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Leptin: The Next Big Thing in Body Composition, Part 1

When you?re dieting, you should refeed before you experience the signs of lowered leptin.

You probably haven’t yet heard of leptin, and even if you have, you likely have no idea how important it is to your efforts in body-composition manipulation’but you soon will. The prediction is that within a year leptin’and what’s called the fed state’will be everywhere in the bodybuilding world, and within two it will be the topic of infomercials. It will be bigger than the Atkins, or ketogenic, diets and bigger than The Zone. It’s the reason that prolonged dieting causes you to stop losing fat and the main reason overfeeding helps you gain muscle. When it comes to body composition, leptin is as close as it gets to a master hormone in the human body.

Background on Leptin

In 1953 Kennedy proposed the existence of a centrally acting lipostatic negative-feedback signal that was produced by adipocytes in proportion to fat content. That feedback signal regulated body stores through alterations in food intake and energy expenditure, and with its discovery the ‘set-point’ theory was born.

In 1994 the ob gene was cloned and found to code for a 16 kDa protein that was called leptin, from the Greek leptos, meaning thin. Leptin was anointed as the magic bullet that would vanquish obesity. As it turned out, however, that was not the case’for reasons you’ll soon learn’and leptin quickly fell off the public radar.

Though it has been out of the public eye, scientists have continued to do considerable research on the subject. There are still numerous unanswered questions, but we have enough data to formulate a very thorough understanding at this point, if you know where to look.

Leptin Physiology

Numerous factors alter leptin synthesis and secretion as well as leptin sensitivity. They include’but are not limited to’genetics, various nutrients, sex hormones, insulin, catecholamines, fat-free mass, fat stores and energy balance.

For any individual the two most important determiners of leptin levels are fat stores’with both the size and number of fat cells being positively correlated with leptin levels’and energy balance. A negative energy balance, created by either fasting or exercise, causes a fall in leptin levels, while a positive energy balance causes a rise. Thus, leptin levels’and, consequently, bodyweight’are regulated in both the short and long term.

Leptin sensitivity, on the other hand, is less well characterized in the literature, although a bit of deductive analysis points strongly to the sympathetic nervous system (think ECA), PPAR (fish oil), AMPK (exercise), the thyroid axis and the androgen axis as modulating a very significant proportion of it in both fat and muscle. That’s not a big deal for dieting bodybuilders who have low bodyfat levels, as leptin resistance is not the primary issue in that case; however, leptin resistance has been quite a problem for the pharmaceutical industry and its plans to promote leptin as an anti-obesity wonder drug.

Leptin and Fat Loss

As mentioned above, leptin was initially considered to be an anti-obesity hormone. When administered to rats, it led to decreased food intake and increased energy expenditure, causing rapid weight loss. Unlike what happens with starvation, the weight loss was confined to adipose tissue, while lean mass was preserved. It seemed as if science had discovered the perfect diet drug.

It soon became apparent, however, that obese humans actually exhibited elevated leptin levels, not a shortage. So not only did exogenously administered leptin prove to be ineffective as a diet drug, but it also turns out that the endogenous leptin made by the body is ineffective as an anti-obesity hormone. As a result, the scientific view of leptin’s roles has shifted, and it’s now considered an antistarvation hormone’although it’s a lack of leptin, rather than leptin itself, that sends the starvation signal. That’s where it becomes so important to bodybuilders.

Anyone who has dieted for an extended period has had the experience of ‘hitting the wall’the dreaded slowing and even complete stoppage of fat loss. Perhaps less noticeable, due to the often fanatical willpower bodybuilders exhibit (or perhaps the fanatical use of ephedrine-and-caffeine stacks), is the accompanying increase in true cravings for food. Increased loss of muscle is another common dieter’s woe, as are susceptibility to illness and fatigue. That’s leptin’or the lack thereof.

Leptin and Appetite

Most people notice that a diet usually starts out quite easy’particularly if you’re fat or have been on a mass phase for an extended period. As time goes on, however, cravings set in and become increasingly intense. Experts have long recommended that dieters use cheat days to prevent that. The explanation generally involves mental well-being; however, although the effect is technically in your head (i.e., in the hypothalamus), the phenomenon is not merely psychological.

Decreases in leptin are strongly associated with increased voluntary food intake in animals and subjective sensations of hunger in humans. What’s more, the lower leptin levels go, the greater the magnitude of the effect. By the same token, giving leptin to animal subjects that have defects in leptin production decreases hunger and food intake.

In other words, the increased appetite and often chronic hunger that dieters experience isn’t just a matter of willpower; it’s a physiological starvation response.

Energy Expenditure

Just as hunger is initially manageable, fat loss is remarkably rapid at the beginning of a diet. Fat loss invariably slows, however, and if you don’t take appropriate steps, it stops. Low leptin levels correlate to decreases in resting energy expenditure, and giving leptin corrects that. It also prevents or reverses the decline in leptin levels caused by fasting.

It’s been common practice, when the manifestations of what we now know to be low leptin levels became apparent to the dieter, to cut calories even further, increase aerobics, start munching Cytomel or all of the above. Unfortunately, that’s just going to decrease leptin further, making the situation that much worse.

What you should be doing is the exact opposite. I don’t like the term cheat day because it implies lack of willpower, so instead I’ll refer to a purposeful, planned ‘refeed.’ You should do it before you experience the signs of lowered leptin, but until you get a feel for how to monitor leptin levels, you can just refeed after you get the message.

The Fed State and Anabolism

Leptin is also responsible for the anabolic-hormonal milieu associated with the fed state’as well as the lack thereof seen during a diet. So, in addition to its supreme importance in your fat-loss efforts, leptin is also extremely important for increasing and maintaining muscle mass. The reason you lose muscle when dieting, despite resistance training and adequate protein intake, is hormonal. The reason you generally cannot gain maximum amounts of muscle without overeating’and gaining some fat’is hormonal. And leptin controls the anabolic hormones with the exception of insulin.

To put it another way, the fed state is conducive to fast, muscular and ‘metabolically inefficient’ phenotypes, and vice versa, with the opposite holding even more true. The literature supports that. Leptin leads to preferential refilling of liver glycogen stores, which is a prime indicator of the fed state. Leptin also increases luteinizing hormone (LH), which leads to increased testosterone. It increases growth hormone, it increases T3, or active thyroid hormone, and it possibly increases the activity of insulinlike grown factor 1 (IGF-1). It also blunts ACTH, the hormone that signals cortisol secretion in the adrenals, as well as directly inhibiting cortisol synthesis.

Obesity does not occur in the wild, where animals eat what they need and then get a signal to stop. But keep Rover and Kitty’s bowls full of delicious vittles, and it’s a different story. Obviously, that communication between nutrient signaling and calories and reward is strong in an even larger percentage of humans.

What does that have to do with we, the lean? Everything.

Lean people very often don’t get the proper ‘fed’ signal either, though that situation is largely a result of self-imposed starvation. What most dieters aren’t aware of is that calories are almost meaningless, per se. It’s the strength of the signal sent at the cell level’as well as which tissues are signaled’that determines the metabolic and hormonal state. And it’s foodstuffs and their metabolic by-products that send those signals.

Some foods send a stronger per-calorie fed signal than others. With proper selection, portions and timing of those substrates, you can achieve the full-fed signal in your muscles and brain without the spillover into fat that normally accompanies a mass-phase bodybuilding diet.

Food and Mood

Obviously, the nutrient state is intimately connected to an organism’s psychological state and motivational drive. Before the evolution of rational man, organisms needed a very strong signal to let them know what they needed to do to survive, particularly in times of scarcity. Things have strong tastes for a reason.

Food restriction increases the subjective reward responses to food and drugs. It also increases dopamine and opiate activity. That makes sense on the micro and macro levels. To begin with, food restriction causes a reaction that mimics the starvation response, so signals of reward and satiation are minimal. As a result, the dieters’ receptors upregulate simply due to diminished ligand binding.

What’s more, the leptin receptor is found all over the neurons for pleasure chemicals found in the areas of the central nervous system that regulate food-related behavior. Not surprisingly, leptin decreases the reward response to food and drugs. When leptin levels are within the optimal range, fed signals go out in a thousand directions. You become chemically satiated and can quit hunting wild game and berries.

Unfortunately, your goals and needs are generally not in harmony, thanks to the evolved genetic tendency toward the yummy-equals-good-for-you response. That has caused an epidemic of obesity in these times of plenty, as it now takes essentially zero effort’physical and otherwise’to attain those wonderful calorie-dense foods in massive quantities.

Many people have come to possess a ‘thrifty’ genotype. In the obese, usually due to the chronic overfeeding and underexercising that accompanies the good life, the feedback system quits working properly. Leptin is increased well above not only normal physiological ranges but also saturation of the receptor, which is slowly downregulated. Ultimately, that removes all restrictions on the reward signal for food.

Thus, the stop-eating signal doesn’t become stronger in proportion to the nutritional state. Even worse, the ultra-high leptin actually aids bodyfat storage. That makes sense from a survival standpoint. The body has a nutrient hierarchy’it’s more important that some tissues have fuel than others. The brain, muscles, organs and bones all have priority over adipose tissue for receiving nutrients. When those essential tissues have all the fuel they require, the massively elevated leptin levels that result signal the body that there’s an overabundance of food. The body then begins to store fat in preparation for times of scarcity, which were inevitable for most of our ancestors.

Sex, Reproduction, Testosterone and More

Humans also need adequate leptin for reproduction. In times of food scarcity, when getting pregnant and having many mouths to feed are conducive to survival, the reproductive functions of both males and females cease. For males that means a drop in LH and testosterone. In female athletes who have low bodyfat levels, the loss of menstrual cycles is common.

Testosterone has been found to suppress leptin synthesis by adipocytes both in cells and in a test tube. Estrogen, on the other hand, has been shown to directly increase leptin. Indeed, women have leptin levels two to three times as high as men at the same bodyfat percentage. Both estrogen and testosterone are likely to contribute to that.

On average, however, women have higher bodyfat percentages, which suggests that they have less leptin sensitivity than men. As alluded to above, it’s quite likely that androgens increase leptin sensitivity via beta-receptor upregulation and alpha-2-receptor downregulation, thus lessening the sexual dysfunction.

That increased sensitivity would also explain the very favorable effects of androgen administration on bodyfat in obese and endomorph males. In the next installment I’ll cover how to apply this information to your training, diet and supplementation efforts and tailor it to your individual biochemistry, your genetic body type and your goals. IM

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