage for Blackwell Publishing Inc.

    If it really doesn't work for you, try going here, and scrolling down to article #255, then you can get it in PDF format

    http://www.blackwell-synergy.com/ser...&part=null
    Again, it says I need a subscription. Please upload the PDF file for us
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    Again, it says I need a subscription. Please upload the PDF file for us
    My hunch is I can get it through my campus ethernet connection, and that's why no one else can. Since I seriously lack computer skills in that department, can somebody gimme a quick tutorial on uploading a PDF?


    4. I can't access that article about uncouplers, I get a login page? You stated: "just think about how those sorts of conditions would affect tissue-turnover rates and protein synthesis in someone endeavoring to gain LBM". My point is that I am cutting, not specifically interested in major LBM gains.If they come, great, if I simply preserve mass while cutting, good enough for me.
    Fine, but the point is that Bobo's cutting too, and he's gaining LBM and strength thanks to the M-1-T. Stacking an uncoupler with it will negate that though. Steroids alter your genetics so that you can lose fat and gain muscle simultaneously. That's why IMO taking an uncoupler is like shooting yourself in the foot gains-wise, because your body can't build muscle when it's 'fighting itself' to keep from overproducing energy.
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    Originally posted by Method


    My hunch is I can get it through my campus ethernet connection, and that's why no one else can. Since I seriously lack computer skills in that department, can somebody gimme a quick tutorial on uploading a PDF?




    .
    Thats probably the reason. Its the same with many online publications (Journal of Endocrinology) that Universties get a free pass.
    For answers to board issues, read the Suggestion and News forum at the bottom of the main page.
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    Originally posted by Method


    My hunch is I can get it through my campus ethernet connection, and that's why no one else can. Since I seriously lack computer skills in that department, can somebody gimme a quick tutorial on uploading a PDF?




    Fine, but the point is that Bobo's cutting too, and he's gaining LBM and strength thanks to the M-1-T. Stacking an uncoupler with it will negate that though. Steroids alter your genetics so that you can lose fat and gain muscle simultaneously. That's why IMO taking an uncoupler is like shooting yourself in the foot gains-wise, because your body can't build muscle when it's 'fighting itself' to keep from overproducing energy.
    1. Save the file to your hard drive. The upload it as youwould any other attachment. We do accept .pdf files as attachments here.

    2. This seems tobe speculation, although not unfounded. I'll probably just run the UCP-1 during the 10 days off, although if one wanted to minimize the amount of lean mass lost, I would certainly think an anabolic agent would do so, no? (i.e like running one while on T3 for example, although I realize T3 and uncouplers do not share the same mechanism of action).
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    Originally posted by Bobo


    Thats probably the reason. Its the same with many online publications (Journal of Endocrinology) that Universties get a free pass.
    Yep, we have many things here at the law school that require the student be on campus to utilize also 
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    Originally posted by Method



    Fine, but the point is that Bobo's cutting too, and he's gaining LBM and strength thanks to the M-1-T. Stacking an uncoupler with it will negate that though. Steroids alter your genetics so that you can lose fat and gain muscle simultaneously. That's why IMO taking an uncoupler is like shooting yourself in the foot gains-wise, because your body can't build muscle when it's 'fighting itself' to keep from overproducing energy.

    I have a feedling with this, it just might be able too. Lets just say I have a *ahem* hunch


    It is DEFINETLY potent.
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    Originally posted by jweave23


    (i.e like running one while on T3 for example,


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    That was giving me way too much trouble, so, eh, **** it:


    Obesity Reviews
    Volume 2 Issue 4 Page 255 - November 2001
    doi:10.1046/j.1467-789X.2001.00043.x


    Mitochondrial uncoupling as a target for drug development for the treatment of obesity
    J. A. Harper 1,2, K. Dickinson 3 and M. D. Brand 1
    Summary

    Mitochondrial proton cycling is responsible for a significant proportion of basal or standard metabolic rate, so further uncoupling of mitochondria may be a good way to increase energy expenditure and represents a good pharmacological target for the treatment of obesity. Uncoupling by 2,4-dinitrophenol has been used in this way in the past with notable success, and some of the effects of thyroid hormone treatment to induce weight loss may also be due to uncoupling. Diet can alter the pattern of phospholipid fatty acyl groups in the mitochondrial membrane, and this may be a route to uncoupling in vivo. Energy expenditure can be increased by stimulating the activity of uncoupling protein 1 (UCP1) in brown adipocytes either directly or through 3-adrenoceptor agonists. UCP2 in a number of tissues, UCP3 in skeletal muscle and the adenine nucleotide translocase have also been proposed as possible drug targets. Specific uncoupling of muscle or brown adipocyte mitochondria remains an attractive target for the development of antiobesity drugs.

    Pharmaceutical interest in uncoupling Go to: Choose Top of page Pharmaceutical interest i... << Standard metabolic rate What is uncoupling? Physiological significanc... Mechanism of proton leak:... Artificial uncoupling by ... Thyroid hormones Inducible uncoupling cata... beta3-Adrenergic receptor ago... Uncoupling proteins 2 and... Is the uncoupling of mito... Acknowledgements References

    Obesity is a disease resulting from a prolonged positive imbalance between energy intake and energy expenditure resulting in the storage of fat. The rapidly increasing world-wide incidence of obesity and its association with serious comorbid diseases means it is beginning to replace under-nutrition and infectious diseases as the most significant contributor to ill health in the developed world (1). Weight loss, induced by dieting, has been shown to be successful in reducing the health consequences of obesity but unfortunately >90% of individuals who lose weight through dietary control eventually return to their original weight (2). Pharmacological treatment may therefore be desirable for those patients with associated comorbid conditions who have been unable to control their obesity through diet and exercise.

    Any treatment for obesity has to reduce energy intake, increase energy expenditure or combine both effects. Current therapies for obesity predominantly lead to decreased energy intake either by acting at satiety centres in the brain (e.g. sibutramine) (3-5) or by reducing the efficiency of intestinal absorption (e.g. orlistat) (6,7). In addition to reducing energy intake, sibutramine increases standard metabolic rate (SMR) profoundly in rodents, but increased energy expenditure appears to be only a minor component of its activity in humans (8,9). Exercise is the most practical and potentially easiest way to increase energy output. Studies have shown a sevenfold-increased risk of the incidence of overweight in those with a physical activity ratio (total energy expenditure: resting metabolic rate) of <1.8 (10). The main benefit of exercise is to increase resting metabolic rate, and overall energy expenditure, by a greater amount than that resulting directly from the exercise (11). Pharmacological agents that increase metabolic rate by increasing uncoupling of mitochondrial oxidative phosphorylation are likely to mimic this beneficial effect of exercise on resting metabolic rate and could provide a useful adjunct to agents acting to reduce satiety; this review will consider how such uncoupling can be achieved.

    As discussed below, uncoupling of mitochondria represents a particularly attractive target, as there is already excellent proof of concept for this approach in humans using 2,4-dinitrophenol (DNP) (12) and in animals using 3-adrenoceptor agonists (13), or overexpression of UCP3 (uncoupling protein 3) (14). However, there are problems associated with the use of chemical uncouplers like DNP. Many of these problems may result from inappropriate activities in critical tissues, and more selective uncoupling would be desirable.

    Skeletal muscle represents a particularly attractive target for directed uncoupling due to the large muscle mass, which accounts for approximately 15-20% of SMR (15,16). The maximal aerobic capacity of a human is generally estimated to be up to 12 times SMR in untrained subjects (17). Most of this increase can be directly attributed to skeletal muscle respiratory activity and it is clear that muscle can greatly increase its metabolic activity. Doubling metabolic rate by modestly uncoupling skeletal muscle should produce few adverse side-effects as this increase would only be equivalent to mild exercise (actually equivalent to approximately the difference between lying down and standing up (17)). Indeed, support for this view has been obtained using proteins that may naturally uncouple mitochondria (uncoupling proteins 1 and 3). High expression of human UCP3 in mouse skeletal muscle led to decreased weight gain despite increased food intake (14), and expression of UCP1 in mouse skeletal muscle led to improvements in insulin sensitivity and resistance to obesity on a high fat diet (18).

    Standard metabolic rate Go to: Choose Top of page Pharmaceutical interest i... Standard metabolic rate << What is uncoupling? Physiological significanc... Mechanism of proton leak:... Artificial uncoupling by ... Thyroid hormones Inducible uncoupling cata... beta3-Adrenergic receptor ago... Uncoupling proteins 2 and... Is the uncoupling of mito... Acknowledgements References

    Basal metabolic rate (BMR) is the minimal calorific requirement for normal life in an organism in the absence of external stimulation, work and growth. It is measured under rigorous conditions at thermoneutrality, in a post-absorptive state. Many physiological processes continue in this minimal state, including ventilation and blood circulation. At the cellular level, the reactions that make up BMR include protein turnover, ion cycling across the plasma membrane, turnover of nucleic acids and lipids, and proton cycling across the mitochondrial inner membrane (uncoupling) (19,20). Resting metabolic rate (RMR) is measured as BMR but not in the post-absorptive state (17). These measurements are not suitable in animals (particularly ectotherms), therefore standard metabolic rate (SMR) is used. SMR is measured under defined conditions which are not necessarily those of BMR; in particular, temperature may vary. SMR varies considerably between species. It is primarily dependant on body mass to approximately the 0.75th power (21,22), so mass-specific SMR decreases as body mass increases (22,23). For example, the SMR per gram of a mouse (body mass 0.05 kg) is approximately 10-fold higher than the SMR per gram of a horse (body mass 500 kg). The field metabolic rate (FMR) is the metabolic rate of an animal in its natural environment. Factors such as digestion, hunting, reproduction, growth and temperature regulation increase the metabolic rate around twofold in humans and around fourfold in other mammals (20), irrespective of body size. In other words, around one quarter of field energy expenditure in mammals is due to SMR (21,24,25). The differences in mass-specific SMR between species indicate the existence of regulatory mechanisms that may be amenable to pharmacological manipulation. Some of these differences in SMR may be caused by differences in mitochondrial proton cycling.

    What is uncoupling? Go to: Choose Top of page Pharmaceutical interest i... Standard metabolic rate What is uncoupling? << Physiological significanc... Mechanism of proton leak:... Artificial uncoupling by ... Thyroid hormones Inducible uncoupling cata... beta3-Adrenergic receptor ago... Uncoupling proteins 2 and... Is the uncoupling of mito... Acknowledgements References

    Mitochondria are normally responsible for 90% of cellular oxygen consumption and the majority of adenosine triphosphate (ATP) production. The flow of electrons from reduced substrate to oxygen is coupled by a proton electrochemical gradient across the mitochondrial inner membrane to the synthesis of ATP from adenosine diphosphate (ADP) and phosphate (Fig. 1). This process of oxidative phosphorylation can be subdivided into two distinct parts: the generation of the proton electrochemical gradient by the respiratory chain and the synthesis of ATP by the Fo-F1 ATP synthase using the potential energy stored in the gradient. However, not all of the available energy is coupled to ATP synthesis. Instead, much is lost by uncoupled reactions when protons move from the cytosol back into the mitochondrial matrix via pathways which circumvent the ATP synthase and other uses of the electrochemical gradient. There are two sorts of uncoupling. Basal uncoupling is not acutely regulated and is present in all mitochondria, whereas inducible proton conductance is catalysed by proteins, tightly regulated, and found in discrete cell types (Fig. 1).

    Physiological significance of mitochondrial proton cycling Go to: Choose Top of page Pharmaceutical interest i... Standard metabolic rate What is uncoupling? Physiological significanc... << Mechanism of proton leak:... Artificial uncoupling by ... Thyroid hormones Inducible uncoupling cata... beta3-Adrenergic receptor ago... Uncoupling proteins 2 and... Is the uncoupling of mito... Acknowledgements References

    Proton cycling is a major contributor to SMR, responsible for around 26% of the oxygen consumed in resting rat hepatocytes (26) and about 52% in perfused, resting rat skeletal muscle (15). Multiplication of these values by the contribution of each tissue to SMR suggests that proton cycling accounts for 20-25% of rat SMR (15). This makes proton cycling the largest single contributor to SMR.

    Under field conditions, ATP turnover increases significantly and the ATP synthase competes with proton leak for the same proton electrochemical energy. It is important to discover whether proton cycling still represents a significant proportion of energy expenditure when ATP synthesis is increased. Rolfe and co-workers (16) showed that when respiration rate was doubled by stimulating ureagenesis and gluconeogenesis in hepatocytes and muscle contraction in perfused rat hindquarters, the rate of proton cycling stayed fairly constant. Of course, proton cycling dropped as a proportion of total respiration rate, but only to 22% in hepatocytes and 34% in muscle (16). Estimates from these experiments suggest that proton cycling in animals under more plausibly physiological conditions uses around 15-20% of total energy consumption and so remains a substantial proportion of SMR.

    SMR varies with body mass, and proton cycling is an important component of SMR. Does proton cycling change in parallel with SMR, or does it change less or more than SMR? Components of SMR such as the urinary excretion of endogenous nitrogen and sulphur (27) and the rates of respiration, circulation and renal activity (28,29) remain a constant proportion of SMR as body mass varies. Only relatively recently has the contribution of proton cycling to SMR been examined in animals of different body mass. Porter and Brand (30) found that proton conductance in liver mitochondria decreased with increasing body mass in mammals. However, the proportion of energy expended via proton cycling was approximately the same in hepatocytes from all mammals (31,32). Around 70% of the proton conductance difference was because of less mitochondrial inner membrane area in cells from larger animals (33). The remaining difference was some intrinsic property of the membrane. Because this intrinsic property can be altered according to body mass it might be modifiable by drugs. If proton leak could be stimulated in some way, then more energy would be dissipated during synthesis of ATP. This partial uncoupling would cause an increase in SMR and an alteration in the balance between energy input and output if energy intake did not rise to compensate. At comparable energy intakes, a 1% change in BMR in humans would lead to loss or gain of about 1 kg of adipose tissue per year, so over a long period it could cause or combat obesity.

    Mechanism of proton leak: passive diffusion Go to: Choose Top of page Pharmaceutical interest i... Standard metabolic rate What is uncoupling? Physiological significanc... Mechanism of proton leak:... << Artificial uncoupling by ... Thyroid hormones Inducible uncoupling cata... beta3-Adrenergic receptor ago... Uncoupling proteins 2 and... Is the uncoupling of mito... Acknowledgements References

    To consider how to increase mitochondrial uncoupling as a means to increase BMR and reduce obesity, it would be helpful to understand how protons re-enter the mitochondrial matrix without passing through the ATP synthase. Diffusion of protons through the phospholipid bilayer is one possible mechanism of basal proton conductance. To judge the physiological importance of this process, phospholipids from mitochondria with different proton conductance were extracted and reformed into liposomes and the proton conductance of the bilayer was examined (34). This experiment allowed two issues to be resolved; first, the percentage of proton conductance that could be explained by proton diffusion across the bilayer; and second, the effect of the phospholipid fatty acyl composition of the bilayer on the conductance. The results showed that passive diffusion in liposomes could account for only 2.5% to 25% of the proton conductance of mitochondria with the same phospholipid fatty acyl composition, implying that some other property of the membrane, such as the presence of proteins, was important in determining the conductance. There was no significant difference in proton conductance between liposomes with very different phospholipid fatty acyl compositions, despite a known relationship between the phospholipid fatty acyl composition of intact mitochondria and proton conductance (34). Perhaps acyl composition is important in mitochondria, but loss of phospholipid asymmetry or of some specific protein causes the effect to be lost in liposomes.

    Mitochondrial membranes containing a higher ratio of polyunsaturated fatty acyl groups (PUFA) to monounsaturated fatty acyl groups (MUFA) may allow a higher molecular activity of membrane proteins, so membrane acyl composition could affect metabolic rate. In particular, n-3 PUFAs have been strongly linked to SMR (35). As described above, mammals with a smaller body mass have higher mass-specific SMR and higher mitochondrial proton conductance than larger mammals. Surface area and fatty acyl composition of mitochondria both vary with body mass (33,35), so either factor could affect proton conductance. Around two-thirds of the difference in proton conductance of mitochondria from mammals of different body mass is due to the amount of mitochondrial membrane, and one-third is due to some difference (protein or phospholipid) in membrane composition (33). Dietary fatty acids can alter the fatty acyl composition of the mitochondrial inner membrane (36), and it is conceivable that diet, or pharmaceutical agents that alter the PUFA : MUFA ratio of fatty acyl groups in the membrane, could affect mitochondrial uncoupling and hence modify BMR and weight gain. For example, fish oil high in n-3 PUFA has been suggested to limit obesity (37,38). Oils that contain high levels of n-3 fatty acids and purport to be beneficial are already on sale, although evidence that they effect weight loss is lacking (39).

    Artificial uncoupling by dinitrophenol Go to: Choose Top of page Pharmaceutical interest i... Standard metabolic rate What is uncoupling? Physiological significanc... Mechanism of proton leak:... Artificial uncoupling by ... << Thyroid hormones Inducible uncoupling cata... beta3-Adrenergic receptor ago... Uncoupling proteins 2 and... Is the uncoupling of mito... Acknowledgements References

    Uncoupling of mitochondria as a treatment for obesity is not unprecedented; the artificial uncoupler 2,4-dinitrophenol (DNP) has been used for this purpose for many years (12,40). DNP is a lipid-soluble weak acid which acts as a protonophore because it can cross membranes protonated, lose its proton and return as the anion, then reprotonate and repeat the cycle. In this way, it increases the basal proton conductance of mitochondria and uncouples. The effect of DNP derivatives was first noted in 1885 when scientists saw thermogenic effects of Martius Yellow (a dinitro-alpha-napthol), a coal tar dye used in the 19th century to give the impression that food was rich in eggs (41).

    DNP was introduced as a drug in the 1930s and used with considerable success, though reports of side-effects (cataracts) and some deaths from overdose led to it being chased off the market by the US Food and Drug Administration (FDA) in 1938. This use of DNP to treat obesity was stimulated by observations of its toxicity in French munitions workers during World War I (the French commonly used a mixture of 40% dinitrophenol and 60% trinitrophenol for their munitions). In animals, it was shown that the drug promoted a direct stimulation of cellular respiration and a consequent rise in body temperature. It led to the almost immediate onset of rigor mortis when death was promoted by large doses (42,43).

    A series of controlled trials in obese patients were prompted by these promising mode of action studies. The most extensive were carried out during the 1930s at Stanford University, CA, USA (44-47), though others also performed careful studies (48). Interpretation of this work can be complicated, as the doses of DNP had to be optimized for each patient (due to the steep dose response and patient to patient variability) and were usually increased as the studies progressed. This means the DNP-sensitive patients on low doses of the drug would show enhanced efficacy compared with the population (and vice versa for patients on high does of DNP). However, there was a clear dependence of metabolic rate on DNP dose (Fig. 2). There was an average 11% increase in metabolic rate for each dosage increment of 0.1 g of DNP (44,48). Doses up to 0.5 g (about 5 mg kg 1) were generally well-tolerated apart from patients almost always reporting a feeling of warmth together with increased perspiration (45,46,48). Between about 5-10 mg kg 1, patients reported profuse sweating but, surprisingly, there was no evidence of increased body temperature or heart rate. Doses above 10 mg kg 1 led to increased heart rate, respiration rate and excessive body temperature rises (45). Single doses of 3-5 mg kg 1 produced an increase in resting metabolic rate of 20-30% within the first hour. This was maintained for 24 h after which a gradual fall became apparent. Daily dosing of 3-5 mg kg 1 produced a gradual increase of efficacy: an average 40% increase in metabolic rate was observed after a few weeks that was then maintained, with no sign of tolerance, for at least 10 weeks (45).

    Weight loss in these studies, where no attempt was made to control diet, was reported to be variable. Of 170 treated patients, a mean of 7.8 kg weight loss was recorded, averaging 0.64 kg week 1 (44) (Fig. 2). There were no clearly reported effects on food consumption. In contrast to the use of thyroid extract (also in common use at the time to treat obesity), DNP did not promote urinary nitrogen excretion, so the assumption was made that weight loss could be attributed to a specific loss of fat (47). One potential complication in the interpretation of weight loss data is the ability of the drug to promote oedema. This effect was reported to account for a common apparent failure to continue to lose weight in the face of a maintained increase in metabolic rate (48). For some patients, withdrawing DNP led to a rapid weight loss that was attributed to loss of excess body water after which DNP dosing could be resumed with its former effectiveness. Therapeutic doses of DNP had no effects on blood pressure or heart rate in normal patients. Interestingly, a subset of 30 hypertensive patients exhibited average falls of 9.4% in systolic and 12.6% in diastolic blood pressure (44). These improvements in hypertension were also noted at doses of DNP insufficient to cause weight loss (48). Some studies were also performed in diabetic patients with inconsistent results but there did appear to be improvements in glucose tolerance after long-term dosing (48). The reported potency of DNP to treat obesity (and associated comorbid conditions) in these early trials compares well with current treatments for obesity (3,4,6).

    This ability of dinitrophenol to produce good reductions in body weight, without the need for dietary restriction, led to its widespread use to treat obesity. In the absence of formal regulatory controls it is not surprising that it was soon prescribed by inexperienced physicians with no access to the metabolic rate measurements necessary to determine optimal doses. DNP was even included in a variety of 'antifat nostrums' that could be used by the public without medical consultation. By 1934 it was estimated that a total of 100 000 patients had been treated (40).

    Given the steep dose dependence of metabolic rate and the widespread use of DNP it is perhaps not surprising that a number of people were 'literally cooked to death' in the 1930s due to accidental or deliberate overdose (40). It was argued at the time that the reported deleterious effects of DNP were remarkably few (when given at the correct therapeutic doses), given the large number of patients who had taken it. The authors did, however, note a 7% incidence of severe skin rashes, necessitating discontinuation of treatment. There was no overt liver or kidney damage, but the same authors voiced some concerns about the incidence of agranulocytosis though they saw no cases in their own long-term studies (44). Of more concern, a number of cases of cataracts were reported in women in 1935 (49,50). In 1938 the FDA acquired more powers to prosecute manufacturers of misbranded therapies and announced that the use of a variety of patent medicines (including DNP) could lead to prosecution (12). These threats led to a withdrawal, in 1938, of the DNP-containing nostrums from the market as well as an end to the official clinical use of DNP. Interestingly, however, there are reports on the Internet that describe the use of DNP by US clinics (who avoided illegal interstate transportation of DNP for human use by synthesizing it within each state), and give detailed protocols for its use amongst the designer drug community of body-builders and those willing to risk self-administration of DNP to lower body mass.

    Given the age of the publications describing the mode of action in rodents, one of us (KD) recently re-evaluated the effects of DNP in rats and confirmed the relative insensitivity of this species and the particularly steep dose response to increase metabolic rate. In contrast to humans, DNP did not significantly increase metabolic rate in rats when dosed orally at 10 mg kg 1 (data not shown) but a good, comparatively long lasting, increase was seen at 30 mg kg 1 that was comparable in magnitude to a rodent 3-adrenoceptor agonist (Fig. 3) (51). Doses of 100 mg kg 1 produced an escalating hyperthermia that necessitated killing the animals to avoid distress.

    Thyroid hormones Go to: Choose Top of page Pharmaceutical interest i... Standard metabolic rate What is uncoupling? Physiological significanc... Mechanism of proton leak:... Artificial uncoupling by ... Thyroid hormones << Inducible uncoupling cata... beta3-Adrenergic receptor ago... Uncoupling proteins 2 and... Is the uncoupling of mito... Acknowledgements References

    Thyroid hormones have a long history in the treatment of obesity (52) and are positively correlated with BMR (53,54). At the cellular level, hepatocytes isolated from hyperthyroid rats have twice the respiration rate of euthyroid controls. About half of the increase is caused by increased mitochondrial proton cycling, which is partly due to greater proton conductance and partly to a greater driving force (proton electrochemical gradient) (55). At the subcellular level, mitochondria prepared from the liver of hyperthyroid animals have increased proton permeability compared with those from euthyroid animals (56,57).

    In the 1950s the respiratory stimulation in isolated mitochondria was attributed to direct uncoupling by thyroid hormones using the same mechanism as DNP (58). However, this effect only occurred in vitro with supra-physiological concentrations of hormones (59). There are now two main hypotheses for the stimulation of respiration and proton conductance in mitochondria and cells by thyroid hormones (60).

    In the first hypothesis, thyroid hormones act directly at the membrane level, rigidifying the bilayer and leading to a compensatory change in the fatty acyl composition of the phospholipids. Alternatively, thyroid hormones could alter membrane composition through transcriptional regulation of desaturases and other enzymes. In either case, the change in phospholipid fatty acyl composition alters the proton conductance and degree of uncoupling of the mitochondrial inner membrane. In support of this hypothesis, the polyunsaturation of mitochondrial phospholipid acyl chains increases in hyperthyroidism (36,60,61), and liver mitochondrial proton conductance correlates with polyunsaturation of mitochondrial phospholipid acyl chains (33,62). Hyperthyroid mitochondria also have less cholesterol and increased cardiolipin (63). Changes in the area of mitochondrial inner membrane are also implicated in the change in measured proton conductance (57).

    In the second hypothesis, thyroid hormones act through transcriptional regulation and affect proton conductance through expression of specific proteins (64). For example, the levels of UCP2 and UCP3 mRNA increase in response to thyroid treatment (65-69).

    Supra-physiological doses of thyroid hormones are no longer used in the treatment of obesity because of unwanted side-effects such as tachycardia, increased heart weight (70,71), thyroid atrophy (72) and a negative nitrogen balance, that is a loss of lean body mass (muscle) (73,74). They may cause loss of water and muscle rather than loss of fat and adipose tissue.

    Inducible uncoupling catalysed by specific proteins Go to: Choose Top of page Pharmaceutical interest i... Standard metabolic rate What is uncoupling? Physiological significanc... Mechanism of proton leak:... Artificial uncoupling by ... Thyroid hormones Inducible uncoupling cata... << beta3-Adrenergic receptor ago... Uncoupling proteins 2 and... Is the uncoupling of mito... Acknowledgements References


    Uncoupling protein 1

    The ability of hibernators, cold-adapted rodents and new-born mammals to produce heat and increase SMR by non-shivering thermogenesis results mostly or only from the activity of uncoupling protein 1 (UCP1) in mitochondria in brown adipose tissue (BAT) (75,76). The identification of UCP1 as the mediator of uncoupling followed from the observation of greater uncoupling of BAT mitochondria than of liver and heart mitochondria (77,78). Importantly, this increased uncoupling was abolished by albumin and by purine nucleotides, indicating that it could be regulated in vivo by free fatty acids and nucleotides (79). The ability of UCP1 to transport protons was demonstrated by mitochondrial swelling experiments (77,79). A 32-kDa protein was observed to be specifically and highly expressed in BAT mitochondria. Photo-affinity labelling identified a 32-kDa protein as the binding site of purine nucleotides and a putative uncoupling protein was proposed (80). Subsequently, the 32 kDa protein was purified from hamster and rat (81,82). The cDNA was sequenced and cloned and the protein's proton translocating activity was demonstrated in transgenic yeast mitochondria (83) and liposomes (84-87). After these experiments it was generally accepted that UCP1 was responsible for the regulated uncoupling of BAT.

    Further experiments were performed with transgenic mice (88). A mouse model in which all UCP1 had been removed by homologous recombination was created by Enerbäck and co-workers (89). These UCP1-deficient mice were more sensitive to cold and showed a greatly reduced effect of 3-adrenoreceptor agonists, indicating reduced thermogenic capacity. However, when they were fed normal or high-fat diets they were not obese. There was an increase in the adiposity of the BAT, as expected if it did not have to oxidize fatty acids as fast to maintain a normal proton electrochemical gradient. Interestingly, other studies in transgenic mice using a diphtheria toxin gene linked to a UCP1 promoter to genetically ablate BAT did show obesity linked to loss of BAT activity (90). As the obesity in this UCP1-DTA model seemed to result predominantly from hyperphagia it appears that the differences between the two models resides in other (non-thermogenic) activities of BAT. Other studies using targeted expression of UCP1 to mouse muscle (18) or white fat (91) demonstrated a resistance to the development of obesity and an improvement in comorbid conditions consistent with increased uncoupling activities in these tissues.


    3-Adrenergic receptor agonists Go to: Choose Top of page Pharmaceutical interest i... Standard metabolic rate What is uncoupling? Physiological significanc... Mechanism of proton leak:... Artificial uncoupling by ... Thyroid hormones Inducible uncoupling cata... beta3-Adrenergic receptor ago... << Uncoupling proteins 2 and... Is the uncoupling of mito... Acknowledgements References

    There has been considerable interest within the pharmaceutical industry in developing specific 3-adrenoceptor agonists that would selectively lead to the activation of uncoupling through UCP1 in brown fat. The ability to selectively uncouple should avoid many of the side-effects that might occur with DNP. The activity of the 3-adrenoceptor to activate lipolysis in both white and brown fat leading to a consequent activation of UCP1 mediated lipolysis in brown fat is now well understood (92-94). Numerous studies in rodents have shown that 3-adrenoceptor agonists produce profound improvements in insulin sensitivity in a number of diabetic animal models and lead to substantial weight loss due to selective fat loss (13,95). These rodent studies provide excellent evidence that activation of uncoupling by brown fat represents an important potential human therapeutic target. Unfortunately, clinical studies have yet to provide proof of concept in humans, though clinical trials are still in progress. It has proved particularly difficult to develop 3-adrenoceptor agonists that lack activity against 1 and 2-adrenoceptors (13,95). This difficulty, coupled with the very low levels of brown fat in adult humans has made the results of the various clinical trials difficult to interpret. However, if 3-adrenoceptor agonists prove capable of reactivating dormant brown fat, or if conversion of white to brown adipose tissue becomes possible, then a suitably selective agent may show relevant activity in humans.

    Uncoupling proteins 2 and 3 Go to: Choose Top of page Pharmaceutical interest i... Standard metabolic rate What is uncoupling? Physiological significanc... Mechanism of proton leak:... Artificial uncoupling by ... Thyroid hormones Inducible uncoupling cata... beta3-Adrenergic receptor ago... Uncoupling proteins 2 and... << Is the uncoupling of mito... Acknowledgements References

    UCP1 is restricted to brown adipocytes, and was originally thought to be the only transporter capable of uncoupling mitochondria (96-98). However, UCP1 probes occasionally gave weak signals in other tissues (93), suggesting the presence of homologues. UCP2 was discovered because of its relatively high sequence identity to UCP1 (59%). UCP2 mRNA has been found in many tissues, including cardiac muscle, BAT, white adipose tissue, skeletal muscle, kidney, non-parenchymal liver cells, lung, placenta, pancreatic cells and the immune system. However, mRNA expression does not necessarily imply protein expression, as UCP2 protein was not detected in heart, skeletal muscle, liver or BAT (99). UCP3 was also discovered by database searching. Human UCP3 is 59% identical to human UCP1 and 72% identical to human UCP2. UCP3 is restricted to BAT and skeletal muscle (100), both tissues that make a major contribution to thermogenesis, making it a more enticing target for drug development than UCP2.

    Evidence that UCP2 and UCP3 are responsible for basal proton conductance comes from experiments employing high expression of mammalian UCP2 and UCP3 in yeast (101-103) and transgenic overexpression of human UCP3 in mice (14). Such high expression lowers mitochondrial membrane potential and increases state 4 respiration, indicating uncoupling. It inhibits the growth of yeast and protects against obesity in hyperphagic mice. However, the normal concentrations of UCP2 (99) and UCP3 (104,105)protein expressed in mammalian tissues are very low. The amounts expressed in transgenic yeast (104) or UCP3-overexpressing mice (14) are strongly supra-physiological and there is good evidence that the uncoupling is an artefact not related to the physiological functions of UCP2 and UCP3 (105,106) (S. Cadenas et al. unpublished data; J. A. Harper et al. unpublished data). Proteoliposomes have also been used in studies of the function and regulation of UCP1 and its homologues (107-110). These studies found different nucleotide sensitivities and low turnover numbers, but they did identify ubiquinone as an essential cofactor for uncoupling in vitro by UCP1 and its homologues (111,112).

    The UCPs have been knocked out in mice, avoiding interpretational problems resulting from the requirement for overexpressed protein to be correctly inserted and folded in membrane. Two studies (113,114) found that UCP2 mRNA was increased in BAT of UCP1 knockout mice with no increased uncoupling. However, UCP2 protein was not measured and may not have changed. The proton conductance of skeletal muscle mitochondria from UCP3 knockout mice was decreased (115,116), indicating that UCP3 is responsible for at least some of the proton conductance in skeletal muscle. However, we have not been able to confirm these observations (S. Cadenas et al. unpublished data). Despite the reported effects in genetically modified mice, natural changes in UCP2 and UCP3 mRNA and UCP3 protein levels do not alter mitochondrial proton conductance. For example, UCP2 and UCP3 mRNA increase in muscle from starved rats (117) despite a known depression in thermogenesis (118). UCP3 mRNA increases fourfold and UCP3 protein doubles but there is no change in the mitochondrial proton conductance (119).

    Taken together, the evidence suggests that UCP1, UCP2 and UCP3 are not responsible for the basal proton conductance of mitochondria. Clearly, UCP1 causes inducible uncoupling in BAT mitochondria, and UCP2 and UCP3 may yet be found to catalyse a similar uncoupling that is induced by unidentified agonists. The UCPs remain important potential targets for specific pharmacological uncoupling as a treatment for obesity. Other members of the mitochondrial carrier family have also been implicated in the uncoupling of mitochondria. In particular, the adenine nucleotide transporter is responsible for uncoupling by free fatty acids (120,121) and AMP (122). These carriers may also be potential drug targets.

    Is the uncoupling of mitochondria a viable target for drug development? Go to: Choose Top of page Pharmaceutical interest i... Standard metabolic rate What is uncoupling? Physiological significanc... Mechanism of proton leak:... Artificial uncoupling by ... Thyroid hormones Inducible uncoupling cata... beta3-Adrenergic receptor ago... Uncoupling proteins 2 and... Is the uncoupling of mito... << Acknowledgements References

    Uncoupling mitochondria is an effective way to increase thermogenesis and basal metabolic rate and it can lead to a substantial reduction in body weight by loss of fat deposits. This has been shown in humans taking DNP orally and in transgenic mice overexpressing human UCP3 or UCP1 in muscle. Proof of concept has therefore been unambiguously established, showing that uncoupling can increase energy expenditure without compensatory mechanisms increasing food intake to the extent that they nullify the uncoupling.

    However, using pharmacological agents to uncouple all mitochondria throughout the body may be a high-risk treatment, because it might compromise energy homeostasis in tissues such as heart and brain. On the other hand, active tissues like these may be less susceptible to mild uncoupling than less active ones like resting muscle or resting BAT because proton conductance has much less control over respiration rate in active mitochondria (123). The small difference between the effective and the fatal doses of DNP, as well as side-effects resulting from its non-selective actions, mean that it is not itself a suitable antiobesity drug. Tissue selectivity and safety need to be improved.

    The UCP3-overexpressing mouse shows that selective uncoupling of muscle mitochondria is sufficient for a strong anti-obesity effect. Specific uncoupling of brown adipose tissue mitochondria through UCP1 or of muscle mitochondria through UCP3 or in some other way remains a viable and attractive target for the development of drugs for the treatment of obesity.


    Acknowledgements Go to: Choose Top of page Pharmaceutical interest i... Standard metabolic rate What is uncoupling? Physiological significanc... Mechanism of proton leak:... Artificial uncoupling by ... Thyroid hormones Inducible uncoupling cata... beta3-Adrenergic receptor ago... Uncoupling proteins 2 and... Is the uncoupling of mito... Acknowledgements << References

    JAH was supported by a BBSRC CASE award with Knoll Ltd.

    References Go to: Choose Top of page Pharmaceutical interest i... Standard metabolic rate What is uncoupling? Physiological significanc... Mechanism of proton leak:... Artificial uncoupling by ... Thyroid hormones Inducible uncoupling cata... beta3-Adrenergic receptor ago... Uncoupling proteins 2 and... Is the uncoupling of mito... Acknowledgements References <<

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    Obesity Reviews
    Volume 2 Issue 4 Page 255 - November 2001

    I have a feedling with this, it just might be able too. Lets just say I have a *ahem* hunch
    Then perhaps I'm comparing apples (DNP) to oranges (UA). I still maintain however, that uncouplers are best used off-cycle, and will deliver categorically better results when each is used separately with a different purpose in mind.

    I would certainly think an anabolic agent would do so, no? (i.e like running one while on T3 for example, although I realize T3 and uncouplers do not share the same mechanism of action).
    I can see where you're going with this, but thyroid is a whole different ball-game. I still hold to my initial recommendations.
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    I think we already have that article somewhere. Maybe in The UA FAQ?


    Well your point is taken but Weave isn't exactly using this for gains, moreso than a cutting agent and from I've seen its a great one. It would be the same if he used Winny, Var or Tren but in this case I tihnk his curiosity is the main culprit for using M1T.
    For answers to board issues, read the Suggestion and News forum at the bottom of the main page.
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    Okay, 1 week in @ 20mg.

    So far up 5lbs but slightly leaner.... very nice

    No major sides to report. Hair and libido is fine. Definitely feel "on" as expected, but no negative reactions at all. This definitely delivers results faster than other delivery methods IMO, although slightly different than other 1-test cycles so far.

    BTW popping milk thistle and potassium like pez
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    About 12 days in and so far....

    up 6-7 lbs and leaner.....hell yeah baby!!

    I think if I would've done more cardio I would be even leaner, but damn I'm impressed.

    Sides:
    Hair - fine, no shedding
    Libido - up and down, lol nothing extreme though I think
    Restlessness - very ancy, definitely feel "on", but I like that, lol
    Pumps - damn nice, lean pumped feeling
    Lifts - all are up slightly, some extra reps some additional weight
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    Originally posted by jweave23
    About 12 days in and so far....

    up 6-7 lbs and leaner.....hell yeah baby!!

    I think if I would've done more cardio I would be even leaner, but damn I'm impressed.

    Sides:
    Hair - fine, no shedding
    Libido - up and down, lol nothing extreme though I think
    Restlessness - very ancy, definitely feel &quot;on&quot;, but I like that, lol
    Pumps - damn nice, lean pumped feeling
    Lifts - all are up slightly, some extra reps some additional weight
    DAMN 6lbs in 12 days. Good sht man.
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    Can you tell us what kind off work out split you are doing and the volume per body part?
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    Originally posted by Molehonea
    Can you tell us what kind off work out split you are doing and the volume per body part?
    4 day split

    Day 1 - Chest/Tri's 3 exercises each, 3 sets of 6-8

    Day 2 - Back/Bicep 3 exercises, 3 sets of 6-8

    Day&nbsp;3 - Shoulder/Traps - 3 exercises, 3 sets of 6-8

    Day 4 - Legs/Abs - 5 exercises for legs of 6-8 reps (Squats, standing calf raise, leg extension, seated ham curl, seated calf raise) 2 exerices (weighted crunches and oblique twists) around 20 reps

    &nbsp;
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    I should add I've been off for almost a week now, totalling up at about a 7-8 lb gain in 2 weeks while slightly leaner, definitely a body composition change. Can't wait till next cycle in a week

    As for the Anarchy/UCP-1/Gugg stack - down about 2lbs this week, not too bad
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    Originally posted by jweave23


    4 day split

    Day 1 - Chest/Tri's 3 exercises each, 3 sets of 6-8

    Day 2 - Back/Bicep 3 exercises, 3 sets of 6-8

    Day&amp;nbsp;3 - Shoulder/Traps - 3 exercises, 3 sets of 6-8

    Day 4 - Legs/Abs - 5 exercises for legs of 6-8 reps (Squats, standing calf raise, leg extension, seated ham curl, seated calf raise) 2 exerices (weighted crunches and oblique twists) around 20 reps

    &amp;nbsp;
    When you say: 3 exercises each, 3 sets of 6-8 - does that mean you do one set for each of the 3 exercises or 3 sets for each exercise?
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    3 sets for each exercise

    i.e flat DB bench 3 sets of 6-8 reps
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    Ok so I took a few&nbsp;random pics tonight and decided to put them up. I was quickly disgusted by my own bodyfat level, so this is all you'll get right now

    &nbsp;
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    #2
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    #3
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    What are your stats bro, you look like a big boy.
  

  
 

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