UCP-1: Why L-Carnitine instead of ALCAR?

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    UCP-1: Why L-Carnitine instead of ALCAR?


    Perhaps Chemo can address this. I've read elsewhere that ALCAR is far more bioavailable than L-Carnitine. Was there a reason for L-Carnitine vs. ALCAR in UCP-1?

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    I question the use of either since both are seemingly worthless for fat-loss unless injected and the jury seems to be out on the effectivness of that.
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    Kerruptt...we did not intend on capitalizing on the fat loss potential of any one ingredient alone but instead engineered the formula to reap the benefits of synergistic action. I agree that the real world results of high L-C and pyruvate doses have been less than promising but we utilize them for their role in supporting the uncoupling agent.

    We have been up front in the past about formulation of the lotions and the movement behind it was one of open source sharing. Let's see if we can work this out with everyone contributing and see if the end result is the same. If nothing else you will see our logic of formulation (why not ALCAR) and at the same time gain a broader understanding of uncoupler theory.

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    ok, here's something from Anabolicexterme (by Grendel) that helped me understand it somewhat.........I think This was in regards to SU, he was talking about Lipokinetix. I used bold for some statements that I thought were relavant to UCP-1.

    http://www.anabolicextreme.com/archi...ipokinetix.htm

    DNP is what is known as a classical uncoupler of oxidative phosphorylation. Oxidative phosphorylation is the mitochondrial process that oxidizes organic substrates such as pyruvate and uses the resultant energy to convert ADP into ATP--the high-energy molecule that the body uses for fuel. Basically the energy from the oxidation is funneled through many complex chemical reactions until finally ATP is formed. The chemical reactions are called coupling sites since they connect (or couple) the flow of energy with the flow of electrons in the chemical reaction.


    Imagine with me for a moment many pipes attached end to end via valves. Now, imagine the pipe connected to a water supply. When the water is turned on it will flow through the pipe until it reaches a valve. As long as the valve is open the water will continue to flow. Closing the valve prevents the flow of water. Pay close attention now! Pick out a joint along the pipeline and imagine poking a hole in the pipe at this point. Water begins to flow through the hole and is wasted. To keep the same amount of water flowing through the pipe beyond the hole you would have to go back to the water supply and increase the flow. If you can understand this, you can understand what happens with oxidative phosphorylation and uncoupling. The pipes are representative of chemicals, the water representative of energy and the valves representative of the electrons (energy) at which the chemical reactions occur. Basically, an uncoupler pokes a hole in the chemical pipeline (at the place of a valve/chemical reaction) allowing energy to escape and be wasted. To compensate for the wasted energy and reduced production of ATP, energy containing substrates such as pyruvate are oxidized at greater rates to free more energy to be used in the process (same as increasing the flow of water). For reference, an inhibitor is analogous to shutting off the valve--energy flow is halted or prevented. We are interested in the phenomenon of uncoupling and not of inhibition. Controlled uncoupling of oxidative phosphorylation can be a very positive thing while inhibition of this process usually brings disastrous results. Interestingly, most uncouplers in high dosages actually become inhibitors and cause toxic phenomenon.


    Thus, as an uncoupler, DNP makes oxidative phosphorylation inefficient. Normally this process is about 60% efficient; DNP steps in and makes the process only 40% efficient. As with any energy converting process, the energy, which is not converted, is wasted as heat--in this case body heat. To maintain its normal supply of ATP, the body steps up its production (metabolism). In this whole process an incredible amount of calories are burned! What's even better is that nearly all of these calories come from fatty acids…i.e. adipose tissue!

    Ok, I think what I'm getting from this is that the more pyruvate that's available to oxidize, the greater the conversion of ADP to ATP, and the more energy that's available to be used for this process. Makes sense to me. Now the l-carnitine, I'll check that out later...... hope this is the basics of where to begin disecting the stack?
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    ok Chemo, maybe I'm grasping at straws here, but this is hard for an IT guy damnit!! So the problem with this study is that is using PCP and rats. PCP acts as the uncoupler here though, so the concept seems the same I think.

    http://envtox001.med.uoeh-u.ac.jp/en...UOEH/JUOEH.htm

    Effects of Pentachlorophenol, Pentylenetetrazol and Carnitine on Mitochondria

    Zhengping YU, Yoshihisa IRYO, Masato MATSUOKA and Hideki IGISU Department of Environmental Toxicology, Institute of Industrial Ecological Sciences, University of Occupational and Environmental Health, Japan. Yahatanishi-ku, Kitakyushu 807-8555, Japan




    <BLOCKQUOTE><I>Abstract</I>: Pentachlorophenol (PCP) increased oxygen consumption and lowered the respiratory control ratio (RCR) in mitochondria from rat liver. These effects of PCP were lessened by 1 mM L-carnitine but not by D-carnitine. In contrast, up to 150 mM of pentylenetetrazol (PTZ) added at state 4 of respiration did not accelerate oxygen consumption. When mitochondria were incubated with 3.3 mM of PTZ, oxygen consumption, RCR and ADP/O ratio were all decreased. Moreover, these could not be suppressed even by high concentrations (~ 20 mM) of L-carnitine. Thus, while L-carnitine could suppress effects of PCP, it could not counteract PTZ in mitochondria. It appears that anticonvulsive effects of carnitine in PTZ-induced seizures may not be due to mitochondrial protection.
    <I>Keywords</I>: pentachlorophenol, pentylenetetrazol, carnitine, seizure, anticonvulsive.


    <CENTER><B>Introduction</B></CENTER>Carnitine (beta-hydroxy-gamma-N-trimethylbutyrate) is widely distributed among tissues including the brain. In extraneural tissues, carnitine is an essential cofactor for the transport of fatty acids through the inner mitochondrial membrane [1]. In the brain, however, fatty acids are not utilized as an energy source, and physiological functions of carnitine are unknown. Previous studies indicated that carnitine can protect the brain from various insults such as hyperammonemia [2,3] and severe ischemia [4]. We have observed that carnitine can also suppress convulsions induced by pentylenetetrazol (PTZ) [5], which is one of the most commonly used epileptogenic agents. However, its mechanism is not clear. We therefore examined effects of PTZ and carnitine on mitochondria comparing them with those of pentachlorophenol (PCP) [6-8] which is a typical chemical that impairs biological membranes including mitochondria.


    <CENTER><B>Materials and Methods</B></CENTER><I>Chemicals</I>. L-Carnitine (inner salt), D-carnitine (inner salt), pentachlorophenol (PCP) and pentylenetetrazol (PTZ) were purchased from Sigma (St. Louis, Mo). All other chemicals were reagent grade.
    <I>Mitochondria.</I> Livers from male Wistar rats were minced quickly in a solution containing 250 mM sucrose, 0.5 mM EDTA and 10 mM Tris-HCl (pH 7.4), and homogenized in a Potter-Elvehjem homogenizer with a teflon pestle. The homogenate was centrifuged at 800 x g for 10 min to obtain supernatant which was centrifuged at 10000 x g for 8 min. After the sediment was resuspended in the solution and centrifuged at 8000 x g for 8 min, the supernatant was discarded. These procedures were all done at 4<SUP>o</SUP>C. Protein of the mitochondiral suspension was determined by the method of Lowry et al [9].
    <I>Oxygen consumption</I>. The solution used to measure oxygen consumption (3 ml) contained 225 mM sucrose, 10 mM KCl, 5 mM MgCl<SUB>2</SUB>, 5 mM potassium phosphate buffer (pH 7.4), 0.5 mM EDTA, 20 mM Tris-HCl (pH 7.4) and mitochondrial suspension (4.5 mg of protein). A YSI Model 5300 Biological Oxygen Monitor (Yellow Spring Instrument, Yellow Spring, Ohio) equipped with a Clark-type oxygen electrode was used and the changes were recorded with a Hitachi 056 recorder. The temperature of the reaction mixture (30<SUP>o</SUP>C) was controlled with a Lauda RM3 high precision circulating water bath (Lauda-Köningshofen). Unless otherwise stated, mitochondrial suspension was first incubated with or without carnitine (L or D-form) for 10 min at 30<SUP>o</SUP>C, and then with or without a chemical (PCP or PTZ) for another 10 min. The reaction was monitored after adding 5 l of 80 mM ADP and 10 l of 200 mM -ketoglutarate. When necessary, chemicals were added through the port of the reaction chamber. PCP was first dissolved in ethanol and then added to the reaction mixture. The final concentration of ethanol was less than 0.3% which did not affect the reaction. The respiratory control ratio (RCR) was calculated as (oxygen consumption at state 3 of respiration)/(oxygen consumption at state 4), and ADP/O ratio as ADP added/oxygen consumed.


    <CENTER><B>Results</B></CENTER>PCP dose-dependently increased oxygen consumption and lowered RCR (Fig. 1). These changes were less marked when 1 mM L-carnitine was present. In addition, L-carnitine dose-dependently suppressed effects of PCP while D-carnitine did not (Fig. 2). On adding PTZ to the reaction mixture successively over a wide range of concentrations (3, 6, 9, 12 and 15 M; 30, 60, 90, 120 and 150 M; 3, 6, 9, 12 and 15 mM; 30, 60, 90, 120 and 150 mM) at state 4 of respiration, no increase of oxygen consumption was observed. When mitochondira were incubated with 3.3 mM of PTZ for 10min, oxygen consumption, RCR and ADP/O ratios were all decreased (Fig. 3). L-Carnitine even at 20 mM did not suppress these effects of PTZ (Fig. 4).


    <CENTER><B>Discussion</B></CENTER>Although PCP has been used widely, it can be toxic to humans and even fatal cases of intoxication with PCP have been reported [7]. The mechanisms of the toxicity have not been fully clarified but PCP has been known to disrupt biological membranes including mitochondria and erythrocyte membrane; PCP is a potent <SPAN id=google-navclient-hilite style="COLOR: black; BACKGROUND-COLOR: cyan">uncoupler</SPAN> of oxidative phosphorylation in mitochondria [6], and it can hemolyze erythrocytes [7]. The increase of oxygen consumption and decrease of RCR in mitochondria seen in the present experiments are consistent with the uncoupling of oxydative phosphorylation by PCP. And these could be suppressed by L-carnitine. This indicates that L-carnitine can protect mitochondria not only in hyperammonemia [10] or damage induced by octanoic acid [11] but also from impairment caused by PCP. Hence, it is of interest that mitochondrial dysfunction caused by different kinds of chemicals can be ameliorated by L-carnitine which plays an important physiological role in inner mitochondrial membrane. Furthermore, it is also of interest that, in the case of PCP as seen in the present experiments, only L-carnitine exerted protective effects while D-carnitine did not because D-carnitine is believed not to occur naturally and has been shown to interfere with some effects of L-carnitine [12]. However, much more work is necessary before any conclusion is drawn concerning whether or not carnitine is effective in prevention or treatment of intoxication with PCP. PTZ is one of the most commonly used epiletogenic agents to evaluate possible anticonvulsive drugs. Although the mechanism of epileptogenesis by PTZ has not been well understood, drugs effective in suppressing PTZ-induced seizures often affect GABAergic systems [13]. On the other hand, it was reported that GABA caused swelling of mitochondria in vitro [14]. Furthermore, ATP content in the brain decreased prior to convulsions induced by chemicals including PTZ [15]. And we previously observed that L-carnitine could suppress seizures induced by PTZ as well as alterations of high energy phosphate compounds in the brain in mice [5]. Hence, it would be of interest to examine effects of PTZ and carnitine on mitochondria in vitro, particularly because the mechanism of the anticonvulsive effects of carnitine is unclear, and because protective effects of carnitine on mitochondria have been suggested in ammonium intoxication and in octanoic acid-induced brain damage [10,11]. Nevertheless, we observed no changes indicating that PTZ uncoupled oxidative phosphorylation in mitochondria i.e. we saw no increase of oxygen consumption by PTZ. But we did observe that PTZ could impair mitochondrial functions; oxygen consumption, RCR and ADP/O ratio were lowered by PTZ. However, these effects of PTZ are most likely to be nonspecific because only high concentrations of PTZ could induce them and because all indices were lowered. Furthermore, while toxicities of PCP could be suppressed by L-carnitine, no protection against PTZ toxicities were provided by L-carnitine, even at high concentrations. Thus, at least in vitro, while L-carnitine could suppress effects of PCP, it did not show any protective effects on mitochondria from PTZ. Hence, it is likely that the anticonvulsive effects of carnitine in PTZ-induced seizures may not be due to mitochondrial protection.


    <CENTER><B>Acknowledgments</B></CENTER>This study was supported in part by a grant-in-aid from the Ministry of Education, Science, Sports and Culture, Japan. Zhengping Yu was a visiting scientist supported by Sasakawa Fellowship.


    <CENTER><B>References</B></CENTER>1. Igisu H, Matsuoka M &amp; Iryo Y (1995): Protection of the brain by carnitine. J Occup Health 37: 75-82 2. Matsuoka M, Igisu H, Kohriyama K &amp; Inoue N (1991): Suppression of neurotoxicity of ammonia by L-carnitine. Brain Res 567: 328-331 3. Matsuoka M &amp; Igisu H (1993): Comparison of the effects of L-carnitine, D-carnitine and acetyl-L-carnitine on the neurotoxicity of ammonia. Biochem Pharmacol 46: 159-164 4. Matsuoka M &amp; Igisu H (1992): Preservation of energy metabolites by carnitine in the mouse brain under ischemia. Brain Res 590: 334-336 5. Yu ZP, Iryo Y, Matsuoka M, Igisu H &amp; Ikeda M (1997): Suppression of pentylenetetrazol-induced seizures by carnitine in mice. Naunyn-Schmiedeberg's Arch Pharmacol 355: 545-549 6. Weinbach EC (1954): The effect of pentachlorophenol on oxidative phosphorylation. J Biol Chem 210: 545-550 7. Igisu H (1993): Haemolysis of human erythrocytes by pentachlorophenol and its suppression by albumin. Br J Ind Med 50: 378-379 8. Igisu H, Hamasaki N &amp; Ikeda M (1993): Highly cooperative inhibition of acetylcholinesterase by pentachlorophenol in human erythrocytes. Biochem Pharmacol 46: 175-177 9. Lowry OH, Rosebrough NJ, Farr AL &amp; Randall RJ (1951): Protein measurement with the Folin phenol reagent. J Biol Chem 193: 265-275 10. Bobyleva-Guarriero V, Di Lisa F, Iannone A &amp; Siliprandi N (1985): Ameliorating effect of carnitine on liver mitochondria functions in ammonium intoxicated rats. IRCS Med Sci 13: 399-400 11. Kim CS, Roe CR &amp; Ambrose WW (1990): L-Carnitine prevents mitochondrial damage induced by octanoic acid in the rat choroid plexus. Brain Res 536: 335-338 12. Fritz IB &amp; Schultz SK (1965): Carnitine acetyltransferase. II. Inhibition by carnitine analogues and by sulfhydryl reagents. J Biol Chem 240: 2188-2192 13. Rogawski MA &amp; Porter RJ (1990): Antiepileptic drugs: pharmacological mechanisms and clinical efficacy with consideration of promising developmental stage compounds. Pharmacol Rev 42: 223-286 14. Marczynski TJ (1998): GABAergic deafferentation hypothesis of brain aging and Alzheimer's disease revisited. Brain Res Bull 45: 341-379 15. Sanders AP, Kramer RS, Woodhall B &amp; Currie WD (1970): Brain adenosine triphosphate: decreased concentration precedes convulsions. Science 169: 206-208


    So I'm guessing that l-carnitine maybe plays some role in the protection of mitochondria, but not sure how that relates exactly
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    Ok, another thing I found:

    http://216.239.51.100/search?q=cache:kMhODWs5qucJ:http://www.funkygrad.com/forum/read_...n&amp;ie=UTF-8


    "Hmm, but fatty acid oxidation through the TCA cycle and ETC is regulated by "end products" such as ATP right? Unless you have some kind of uncoupler that uncouples the oxidation from ATP production. DNP was used in the past but discontinued since several people had died. Incidentally, my lecturer had questioned the effectiveness of carnitine since it is only a fatty acid carrier."

    Again, not good with the analyzation of the statement, but seemed relevant
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    yet another from Elite of all places:

    http://www.elitefitness.com/ubb/Foru...00/028670.html

    Here's an interesting study: Pharmacol Res 1995 Dec;32(6):383-9 "Protective actions of L-carnitine and acetyl-L-carnitine on the neurotoxicity evoked by mitochondrial uncoupling or inhibitors." Virmani MA, Biselli R, Spadoni A, Rossi S, Corsico N, Calvani M, Fattorossi A, De Simone C, Arrigoni-Martelli E Sigma-Tau, Pomezia, Rome. The mechanism for the pathological increase in cell death in various disease states e.g. HIV immunodefficiency or even ageing or Alzheimer's disease, occurs by complex and as yet undefined mechanism(s) related to immunological, virological or biochemical disturbances (i.e. energy depletion, oxidative stress, increased protein degradation). We have studied mitochondrial uncoupling or inhibitor toxicity on neurones at the cellular level and at the mitochondrial level using rhodamine (Rh123) and 10-nonylacridine orange (NAO) fluorescence with confocal microscopy. Blockade of the mitochondrial chain complexes at various points was studied. The possible protective effects of the compound L-carnitine, which plays a central role in mitochondrial function, was tested in this form of neurotoxicity. It appears that L-carnitine and its acetylated form, acetyl-L-carnitine, can attenuate the cell damage, as assessed by lactate dehydrogenase (LDH) release, evoked by the uncoupler, p-(trifluoromethoxy)phenylhdyraz one (FCCP), or by the inhibitors, 3-nitropropionic acid (3-NPA) or rotenone. Further, the FCCP-induced inhibition of Rh123 uptake was antagonized by the preincubation of cells with L-carnitine. Since such neurotoxic mechanisms may be operating in the various pathological forms of myotoxicity and neurotoxicity, these observations suggest potential for a therapeutic approach.
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    Originally posted by Kerruptt
    I question the use of either since both are seemingly worthless for fat-loss unless injected and the jury seems to be out on the effectivness of that.
    Not the case. There is strong evidence that Alcar works well orally adminstrated from what I've read. (Bobby Ames, that says enough right there) "Ames reasoned that high levels of Alcar might also combat the problems of aging membranes and decrepit enzymes. He began *feeding* Alcar...."

    Key word is feeding.
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    jweave,

    Your first post by Grendel is a good laymen approach to understanding uncoupler theory...I should tweak it just a bit but for now let it be so all can get a basic understanding before jumping into advanced topics. Our goal here is to teach bros the basic theory so we will try not to go over everybodies head with 5 cent words...

    Your post on the L-car article is on the money...and is actually one in our arsenal As you can see, we did not include it as a fat loss agent but rather to support the uncoupler (in the case of UCP-1 it is usnic acid).

    Very good job digging up those posts...and we're getting closer to the final choice of ingredients but how about the doseages? At the rate you're going we'll have this thread wrapped up in a few more days

    Chemo
  

  
 

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