An Introduction to Leptin


Introduction

Most of you have probably not yet heard of leptin, and, unless you follow the MFW newsgroup, even if you have heard it mentioned somewhere, you probably have no idea of its profound significance in the manipulation of body composition. You soon will.

I would expect that within a year, it will be everywhere in the bodybuilding world, and within two, it will be the topic of infomercials. It will be bigger than Atkins/ketogenic diets, and bigger than The Zone. When it comes to body composition, this is THE master hormone that controls almost all of the others. It is the reason that prolonged dieting causes fat loss to stop and the main reason overfeeding helps us gain muscle.

I would love to say "you heard it here first" but I must give credit where credit is due. Lyle McDonald discovered its supreme importance for bodybuilding in the summer of 2000. I had it on my "to do" list at the time because it kept popping up in any research I did on fat loss, but it was not a priority. Lyle, in a moment of ill-advised excuuberance over his discovery made a couple of posts on MFW mentioning it -- and, because I consider him to have the best combination of knowledge and mind in this field, it immediately moved to the top of my list. I believe he communicated his thoughts on its importance to Elzi Volk at the time, but she dismissed it somewhat for a period, so I think it is accurate to say I was the second person to really look into it.

With that aisde, let us get down to business. This will be the first part of a several part series -- probably at least 4 or 5 -- as this is a massively complicated subject. The present article will be a mere introduction, just to give you some idea of how important this hormone is and how widespread its actions are. In later articles we will delve much deeper into the subject -- from the hard-core, basic science, to the real-world ways in which we can manipulate leptin levels through alterations our diet and supplementation.

And, I promise the follow-up articles will not be delayed to the same extent that this third issue has been



Background

In 1953, Kennedy (1) proposed the existence of a centrally acting lipostatic negative feedback signal, produced by adipocytes, in proportion to triacylglycerol content, which regulated body stores via alterations in food intake and energy expenditure -- thus the adipostatic model of weight regulation (aka the "Set-point" theory) was born.

Strong evidence in favor of this idea came with the discovery of the mutation obese (ob) in mice, which led to early onset of obesity (2), and the subsequent use of parabiosis studies (shared blood supply between two organisms) in the late 60's and early 70's which found that overfeeding of one of the pair, led to decreased food intake in the other (3,4).

In 1994, the ob gene was cloned and found to code for a 16 kDa protein which was termed "Leptin" from the Greek "leptos", meaning "thin" (5,6). Leptin was the long-sought lipostatic signal and was anointed as the magic bullet that would vanquish obesity. However, this would not be the case, for reasons you will soon learn, and leptin quickly fell off the public map.

Though, it has remained out of the public eye, a huge amount of research has continued on the subject (and as usual, most of the researchers have shown a gross lack of understanding of leptin -- though of late a few do seem to be getting it, and a huge number of good reviews have been published in the last 2 years.) -- and, though there are numerous unanswered questions, there is enough data to formulate a pretty thorough understanding.


Physiology

Leptin belongs, structurally, to the cytokine family (7) -- which includes interleukin-2 (IL-2), interleukin-12 (IL-12), and growth hormone (GH) -- and is synthesized primarily in adipose tissue, with minor contribution coming from gastric mucosa, skeletal muscle (8), and possibly the brain (9). In mice, mutations of the ob gene (and subsequent lack of leptin production) cause early and rapid onset of obesity -- However, this mutation is quite rare in humans (10).

In human obesity, rather than being absent, serum leptin levels are actually significantly elevated -- Leptin is thought to primarily exert its effects on food intake and energy expenditure, centrally, in the hypothalamus (11,12) -- thus, pointing to a defect in leptin sensitivity. For simplicity's sake, we will use the terms "sensitivity" (as well as "resistance") as encompassing problems in transport accross the Blood Brain Barrier (BBB), receptor issues, and post-receptor signalling issues.

Numerous factors alter leptin synthesis and secretion, as well as leptin sensitivity including genetics, various nutrients, sex hormones, insulin, catecholamines, fat free mass, fat stores, and energy balance (8, 13, 14). Within an individual, the two most important factors are fat stores, with both fat cell size and fat cell number being positively correlated with leptin levels (15,16), and energy balance -- a negative energy balance, either through fasting or exercise causes a fall in leptin levels, while a positive energy balance, with glucose metabolism being of particular importance (17), causes a rise in leptin levels (8,13). Thus, leptin levels, (and consequently, bodyweight) is regulated in both the short and long-term.

Factors contributing to leptin resistence are less well understood. This is not a big deal for the dieting bodybuilder with low bodyfat levels as leptin resistance is not the issue, but it has been considerably problematic for the pharmaceutical industry and its plans for leptin as an anti-obesity wonder drug.

It is not known to what extent poor BBB transport is responsible for obesity and to what extent obesity is responsible for poor BBB transport, but it is known that the obese demonstrate an elevated serum to brain leptin ratio vs. the non-obese (18), that the serum levels are well over the transport saturation point (19), and that elevated leptin levels downregulates leptin transport (20).

Another possibility is that leptin reaches the brain via the cerebrospinal fluid (CSF), and indeed CSF leptin levels were found to be identical in the obese and non-obese despite drastic differences in serum levels (21).

There exist at least 6 isoforms of the leptin receptor (21b), with Ob-Rb (long form) being the only opetersQrmne capable of activating signal transduction (22). The purpose of the other five is not fully understood. Alterations in Ob-Rb expression is likely to be a contrubutor as mutations causes obesity in mice (23), and, while this condition is rare in humans (24), elevated leptin levels have been shown to downregulate Ob-Rb expression (25). Ob-Rb is present in the hypothalamic region of the brain where it signals various mediators such as Neuropeptide-Y (NPY), proopiomelanocortin (POMC), and ultimately, the sympathetic nervous system, which in turn alters food intake and energy expenditure (26).

Another likely possibility for leptin sensitivity problems is post-receptor signalling. SOCS-3, a member of the supressor of cytokine signalling family, is known to inhibit leptin signalling, and upregulation of its activity has been seen following leptin exposure. Thus, it likely acts as a negative feedback mechanism (27, 28).


Fatloss

As mentioned, when it was discovered, leptin was considered an anti-obesity hormone (29). Its administration to rats decreased food intake and increased energy expenditure, causing rapid weight loss, which, unlike starvation, was confined to adipose tissue -- lean mass was preserved (30). It appeared the perfect diet drug had been discovered.

However, it soon became apparent that humans actually exhibited ELEVATED leptin levels (31), thus not only was exogenously administered leptin ineffective as a diet drug, but endogenous leptin was ineffective as an anti-obesity hormone (32). Thus, the view of leptin's roles has shifted, and leptin is now considered an anti-starvation hormone (33). Though, it is a lack of leptin, not leptin itself that sends the starvation signal. This is where it becomes so very important to bodybuilders.

Anyone who has dieted for an extended period of time has experienced "hitting the wall", the dreaded slowing and even complete stoppage of fat loss. Perhaps less noticeable, due to the often fanatical will-power of bodybuilders (or perhaps the fanatical use of EC , is the accompanying increase in true cravings for food. How about increased loss of muscle... And susceptibility to illness... And fatigue...


This is leptin.

As briefly mentioned, leptin's actions are controlled primarily by various neuropeptide systems in the hypothalamus, we will get into a bit more detail on the individual mediators involved, below, but for now we will focus on the overall effects produced by elevated and lowered leptin levels.


Appetite

Most people have noticed that a diet usually starts out quite easy -- particularly if one is fat or has been on a mass phase for an extended period. However, as the duration of the diet is extended, cravings start to set in and become more and more intense. It has long been recommended that "cheat" days be employed to prevent this -- the explanation given is generally in terms of mental well-being. However, though it is technically 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 in humans, independent of the degree of reductions in food intake (34,35). 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 (36).

In other words, this is not just a matter of will-power, it is a physiological starvation response.


Energy Expenditure

Just as with hunger control, fat loss is remarkably rapid at the beginning of a diet, however, it invariably slows, and if appropriate steps are not taken, it stops. Low leptin levels are correlated with decreases in resting energy expenditure (37, 38, 39), and administration of leptin corrects this in animals with defects in leptin production, as well as preventing or reversing the decline seen with fasting (40).

It has previously been common practice, when the manifestations of low leptin levels become apparant to the dieter, to cut calories even further, increase aerobics, start munching Cytomel, or all of the above. Unfortunately, this is just going to decrease leptin even more, making things that much worse.

What you should be doing is the exact opposite. I do not like the term "cheat day" because it implies lack of will-power, so we will reserve them for the glutton. What should be employed is a purposeful, planned REFEED. These should actually be done BEFORE the signs of low leptin become manifest, but until you get a feel for that, it will suffice to use them after.



The Refeed

As mentioned, there are numerous factors that determine leptin expression, but an exhaustive presentation is beyond the scope of this part of the article, and will be covered in the succedding months. Instead, we just take a brief look at refeeding.

The primary determinate of leptin expression is glucose metabolism (41). This gives us a really good idea of the macronutrient profile of our refeed. Fat, fructose, protein, and alcohol do not have the same effect on leptin expression that glucose does.

Assuming we have not created drastically low leptin levels, our refeed will be between 20 and 50% ABOVE maintenence, for 12-48 hours -- the higher the calories, the shorter the refeed -- there are arguments in support of both. If they are drastically low, 5-7 days of 20% above is recommended. In general, the lower you are below your natural bodyfat setpoint, and the longer or more drastic your diet, the more frequent the refeed.

Because we are eating above maintence, we are most likely accepting some fat gain (though, if leptin levels are really low, the opposite could very well occur due to increases in metabolic rate as leptin is increased), so we want to get the most bang for our buck. Thus, our primary macronutrient will be carbohydrates that enter the blood as glucose -- this means glucose, glucose polymers such as maltodextrin, and starches. Insulin also potentiates glucose stimulated leptin production (13, 41), thus high GI carbs are most ideal. Protein should be 1g/lb, and a bit of fat and fructose in foods you enjoy is acceptable, but the rest is non-fructose carbohydrates.



The Fed State

It is also leptin which is responsible for the anabolic hormonal millieu associated with the so-called "fed state", and the lack thereof during underfeeding (42, 43). Thus, in addition to its supreme importance in our fat loss efforts, it is extremely important in increasing and maintaining muscle mass.

The reason we lose muscle when dieting, despite resistence training and adequate protein intake, is hormonal. The reason we cannot gain maximal amounts of muscle without overeating, and thus accepting some fat gain, is hormonal. And, with the exception of insulin, leptin controls these anabolic hormones -- and both insulin and leptin are mediated by glucose, thus they go hand in hand.

Increased leptin leads to preferential refilling of liver glycogen stores (44), a prime indicator of the fed state (45). It increases LH which leads to increased testosterone (46). It increases growth hormone (47), it increases t3 (42), and possibly the activity of IGF-1 (48,49). It also blunts ACTH (the hormone that signals cortisol secretion in the adrenals) (50), as well as inhibitng cortisol synthesis directly (51).

Adequate leptin levels are also necessary for reproduction (52) -- in times of scarcity, when pregancy and another mouth to feed are obviously not a good thing, the reproductive functions of both males and females cease. For males, this goes hand in hand with the drop in testosterone we mentioned, and in women, this is responsible for the loss of menstrual cycles often seen in athletes at low bodyfat levels (53).



Immune System

Leptin also mediates the immune suppression seen with fasting and dieting through its direct regulation of T lymphocytes and cytokine production, as well as the activation of monocytes/macrophages (54). Alterations in immune responses are present in leptin-, or leptin-receptor, deficient animals (55). In addition, leptin replacement reverses the immunosuppressive effects of acute starvation in mice (56).


Nutrients

There are numerous nutrients which have been shown to positively modulate leptin levels or sensitivity -- many of which are freely available as dietary supplements, some of which are not, and most of which are certainly not being strategically utilized for this purpose. Vitamin E (57), Zinc (58) (400-1200 iu and 25-50mg/day, respectively) and nicotine (59) are three that you can throw into the mix now, an exhaustive presentation will be forthcoming.


Beyond Leptin

Though leptin is the master hormone, there are numerous other signals involved in adipostatic control -- and this is where it REALLY gets complicated. Some of these signals are directly modulated by leptin (anorexic peptides are increased, orexigenic are decreased), and some are not. Some are redundant (meaning if they are taken out of the equation, something else takes over) others are not. At last count, there were about 15 of them -- cortisol, gherelin, Neuropeptide-Y, Orexigen a & b, melanin concenrating hormone, cotropin-releasing hormone, and agouti-related peptide are a few that come to mind -- and there are almost certainly many more that we are not yet aware of.