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Leptin: The Next Big Thing – Par III

In the first two installments of this series, we covered the “what” and the “how” of leptin. This segment covers a huge amount of information, much of which is fairly complicated, so it will be broken into at least two installments. This one will cover the “why”.

As we have discussed briefly, when leptin, the long sought after lipostatic signal, was discovered in 1996, it appeared that the key to solving the epidemic of obesity had been found. Rats with a defect in the gene responsible for its production were profoundly obese, and the administration of recombinant leptin to these rats profoundly decreased food intake and increased energy expenditure as well, resulting in rapid weight loss, which, unlike starvation, was confined solely to adipose tissue — lean mass was preserved (1). Leptin was quickly anointed as THE anti-obesity hormone (2), and it was only a matter of time and FDA approval before the perfect diet drug would be unleashed upon the gluttonous world.

But, alas, it was not to be. Unfortunately, for the pharmaceutical industry and fat people everywhere, it soon became readily apparent that, rather than suffering from a lack of leptin, obese humans actually exhibited ELEVATED levels (3), thus not only was exogenously administered leptin going to be ineffective as a diet drug, endogenous leptin was not even fulfilling its supposed role as an anti-obesity hormone (4).

Thus, the view of leptin’s role shifted, and it is now considered an anti-starvation hormone (5) — though, it is a lack of leptin, not leptin itself, that sends the starvation signal. It is this role that makes it of paramount importance for the dieting bodybuilder.

Anyone who has dieted for an extended period of time has experienced “hitting the wall”, so to speak — the dreaded slowing, and even complete stoppage, of fat loss.

This is leptin.

Perhaps just as noticeable, or perhaps not — due to the often fanatical willpower of bodybuilders (or perhaps the fanatical use of EC 🙂 — is the accompanying increase in appetite, often manifested as true, almost uncontrollable, cravings for food.

This is also leptin.

Then, there is the increased loss of muscle….. And susceptibility to illness….. And fatigue…..



Energy Expenditure

Fat loss is sufficiently, if not remarkably, rapid at the beginning of a diet, with two pounds a week being not at all uncommon, even for someone who is fairly lean. However, it soon falls victim to the (not so) wonderful world of evolution. In times of scarcity, the survival advantage of thrifty metabolisms should be fairly self-evident — Those that had them would be more likely to survive and reproduce than those that needed 5000 calories a day just to keep their skinny asses alive.
Over millions of years, this has become firmly entrenched in the genetic code. Thus, slowly (if you are lucky) but surely, when conditions of scarcity are self-imposed (i.e. when you diet), metabolism, thus fat loss, invariably slows, and if appropriate steps are not taken, it stops completely.

And, just so we do not confine ourselves to anecdotal evidence and conjecture, I will note that, indeed, low leptin levels have been found to be correlated with decreases in resting energy expenditure (6, 7, 8), and the administration of recombinant leptin corrects this in animals with defects in leptin production, as well as preventing or reversing the decline seen with fasting (9).


As if that were not enough, your body fights your fat loss efforts furiously o­n another front as well. Just as with the rate of fat loss, diets generally start out quite favorably in regards to appetite control — particularly if o­ne is fat or has been o­n a mass phase for an extended period. A this point, adjusting o­ne’s lifestyle around a diet tends to be far more challenging than merely resisting food. However, as the duration of the diet is extended, the tables turn — cravings start to set in, becoming more and more intense with each passing day, until they dominate o­ne’s thoughts.

It has long been recommended that “cheat days” be employed to prevent this — and rightly so. But, the explanation given is generally in terms of mental well-being — i.e. a reward for your hard work or a way to overcome a “want what you can’t have” mentality. However, contrary to popular belief, and even though it IS technically “all in your head” (i.e. in the hypothalamus), this phenomenon is NOT psychological.

Decreases in leptin are strongly associated with increased voluntary food intake in animals and subjective sensations of hunger, desire to eat, and expected consumption in humans, independent of the degree of changes in adiposity and food intake (10, 11). And, the lower leptin goes, the greater the magnitude. By the same token, The administration of exogenous leptin decreases hunger and food intake in animals with defects in leptin production (12).

In other words, this is not just a matter of willpower — it is a PHYSIOLOGICAL STARVATION RESPONSE, formed by millions of years of evolution in a world without supermarkets. It is your body commanding you to find food, right now, even if you would rather be sitting o­n your ass being attended to by a female member of your species.

Your genotype was forged in a world where there existed periods of extreme scarcity, low energy density foods, and a need to actually hunt down your next meal — in other words, a world where you had to be motivated to put a great deal of effort into merely getting enough food to live. And, since you are alive today, it means this command was (and is) so powerful, that it was sufficient to make every single member of your direct genetic lineage (a lineage stretching millions and millions of years) keep itself alive long enough to reproduce.

This exact same genotype now inhabits a world where an entire day’s calories can be procured in half an hour, counting the time it takes to work to earn the money to buy it — all with very little physical effort.

I think you can see why getting to 6% bodyfat is easier said than done.

The Answer

It has previously been common practice, when the manifestations of low leptin levels become apparent to the dieter, to cut calories even further, increase aerobics, start munching Cytomel, or all of the above, to o­nce again create a calorie deficit, in an effort to get fat loss back o­n track. This might work for a very short period of time, but it will also decrease leptin even more, making things that much worse.

At this point the dieter will generally do o­ne of two things: 1) they will repeat the steps above, creating a vicious circle, which will ultimately will result in an absolute inability to drop bodyfat, no matter how low calories are taken. And, for the smart guys, or so called smart guys, this is NOT going against the laws of thermodynamics. o­ne still has another ready supply of energy, known to the laymen as “muscle”, which the body will be all too ready to utilize in its current hormonal state (this will be the subject of an upcoming installment) or 2) They will give up o­n dieting altogether, self-righteously declare that big is beautiful, and become a regular poster o­n 🙂

But hope is not lost…

What I am now going to suggest that the dieter should do may appear, o­n the surface, to fly in the face of common sense. In order to keep fat loss going, the dieter needs to eat MORE, not less. And, I do not mean having a slice of pizza or eating maintenance calories for a day. I am talking about what is essentially pigging out for 12-48 hours — and, to top it off, most of your calories will come from the evil “carbohydrate”.

I do not care for the term “cheat day”, because it implies that you are doing something wrong. What I am suggesting are PURPOSEFUL, and they are PLANNED — thus, I use the term “refeeds”. “Cheat days” will be left to the glutton.

These refeeds will ideally be done done o­n a regular basis, BEFORE all of the afore mentioned signs of low leptin become manifest. For that reason, we need to take a look at leptin levels in relation to bodyfat as well as the time table for their fall when dieting before we get into the specifics of the refeed.

Dieting and Leptin Levels

Recall that leptin levels are determined, in the long and short term, by adipose tissue stores and calories balance, respectively. An individual’s genetics is also going to play a role in determining leptin level — This component is depends o­n the individual’s so-called body fat “set point”. Generally, someone with a higher genetic setpoint will have lower CNS leptin levels at the same bodyfat and someone with a low setpoint will have higher levels.

In addition, the higher an individual’s current bodyfat has become compared their setpoint (from overeating/underexercising), the higher the leptin level will be, and the lower the bodyfat level has become vs. the setpoint (via dieting and/or physical activity, the lower leptin levels will be.

These differences in CNS levels can be a result of of differences in serum levels or differences in transport across the blood brain barrier. As we have noted, it is the latter that is the primary factor in the obese, and probably lean people as well to a lesser extent. This complicates thing greatly, as most of the literature has looked o­nly at serum levels, but leptin transport into the CNS is downregulated by high serum levels as well as by caloric restriction. And, we still do not know to what extent obesity contributed to poor BBB transport and to what extent poor BBB contributes to obesity.

An exact determination of CNS levels is far too invasive to be at all practical. They could be estimated by comparing o­ne’s body fat % with data of individuals of similar serum levels and nutritional state whose CNS levels are known, but the lack of CNS data could limit this — not to mention that such tests are not even available outside of a research setting and would probably not be any more widely utilized than testosterone tests currently are. Thus, another means of estimation is needed.

We shall attempt to make an educated guess based o­n an analysis of the plethora of data available to us in the literature (average leptin levels for a particularly body fat and studies o­n the dynamics of leptin levels with changes in calorie balance) combined with your individual setpoint, which you will determine. This will get fairly complicated, but I will try to simplify it as much as possible.
As mentioned, there is too much information to cover it all in o­ne article without it being totally overwhelming, so today we will look at the average levels for a given bodyfat and the determination of setpoint. In the next installment, we will turn to studies o­n fasting and dieting, to get an idea of the time-frame and degree of fall of serum levels and BBB transport with different lengths and degrees of caloric deficit, in different populations. We will also look more closely at the refeed.

Leptin Levels

Fortunately, Ruhl and Everhart (13,14) were kind enough to provide the world with an epidemiological study which surveyed serum leptin levels in 3366 women and 2937 and broke them up into cohorts based o­n body fat percentile.


BF Percentile
BF% Men
BF% Women
Leptin ug/L (Men)
Leptin ug/L (Women)


Assuming you are not obese, your serum level will be a fairly good predictor of your CNS level. If we were not in a society of fat-asses, logic would dictate that where the leptin level of the average person (i.e. those in the 50th percentile) settled would be the level associated with our setpoint. However, lifestyle has shifted bodyfat percentages considerably to the right. A more natural bodyfat for the average person is probably more like the 15th percentile. We will get more into the specifics of the affects of various levels, including trying to pin down a magic number associated with hitting the wall, in the next installment when we look at drops in leptin levels with dieting.


Now, let us talk a little bit about estimating body fat “setpoint”. This will determine if you CNS levels fall to the left or the right side of the bell-curve for those at the same body fat level.

The setpoint is the level your body “wants” to exist at, so the best way to figure this out is going to be to pay very close attention to when it fights back against changes in bodyfat level that you have forced upon it. In practical terms: to estimate the low end, you are going to note what body fat levels your body starts showing overt signs of leptin suppression during a diet (appetite, decreased fat loss, increased loss of muscle, susceptibility to illness, irritability/fatigue — which o­nes show up first will depend o­n the individual), and to get the high end, you will note when the fat gain slows and appetite decreases when o­n a mass phase or when the level you settle at when just eating whatever you want for an extended period. The level halfway in between is a good estimate of your setpoint.

Obviously, this is going to require careful monitoring of both objective and subjective data. Skinfolds should be taken weekly, and a journal should be kept of subjective manifestations. Anything that can increase or decrease appetite will be a confounding variable, so androgens, marijuana, EC, PPA, and prescription or illicit stimulants should, ideally, be avoided while this determination is being made. In addition, the omnipresence of palatable foods could skew things, so vacations and holidays are not an ideal time to make a determination. Boredom, stress, and depression can also influence these parameters. Obviously, it is impossible to totally avoid all confounding variables, so multiple testing periods will result in greater and greater accuracy.


Hopefully, I have not confused you too much. And, even if I have confused you a bit, don’t worry, because it should all begin come together when we start looking at the numbers. In the meantime, you can begin figuring out your setpoint or, at the very least, start paying attention and making a mental note of when you notice subjective sign of lower leptin levels.


1. Halaas JL, Boozer C, Blair-West J, Fidahusein N, Denton DA, Friedman JM. Physiological response to long-term peripheral and central leptin infusion in lean and obese mice. Proc Natl Acad Sci U S A 1997 Aug 5;94(16):8878-83

2. Spiegelman BM, Flier JS. Adipogenesis and obesity: rounding out the big picture. Cell 1996 Nov 1;87(3):377-89

3. Maffei M, Halaas J, Ravussin E, Pratley RE, Lee GH, Zhang Y, Fei H, Kim S, Lallone R, Ranganathan S, et al. Leptin levels in human and rodent: measurement of plasma leptin and ob RNA in obese and weight-reduced subjects. Nat Med 1995 Nov;1(11):1155-61

4. Frederich RC, Hamann A, Anderson S, Lollmann B, Lowell BB, Flier JS. Nat Med 1995 Dec;1(12):1311-4 Leptin levels reflect body lipid content in mice: evidence for diet-induced resistance to leptin action.

5. Unger RH. Leptin physiology: a second look. Regul Pept 2000 Aug 25;92(1-3):87-95

6. Doring H, Schwarzer K, Nuesslein-Hildesheim B, Schmidt I. Leptin selectively increases energy expenditure of food-restricted lean mice. Int J Obes Relat Metab Disord 1998 Feb;22(2):83-8

7. Pelleymounter MA, Cullen MJ, Baker MB, Hecht R, Winters D, Boone T, Collins F. Effects of the obese gene product o­n body weight regulation in ob/ob mice. Science 1995 Jul 28;269(5223):540-3

8. Doucet E, St Pierre S, Almeras N, Mauriege P, Richard D, Tremblay A. Changes in energy expenditure and substrate oxidation resulting from weight loss in obese men and women: is there an important contribution of leptin? J Clin Endocrinol Metab 2000 Apr;85(4):1550-6

9. Scarpace PJ, Matheny M, Pollock BH, Tumer N. Am J Physiol 1997 Leptin increases uncoupling protein expression and energy expenditure. Jul;273(1 Pt 1):E226-30

10. Brunner L, Nick HP, Cumin F, et al. Leptin is a physiologically important regulator of food intake. Int J Obes Relat Metab Disord 1997;21:1152–60.

11. Keim NL, Stern JS, Havel PJ. Relation between circulating leptin concentrations and appetite during a prolonged, moderate energy deficit in women. Am J Clin Nutr 1998 Oct;68(4):794-801

12. Campfield LA, Smith FJ, Guisez Y, Devos R, Burn P. Recombinant mouse OB protein: evidence for a peripheral signal linking adiposity and central neural networks. Science 1995 Jul 28;269(5223):546-9

13. Am J Clin Nutr 2001 Sep;74(3):295-301tLeptin concentrations in the United States: relations with demographic and anthropometric measures. Ruhl CE, Everhart JE.

14. Adapted from American College of Sports Medicine Chart — Subject age: 20-59.

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