Sunday, November 3, 2013

Choline Maximizes Carnitine Retention & Effects. Together, These Supplements May Promote Fat Loss + Lean Mass Gains and Boost Both Metabolic & Brain Health

The more choline the better the carnitine retention; and the better the retention the less high carnitine red mead you'll have to eat ;-)
If you are one of the many people who frequent boydbuilding-oriented bulletin boards, it is likely that you will have heard about the beneficial effects of exogenous insulin on the tissue storage of supplemental l-carnitine. When you hear something like this, or, as in this case, read about it in a forum, you can easily get the impression that it's only a matter of how much insulin you inject to turn an ergogenic aid, of which the majority of the scientific papers say that it is of questionable value, into a fat burning high performance powerhouse.

If said bulletin boards are not the only thing you frequent, i.e. if you are a regular at the SuppVersity, as well, you will probably also be aware of the fact that I strongly discourage the use of insulin in non-diabetic individuals - especially in cases as the one at hand, where it appears as if there were non-pharmacological alternatives to achieve increases in carnitine retention.

Using choline instead of insulin to maximize carnitine retention

I guess I could start this paragraph by stating that "it is a wonder that nobody appears to know about the interactions between choline and carnitine", but honestly, I have long given up to wonder when the respective information has to be looked up in studies that are older than 2-3 years. Studies as the one by Dodson and Sachan that was conducted at the University of Tennessee in the mid 1990 and the results of which werr published in the American Journal of Clinical Nutrition in 1996.

In the corresponding paper, Dodson and Sachan report the results of two experiments that were conducted to determine the effects of supplementary choline and/or pantothenate on the carnitine and lipid status of free-living humans:
Carnitine as Repartitioning Agent? + 7% Improvement in Lean- to Total Mass Ratio W/ HED of 1-1.5 of Carnitine/Day | more
"In experiment 1, adults receiving 13.5 mmol choline plus 1.4 mmol pantothenate/d had a significant decline in urinary carnitine excretion and renal clearance with nonesterfied carnitine (NEC) declining the most dramatically, 84%.

Additionally, serum NEC and total carnitine concentrations decreased significantly. No changes were observed in any of the serum lipids examined." (Dodson. 1996)
In the follow up experiment, Dodson and Sachan were able to show that the beneficial effects choline had on the retention of supplemental carnitine were not influenced by the provision of panthothenate, which had previously been used as a complement to carnitine and choline in clinical trials for a variety of neurologic and hyperlipidemic conditions.

Choline doesn't work for supplemental carnitine, only

Most of you will know that carnitine is not just a supplement, but also a non-essential nutrient. As long as we consume large enough quantities of lysine and methionine, the building blocks our bodies use to produce carnitine "on demand" we don't really need supplemental and probably not even dietary carnitine sources to survive (Mitchell. Feb. 1978).
Table 1: Total carnitine content of various foods (Mitchell. 1978)
Did you know that l-carnitine has for quite some time been touted to be a vitamin? The name vitamin BT is actually still sometimes used to refer to beta-hydroxy-y-trimethylamino butyrate aka carnitine; and that despite the fact that it can synthesized endogenously in mammals. It is thus not surprising that most carnitine-rich foods are animal products (see Table 1).
In view of our ability to produce "all the carnitine we need", it's actually not surprising that a sedentary slough is not going to benefit from respective supplements. And still, I had my reasonst to put the "all the canritine we need" in quotation marks. There are in fact situations, where research suggests that a lack of carnitine can become the bottle neck to fatty acid oxidization. The interesting thing about choline is now that it does not make a difference between endogenous and exogenous carnitine: Both are retained more effectively with an adequate / increased choline supply (Tsai. 1974, 1975; Carter. 1978; Hoppel). Low choline intakes, on the other hand, have been found to increase the urinary carnitine concentration and deplete the tissue stores independent of the overall nutritional status of the lab animals (Sheard. 1994).
In other words, the equation "higher choline = better carnitine levels" is valid irrespective of whether you are supplementing with beta-hydroxy-y-trimethylamino butyrate or simply producing it yourself.
SuppVersity Suggested Read: "Carnitine Loading Revisited: 3g Carnitine per Day Ward Off Vitargo Induced Fat Gain by Increasing Fatty Acid Oxidation and Total Energy Expenditure in 12 Week Human Study" | read more
Apropos nutritional status: I guess it's worth mentioning that fasting has been shown to lead to an increased mobilization of carnitine in order to facilitate the necessary increase of the carnitine-driven influx of fatty acids into the mitochondria in the absence of which the lean and obese subjects in a 1980 study by Hoppel et al. would have been starving.

Against that background it does not come as a surprise that the carnitine demands increase, when you go on a low carb or even ketogenic diet. In fact, Balaban-Gil et al. mention diet-induced carnitine deficiency as a potentially hepatoxic (=liver-damaging) side effect of long(er)-term ketogenic dieting (Balaban-Gil. 1998). They do yet also point out that the beginning liver damage can be sent into remission by the timely provision of supplemental l-carnitine.

On a side note: You do remember having read about the beneficial effects choline has on liver, did you? If not, I'd suggest you review my previous article "Choline: Stronger, Faster, Leaner & More Muscular, or Just Another Dumb-and-Barbell Story?" | read more.

More than just a life-insurance for the livers of keto dieters

As a diligent SuppVersity reader you will probably already know that choline, which used to be a staple supplement in the earlier days of bodybuilding, is a potent synergist to caffeine and carnitine - so potent in fact that I already devoted a whole post to the fat burning magic of the "CCC Stack" (read more).

Suggested Read:"Forgotten Dieting Aids: Choline, Carnitine, Caffeine and the Anti-Weight-Loss Plateau Effects of Sugar and Phosphates" | learn more
It would be pointless to repeat the discussion of the results of the 2003 study by Hongu and Sachan, so I'd suggest you (re-)read the corresponding article from February 2012, if you are interested how this combination lead to effortless weight loss in 19 healthy non-obese women.

I'd rather take a parting look at what actually happens to the carnitine in the Dodson and Sachan study. It was neither excreted nor pooling up in the blood of the 29 healthy volunteers when they consumed 13.5mmol of choline (ca. 1.4g of choline) as choline bitartrate (~3g) for 7 days and choline + of carnitine for additional three days.

Due to the fact that Dodson and Sachan who have been working at the University of Tennessee, back in the day, did not conduct muscle, let alone heart, brain, kidney and liver biopsies. We will (unfortunately) have to content ourselves with the results of a 1998 guinea pig  study from the same work group (Daily. 1998), if we want to understand the fate of the "missing" carnitine.
Total ingested (full bars) and absorbed (blue part of the bar) amount of dietary carnitine in mg/kg body weight (from Amino Acids for Super Humans)
When and how do you take carnitine and choline? If we put some faith into the non-published data from previous experiments by Dodson & Sachan, the responses should identical irrespective of whether you take the supps at one time or in several doses throughout the day. If we do now take the study by Hongu and Sachan as a guide the "recommended dosage" would amount to ~3g of choline bitartrate + 1.4g of carnitine - in view of the fact that Hongu's & Sachan's subject were women maybe up to 4g choline + 2g of carnitine per day for the heavier guys out there.
I know an animal model is not ideal, but it's better than trying to guess what caused the slight decline in serum levels and significantly lower urinary losses in the human trial from 1996 (Dodson. 1996); and the interaction of choline and carnitine in guinea pigs is more akin to humans than that of rodents, which is, according to Daily et al. (1998), probably a direct consequence of a lower choline oxidase activity in Guinea pigs vs. rats / mice.

What exactly happens to the carnitine, when you consume extra choline?

The study protocol Daily et al. used was slightly different from the one Dodson and Sachan had used in their 1996 human trial: Instead of carnitine and choline, the guinea pigs received only choline (+200% more than the regular diet would offer).
Figure 1: Changes in carnitine content of brain, liver, heart, kindney and muscle (left) and differences in body composition (right) extra choline vs. normal chow (Daily. 1998)
As you can see in Figure 1, there was a significant reduction in kidney carnitine (remember that this is where the carnitine is extreted) and concomittant increases in brain (specifically acetyl-carnitines) and muscle carnitine (total carnitine) content. The levels in the livers and hearts of the guinea pigs, on the other hand, remained stable (p > 0.05).

The question whether these changes were the cause or just correlates to the beneficial effects the provision of additional choline had on the body composition (see Figure 1, right) of the hairy mini remains to be answered, though. On the other hand, it is quite certain that the observations Daily et al. made in their lab animals stand in line with the results of Hongu et al.'s human trial from 2003, which clearly suggests that the "selective accretion of nitrogen and depletion of fat", of which Daily et al. state that it is an "important and unique consequence of choline–carnitine interactions" is not species dependent and occurs even in the absence of caffeine, the CNS stimulant Hongu et al. added to the equation.
Is choline the missing link, or rather the missing synergist due to which most of the studies that investigated the ergogenic effects of l-carnitine yielded very disappointing results?
In view of the fact that reviews as the one by Bass regularly refer to the fact that "muscle carnitine content is not easily increased with carnitine supplementation" (Brass. 2004) as one of the underlying reasons for the disappointing results that have been reported in a whole host of studies, it appears not too far-fetched to hypothesize that some of the trials may have yielded very different results if the researchers had used a combination of carnitine and choline.
Speaking of the synergy of choline + carnitine: You probably remember the study that claimed to show that the "high" carnitine content of red meat was carcinogenic, right? I have discussed the fallacy of this assumption in a separate article (read more) and I am not really interested to revive this discussion, that the moment.
What I am interested in, though, is red meat or rather the fact that the major carnitine sources in our diet, i.e. animal products, always come with choline. For beef, for example, the ratio is almost 1:1 (depending on the reference you use). At this point I could probably say something about "nature knows" best. That would be an understatement, though. If we are honest with ourselves, it's after all more like "nature knows" and "we are groping in the dark" - wouldn't you agree?
Bottom line summary: Before I summarize what you could have learned today if you actually read the article, I briefly want to remind you of the general health & performance benefits of choline I wrote about before (read more). After reading today's article you can thus expand the said list or your own mental notes about the useful effects of choline by the following items::
  • The provision of choline reduces the high urinary excretion of carnitine which has always been the bottleneck of carnitine supplementation.
  • In human studies, the combination of choline + carnitine + caffeine has been shown to promote fat loss. If we take the corresponding study as a reference, an effective dosing regimen would contain ~3g of choline bitartrate + 1.4g of carnitine.
  • From animal trials we know that the changes in body composition are accompanied by significant increases skeletal muscle and brain total and acyl-carnitine levels. In view of the physiological role carnitine plays in the oxidation of fatty acids in the mitochondria, it is likely that the increase in muscular carnitine levels is mechanistically involved in the repartitioning effects (increased muscle decreased fat mass).
  • The increased mobilization and clearance of carnitine in the fasted state suggest that choline and carnitine will be most useful, when you are dieting - in  this case even in the absence of additional caffeine, which is otherwise needed to increase the serum levels of readily oxidizable free fatty acids.
  • Case reports from children on ketogenic diets suggest that l-carnitine supplementation can become mandatory to avoid liver damage, when patients are in full ketosis for a long period of time. Even in the absence of specific trials, it is thus reasonable to assume that a combination of l-carnitine and choline should have beneficial effects for anyone following a ketogenic or very low carb diet.
One last note: If you take a look at the interaction between choline and carnitine and the role carnitine plays in liver (=help oxidize fatty acids before they start clogging the liver → NAFLD), brain (=improve + maintain cellular energy status & neuronal function) and muscle (=improve fatty acid oxidation), it cannot be excluded that many of the previously listed health & perfomance effects of choline are actually mediated by its interaction with endogenous carnitine.
  • Ballaban-Gil K, Callahan C, O'Dell C, Pappo M, Moshé S, Shinnar S. Complications of the ketogenic diet. Epilepsia. 1998 Jul;39(7):744-8.
  • Brass EP. Carnitine and sports medicine: use or abuse? Ann N Y Acad Sci. 2004 Nov;1033:67-78. Review.
  • Carter AL, Frenkel R. The relationship of choline and carnitine in the choline deficient rat. J Nutr l978;108:l748-54.
  • Daily JW III, Hongu N, Mynatt RL, Sachan DS.  Choline supplementation increases tissue concentrations of carnitine and lowers body fat in guinea pigs. The Journal of Nutritional Biochemistry. 1998; 9(8): 464–470.
  • Dodson WL, Sachan DS. Choline supplementation reduces urinary carnitine excretion in humans. Am J Clin Nutr. 1996 Jun;63(6):904-10. 
  • Hongu N, Sachan DS. Caffeine, carnitine and choline supplementation of rats decreases body fat and serum leptin concentration as does exercise. J Nutr. 2000 Feb;130(2):152-7.
  • Hongu N, Sachan DS. Carnitine and choline supplementation with exercise alter carnitine profiles, biochemical markers of fat metabolism and serum leptin concentration in healthy women. J Nutr. 2003 Jan;133(1):84-9.
  • Hoppel CL, Genuth SM. Carnitine metabolism in normal-weight and obese human subjects during fasting. Am J Physiol. 1980 May;238(5):E409-15.
  • Mitchell ME. Carnitine metabolism in human subjects. I. Normal metabolism. Am J Clin Nutr. 1978 Feb;31(2):293-306. Review.
  • Mitchell ME. Carnitine metabolism in human subjects. II. Values of carnitine in biological fluids and tissues of "normal" subjects. Am J Clin Nutr. 1978 Mar;31(3):481-91. Review.
  • Sheard NF, Krasin B. Restricting food intake does not exacerbate the effects of a choline-deficient diet on tissue carnitine concentrations in rats. J Nutr. 1994 May;124(5):738-43.
  • Tsai AC, Romsos DR. Leveille GA. Significance of dietary carnitine for growth and carnitine turnover in rats. J Nutr l974;104:782-92.
  • Tsai AC, Romsos DR. Leveille GA. Determination of carnitine turn over in choline-deficient and cold-exposed rats. J Nutr 1975;105: 301-7.