Leptin: The Next Big Let-Down?
No doubt if you've made it this far and are still attentively reading, you are probably aware of what leptin is and have read what there is to read about it. How it supposedly works, and what the claims being made are. Well, don't be surprised, but I'm actually basing myself on the exact same research to show you that you need to think twice before deciding if these new leptin related products are worth your hard-earned buck.
I'm going to break this discussion down in three parts. First I want to address concerns regarding whether or not we can increase leptin sufficiently to consider it a successful target of supplementation, in the second part I want to alert you to some oddities about the claims being made that show that increasing leptin may not be so very wise after all, and that is definitely not the revolution some people would have you believe it is, and lastly I want to discuss some of the ingredients currently used in leptin related products and some things you will be real interested in knowing about in that regard. So without further ado:
1) Can We Increase Leptin Sufficiently?
When we diet, eventually leptin levels will begin to drop. The idea of supplementation is that we should keep our levels higher as we diet. What everyone seems to forget to mention right around here is that leptin levels WILL drop regardless and that as our body-fat percentage is lowered (which is still the idea I assume) we also lose our capacity to produce leptin to the same extent.
The discovery of leptin began with the presumption of Kennedy (1953) that there was a feedback signal related to the triacylglyceride content of the fat cell. Triacylglycerides are the way fats are generally stored in adipocytes, esterifying three fatty acids with a glycerol backbone.
As a direct signal leptin is increased when fat cells increase in size and they are full of triacylglycerides, with little room left over. Leptin acts on peroxisome proliferator activated receptor gamma, a nuclear receptor, and via this pathway it achieves the differentiation of pre-adipocytes into full grown fat cells. In plain English you will be growing more fat cells, and the triacylglyceride content will be spread over these new fat cells.
Because triacylglyceride content per cell has now been diminished, leptin output by these cells is decreased. Now consider our situation, where you start to diet down. Via lipolysis, the first step in burning fat, we de-esterify fatty acids, reducing Triacylglyceride content of the cell.
In the first example, where the individual is clearly getting fatter, the loss of leptin is somewhat compensated by the increased number of fat cells producing leptin. In our situation however, there is no increase in fat cell number, merely a decrease in the capacity to produce leptin. This is why leptin levels are exponentially lower in leaner individuals than in individuals with a higher body-fat percentage.
As an aside, I put this proposition to a well-known leptin Guru, and his only reply was that leptin is also produced in other tissues. A very poor excuse as it was he himself who had previously stated that these other tissue's contributions to the total leptin pool were minor at best (Ahima et al, 2000 and Korbonits et al, 2001).
What is the implication of this for us ? Well, having a look at two nutrients known to increase leptin, we see that zinc raises leptin levels 142% (Chen et al, 2000) and that Vitamin E increase leptin by approximately 17% (Iserman et al, 1999). It doesn't take a genious to figure out that the leptin increase for a woman with and average body-fat percentage of 25 and an average serum leptin level of 13.2 mcg per liter, will be phenomenally larger than for a male with a body-fat percentage of 8% with a serum leptin level of 1.4 mcg per liter.
Because let's face it, when I'm at 15% I don't have that much trouble getting down to 8% without any loss of muscle. But when I'm at 8%, taking some zinc might raise my leptin from 1.4 to 3.3 mcg per liter (provided I am zinc deficient, which is unlikely since I supplement zinc year-round, as any athlete should). If I was that woman, I would see an increase from 13.2 mcg to 32 mcg per liter. Moral of the story, raising leptin is feasible, but unless you are a female with an average body-fat percentage, don't expect to get the same out of it as if you are a dedicated male bodybuilder.
Leptin also continually downregulates itself. Making it harder and harder to raise serum levels, especially if you are still losing weight and remain on a hypocaloric diet. Leptin will increase Arginine-vasopressin (AVP), and the increased AVP will reduce leptin (Rubin et al, 2003). Leptin activates PPARgamma, and PPARgamma in turn will downregulate leptin. Leptin increases growth hormone, and GH in turn lowers insulin and leptin sensitivity.
The list goes on and on. Leptin also lowers Thyroid stimulating hormone, one of the few hormones that can actually increase leptin. Leptin has such a multitude of negative feedback signals, that shutdown is imminent and leptin levels will continue to decrease no matter what. Combine that little fact with the decreased ability to produce leptin and you will see that short term attenuation of the decline, will only increase problems with lower leptin after that.
This is only a slight illustration of the difficulty one would experience trying to raise leptin. But I want you to keep this in the back of your head for the next section as well, as you begin to understand that perhaps even these slight increases in leptin levels may not be all that beneficial.
2) Should We Increase Leptin?
This will span several points, and in attempting to cover them all, I may not be too elaborate about each, but will try to make it as understandable as I can. Most of these points are direct concerns with regards to scientific studies that the leptin guru's are using to promote the use of leptin-related products, but some points are also just plain common sense.
Things you need to reflect on for a while and then let it sink in. Then read it again and realize that what is being said is an embellishment of the truth. You can make everything look good, everything in your body has some necessary function. But often people forget to mention the downsides (gee, I wonder why ?) and as you will often see, these downsides are often more expressed than the benefit being claimed.
My first concern however is a simple remark. Leptin will decrease GnRH and TSH. Two hormones needed to maintain a speedy metabolism and still retain as much muscle as possible while dieting since they are necessary steps in the production of testosterone and T3 respectively. No biggie of course, since leptin will maintain testosterone and T3 to some extent in and of itself. But now I want you to remember the first section.
How leptin WILL lower regardless and relentlessly. If you know this, then you can also understand that the longer we remain in a low glucose, high leptin state, the more detrimental it will become. The longer leptin is the dominant signal, the more TSH and GnRH are being reduced.
And when leptin levels do drop, and they do, these signals become the dominant determinants of testosterone and T3. The result being that the person that kept his leptin just a little higher, just a little longer, will experience a much greater loss of metabolism and muscle towards the end of a diet, when these factors are most detrimental, than the person who did not attenuate his decrease in leptin. If anything, this would make a perfectly good case for lowering leptin before glucose levels becomes too low. But of course that's an equally unsubstantiated idea as saying leptin is the end-all of dieting...
A second major concern is that leptin in many ways acts via similar pathways as insulin (JAK3, PI3K and RAS/RAF) and that leptin sensitivity automatically translates to insulin sensitivity. One trend I have noticed is the use of nutrients that increase insulin sensitivity in these leptin-related products. This is a tactic that has been tried a few times by dieting bodybuilders, and has failed miserably.
The reason being that an increase in insulin sensitivity will make it easier for the body to rebuild glycogen stores, and that brings you back to the point where your norepinephrine (and you invest good money in ephedrine to raise NE levels) is now doing its best to turn over glycogen to glucose, instead of increasing lipolysis. If anything, people who have been sucked up in this trend have noticed fat loss is considerably slowed down, and fat gain after the diet is considerably facilitated due to the use of insulin sensitivity enhancers (or need I remind you of another bogus product that was recently overhyped ? Remember R-ALA ?).
If leptin is really enhanced, then it will be a status quo as leptin itself should lower its own sensitivity. But if leptin is not enhanced, and lets face it, its not being enhanced to any considerable degree, then this will actually be contradictory to your efforts to lose body-fat.
In a discussion on the actual effects of leptin, it may be wise to start with its neural, whole-body effects. We can split this up into two main parts. The effect leptin has on the Para-Ventricular Nucleus via the Ventro-medial Hypothalamus, where leptin will exert the opposite effect of glucose, and the effect it has on the Lateral Hypothalamus, mediated by the Arcuate Nucleus. An area where it will exhibit similar effects to glucose.
In the first case, the effects on the para-ventricular nucleus, we see that a decrease in glucose leads to leptin being the dominant signal. In doing so it lowers TRH and GnRH (controlling thyroid and testosterone levels) and it increases CRF, which results in more cortisol being produced.
This means more muscle breakdown, less anti-catabolic power and a lower metabolism, thus slower fat loss. Not exactly sounding like you best friend now huh? As long as leptin remains elevated, this will not come to expression considerably, but leptin WILL lower because capacity to produce leptin is lowered, and that will result in said symptoms. We should also note that it increases the output of Growth Hormone, which will reduce leptin sensitivity and bring these traits to the foreground.
In the second case we will see that leptin will lower Neuropeptide Y, a peptide strongly related to hunger and which exerts a negative effect on Thyroid levels. So reducing it is an absolute positive thing. Well you won't hear any different from me. This is absolutely fantastic. Seems like a bit of a stretch to pay 120 dollars for this, when you can get ephedrine for maybe 15 bucks to do a better job. Not only that, but ephedrine keeps thyroid elevated for considerable amounts of time, while leptin decreases thyroid, both by lowering TSH and decreasing its own sensitivity.
Even with leptin's positive effect on the thyroid itself, it leaves you with less metabolism for more money. Another dire concern is of course that leptin increases Arginine Vasopressin as well as CRF, causing a much larger increase in cortisol than one would see with ephedrine since the AVP appears to be synergistic to the CRF. So it may be far more detrimental to the amount of muscle mass retained if you elevate leptin long term.
Now its time to have a look at the direct effects of leptin. Lets start with its effect in fat cells. In the adipocyte that is full, PPARgamma will be downregulated, this allows for a large increase in leptin and lowering of Fatty acid synthase. That makes sense, since the cell is full, can't add any more fatty acids and you need to signal that it is full so you can make more room. Leptin hops over to some neighbouring pre-adipocytes and activates PPARgamma. This causes the pre-adipocyte to graduate to a full-fledged fat cell. In this new cell we are seeing an INCREASE in Fatty acid synthase on account of the PPARgamma activation (Dressel et al, 2003), an increase in glucose uptake and lipid storage.
Not to let out the word on this one, but this is pathway number one to INCREASE fat, not decrease it. We are now seeing an increase in total tri-glyceride content in the body, but less Tri-glycerides per fat cell so a decreased capacity to produce leptin. For the faithful readers, this may be a good time to remember my first column where I spoke of PPARgamma ANTAGONISM as one way to increase fat loss. That leptin's activation of this receptor is not beneficial is all the more evident in people who experimented with PPARgamma ligands (like metformin) to increase muscle mass, only to find it was fat and not muscle they gained.
One interesting thing to note is the effect on insulin sensitivity. Leptin lowers insulin and thus leptin sensitivity, only when levels are VERY HIGH or VERY LOW. Well unless you are obese, levels won't be very high. That means you need them very low to enjoy lowered sensitivity to insulin. Note that a lot of fat loss enhancers work in large part by reducing insulin sensitivity (ephedrine, GH, etc) which keeps glycogen depleted.
A glycogen depleted state promotes lipolysis, fatty acid oxidation and a host of other benefits to fat loss. So in essence, by increasing leptin, or attenuating its decrease, you are losing a valuable benefit in fat loss. Leptin has been shown to increase Liver glycogen stores, which would also lower fatty acid oxidation in this area. Together with an increase in cortisol created by that same leptin, this could promote central obesity more than it helps it.
In short, this list of effects I have compiled are just some of the things you should take a minute to read and remember before making up your mind about the current train of thought on leptin manipulation as a valid target of supplementation. As time passes and research progresses, many more positive and negative effects of leptin will be demonstrated, as well as new barriers in manipulation being exposed. As negative as this sounds (you can get all the good stuff hyped to the max at the sites owned by leptin guru's) the main point here is to demonstrate that leptin is just another point of research.
It is of crucial importance to our understanding of the human body and its intricacies, but not intended as a sales pitch for money-hungry, unscrupulous company owners to suck dry the wallets of unsuspecting consumers. I'm sure they all claim the best intentions, but this is an obvious case of bandwagon hopping. This can have only two simple causes : a lack of understanding of basic physiology and the homeostatic principle, or just plain greed. I'll let these guru's decide which category they fall under.
3) A Look At Leptin-Related Products.
Now comes the piece de resistance. Let's have a look at the products that are using the leptin hype as a pitch. Now the first thing I want you to do, is have a very close look at the ingredient list. Give it a moment, absorb it, and then tell me what you think. Well, I will tell you what my first thought was : What exactly in these products makes it so revolutionary ? None of these products are new or special, half of them you are probably already using on a diet, and half of them simply have no real use when on a diet. But the million dollar question ? What exactly makes it cost what it costs ? And isn't that the consumer's first concern ? Why pay more if you can pay less?
To break it down, lets first look at all this wonderful feedback they claim to have. Well, without exception, all of the feedback seems to center around a reduction in appetite. Wow, that's really amazing. Reduced appetite. But that's not so hard when you see that it includes synephrine. Via its alpha1 agonism it will naturally reduce appetite. Want to know what else will do this ? Yep, that same good old ephedrine. I'll do you one better, it will do the job better since its also an alpha2 agonist, known to decrease NPY and increase thyroid levels. And all of that for 1/8th of the price.
Seems to good to be true doesn't it ? On top of that you should know that the benefit of synephrine has been attributed to its increase in bloodflow (Schimmel et al, 1987) and that this occurred through a pathway other than via glycerol release. Well the only other pathway that comes to mind is adenosine. And if adenosine is being increased, that means less fat is being freed up. Of course that is not a stab at synephrine, since ephedrine would have the same effect. Merely an indication that the multi-facetted ephedrine enjoys a better status, and that synephrine most likely does not exert a synergistic, but rather an overlapping effect.
One or two of the feedback posts do seem to point out some type of volumizing effect. Not at all so surprising if you spike your product with creatine. Interesting thing to know about this is that creatine seems to slow down fat loss as well (Huso et al, 2002), which is the same reason I have been telling people to refrain from using creatine when dieting for nearly 3 years now (that was even before that study came out !). So far we are not doing to well are we ?
Another set of potent ingredients is the addition of BCAA's. BCAA's can enhance the uptake of amino acids via the activation of PI3K (Higaki et al, 1999 and Doi et al, 2003) but this also seems to increase glycogen uptake (Doi et al, 2003) and the sensitivity of glucose transporters to insulin (Bogan et al, 2001).
First of all, if you want this, Bodybuilding.com has a nice selection of whey proteins that will enhance BCAA levels and give you the added benefit of increasing most of your other amino acids, but before you do consider that the use of BCAA rich protein has often lead to a dramatic spike in amino acid levels, but an equally dramatic drop and actually a negative nitrogen retention balance. This is the reason preference is given to more anti-catabolic, slow acting, long lasting protein sources for the dieting bodybuilder, such as casein.
Vitamin E, obviously one of the products known to enhance leptin, would have to be included in this mix. One thing you should know about using excess vitamin E however, is that it is catabolic, it reduced the secretion (Hartman et al, 2001) and efficacy (Thompson et al, 2003) of testosterone. One of the reasons high-dose vitamin E supplementation (more than 40 IU per day) is never advised to users of androgens.
What about zinc ? Well, you won't ever hear me say a bad thing about zinc. On the contrary, its one of the few minerals you are actually likely to be deficient in and I have been promoting it as standard supplementation for, I guess, about 5 years now. Which is exactly why you should already be taking it. And a month's supply will really not set you back 100 or 120 dollars (Editor's Note: Actually it will cost you around $ 5.00 for 90 days, click here).
Obviously the list goes on, as is common with this type of product, a multitude of ingredients is used to divert attention from the uselessness of each individual nutrient. We can address each nutrient individually, but this column is already running long for a one-topic article. I trust it doesn't take a wizard to see there is nothing magical about the ingredients in these products, and to notice that half of them have no use or are even contradictory (such as creatine, inositol and ALA) for fat loss, and that the few that are useful are either redundant (synephrine) or should already be taken regardless (zinc, calcium).
This gives you some food for thought, and I promise, it contains less calories than leptin related products
