At a very fundamental level, the problem that natural bodybuilders and athletes have is one of partitioning; that is, where the calories go when you eat more of them or come from when you eat less of them. In an ideal universe, every calorie you ate would go to muscle tissue, with none going into fat cells; you’d gain 100% muscle and no fat. In that same ideal universe, every calorie used during dieting would come from fat stores; you’d lose 100% fat and no muscle. Unfortunately, we don’t live in an ideal universe.

As I mentioned early in this book, some hapless individuals will lose as much as one pound of muscle for every 2-3 pounds of fat that they lose when they diet. Typically, those same individuals will put on about the same amount of fat and muscle when they overfeed. Thus is the balance of the universe maintained. More genetically advantaged individuals tend to put more calories into muscle (meaning less into fat) when they overeat and pull more calories out of fat cells (and less out of muscle) when they diet. They stay naturally lean and have few problems dieting. Once again, you aren’t one of them or you wouldn’t be reading this booklet in the first place.

When talking about partitioning of calories, researchers refer to something called the P-ratio. Essentially, it represents the amount of protein that is either gained (or lost) during over (or under) feeding. So a low P-ratio when dieting would mean you used very little protein and a lot of fat. A high P-ratio would mean that you used a lot of protein and very little fat. It looks like, for the most part, P-ratio is more or less the same for a given individual; as I mentioned above, they will gain about same amount of muscle when they overfeed as they lose when they diet. This is yet another example of the body’s attempts to maintain itself at a ‘normal’ level.

So what controls P-ratio. As depressing as this is, the majority of of the P-ratio is out of our control; it’s mostly genetic. We can control, maybe 15-20% of it with how we eat or train. Supraphysiological amounts of certain compounds (supplements) and, of course, drugs, can also affect the P-ratio.

So what are the main determinants of calorie partitioning? Obviously, hormones are crucially important. High testosterone levels tend to have positive paritioning effects (more muscle, less fat) while chronically high levels of cortisol have the opposite effect (less muscle, more fat). Thyroid and nervous system activity affect not only metabolic rate but also fat burning; optimized thyroid and nervous system levels mean better fat burning, which means less muscle loss when you diet. It also means less fat gain when you overeat. Unfortunately, levels of these hormones are basically ‘set’ by our genetics; the only way to change them significantly is with supplements or drugs. Beyond that, there’s not a whole lot we can do to control them.

Another factor controlling P-ratio is insulin sensitivity which refers to how well or how poorly a given tissue responds to the hormone insulin. Now, insulin is a storage hormone, affecting nutrient storage in tissues such as liver, muscle and fat cells. In that same ideal world, we’d have high insulin sensitivity in skeletal muscle (as this would tend to drive more calories into muscle) and poor insulin sensitivity in fat cells (making it harder to store calories there). This is especially true when you’re trying to gain muscle.

In contrast, when you diet, it’s actually better to be insulin resistant (note that two of the most effective diet drugs, GH and clenbuterol/ephedrine cause insulin resistance). By limiting the muscle’s use of glucose for fuel, you not only spare glucose for use by the brain, but you increase the muscles use of fatty acids for fuel.

In addition to hormonal advantages, it’s likely that the genetic elite have high skeletal muscle insulin sensitivity. They store tremendous amounts of calories in muscle which leaves less to go to fat cells. Their bodies also don’t have to release as much insulin in response to food intake.

In contrast, individuals with poor skeletal muscle insulin sensitivity tend to overproduce insulin, don’t store calories in muscle well (part of why they have trouble getting a pump, poor glycogen storage in muscle cells) and tend to spill calories over to fat cells more effectively.

So what controls insulin sensitivity? As always, a host of factors. One is simply genetic, folks can vary 10 fold in their sensitivity to insulin. Another is diet. Diets high in carbohydrates (especially highly refined carbohydrates), saturated fats and low in fiber tend to impair insulin sensitivity. Diets with lowered carbohydrates (or less refined sources), healthier fats (fish oils, monounsaturated fats like olive oil) and higher fiber intakes invariably improve insulin sensitivity.

Another major factor is activity which influences insulin sensitivity in a number of ways. The first is that muscular contraction itself improves insulin sensitivity, facilitating glucose uptake into the cell. Glycogen depletion (remember this, it’s important) improves insulin sensitivity as well.

So what else controls the P-ratio. As it turns out, the primary predictor of P-ratio during over- and under-feeding is bodyfat percentage. The more bodyfat you carry, the more fat you tend to lose when you diet (meaning less muscle) and the leaner you are, the less fat you tend to lose (meaning more muscle). The same goes in reverse: naturally lean (but NOT folks who have dieted to lean) individuals tend to gain more muscle and less fat when they overfeed and fatter individuals tend to gain more fat and less muscle when they overfeed.

The question is why, why is bodyfat percentage having such a profound impact on P-ratio. Well, there are a few easy answers. One is that bodyfat and insulin sensitivity tend to correlate: the fatter you get, the more insulin resistant you tend to get and the leaner you are the more insulin sensitive you tend to be.

A second is that, the fatter you are, the more fatty acids you have available for fuel. In general, when fatty acids are available in large amounts, they get used. This spares both glucose and protein. By extension, the leaner you get, the more problems you tend to have; as it gets harder to mobilize fatty acids, the body has less to use. This increases the reliance on amino acids (protein) for fuel. The original Ultimate Diet advocated medium chain triglycerides (a special type of fatty acid that is used more easily for fuel than standard fats) and this can be a good strategy under certain circumstances. The newly available DAG oil (http://www.enova.com) might have some use in this regards too.

But that’s not all and it turns out that bodyfat percentage is controlling metabolism to a much greater degree than just by providing fatty acids. Research over the past 10 years or so has identified bodyfat stores as an endocrine tissue in its own right, secreting various hormones and protein that have major effects on other tissues. Perhaps the most important, and certainly the one most talked about is, leptin but that’s far from the only one. Tumor necrosis factor-alpha, the various interleukins, adiponectin and other compounds released from fat cells are sending signals to other tissues in the body which affect metabolism.

Without getting into all of the nitpicky details (many of which haven’t been worked out yet), I just want to talk a little about leptin (if you read my last book, this will all be familiar ground).

Leptin: The Short Course

Leptin is a protein released primarily from fat cells although other tissues such as muscle also contribute slightly. Leptin levels primarily correlate with bodyfat percentage, the more fat you have the more leptin you tend to have (note: different depots of fat, visceral versus subcutaneous, show different relationships with leptin). At any given bodyfat percentage, women typically produce 2-3 times as much leptin as men.

In addition to being related to the amount of bodyfat you have, leptin levels are also related to how much you’re eating. For example, in response to dieting, leptin levels may drop by 50% within a week (or less) although you obviously haven’t lost 50% of your bodyfat. After that initial rapid drop, there is a slower decrease in leptin related to the loss of bodyfat that is occurring. In response to overfeeding, leptin tends to rebound equally quickly. In contrast to what you might think, it looks like leptin production by fat cells is mainly determined by glucose availability (you’d think it was fat intake). So whenever you start pulling glucose out of the fat cell (dieting), leptin levels go down, when you drive glucose into fat cells, it goes up.

Basically, leptin represents two different factors: how much bodfyat you’re carrying, and how much you’re eating. That is, it acts as a signal to the rest of your body about your energy stores. I’ll come back to this in a second.

Like most hormones in the body, leptin has effects on most tissues in the body and leptin receptors have been found all over the place, in the liver, skeletal muscle, in immune cells; you name it and there are probably leptin receptors there. There are also leptin receptors in the brain but I’ll come back to that below. For now, let’s look at a few of the effects that leptin has on other tissues in the body.

In the liver, leptin tends to reduce insulin secretion from the beta-cells. In skeletal muscle, leptin promotes fat burning and tends to spare glucose (and therefore amino acid use). In fat cells, leptin may promote fat oxidation as well as making the fat cell somewhat insulin resistant. Leptin also affects immune cell function, decreasing leptin impairs the body’s ability to mount an immune response. Now you know at least part of the reason you tend to get sick more when you diet. On and on it goes.

Leptin and the Brain

Now, I want you to think back to the first couple of chapters of this book, where I talked about the evolutionary reasons it’s so hard to lose bodyfat. To your body, becoming too lean is a very real threat to your survival. From a physiological standpoint, that means that your body needs a way to ‘know’ how much energy you have stored.

As you may have guessed (or knew from my last booklet), leptin is one of the primary signals (along with many others including ghrelin, insulin, protein YY and god knows what else will turn up) that signals the brain about how much energy you have stored and how much you’re eating.

All of these hormones send an integrated signal to a part of the brain called the hypothalamus that ‘tell’ it what’s going on elsewhere in your body. This causes changes in various neurochemicals such as NPY, CRH, POMC, alpha-MSH and others, to occur. This has a variety of effects (mostly bad) on metabolic rate, hormone levels and nutrient partitioning.

So metabolic rate goes down, levels of thyroid stimulating hormone, leutinizing hormone and follicle stimulating hormone (TSH, LH and FSH respectively) go down meaning lowered levels of thyroid and testosterone, levels of growth hormone releasing hormone (GHRH) go down meaning GH output can be impaired, sympathetic nervous system activity goes down, cortisol levels go up as does hunger and appetite, etc., etc. What you end up seeing is an all purposes systems crash when you try to take bodyfat below a certain level.

I want to point out that falling leptin has a much larger impact on the body’s metabolism than raising leptin does (unless you’re raising it back to normal). That is, the body fights against dieting to a far greater degree than it does overfeeding. This is why, generally speaking, it’s a lot easier to get fat than it is to get lean. Of course, there are exceptions, folks who seem to resist obesity (or weight gain altogether). Research will probably find that they are extremely sensitive to the effects of leptin, so when calories go up, they simply burn off the excess calories without getting fat.

Most of us aren’t that lucky. Rather, like insulin sensitivity discussed above, researchers will probably find that leptin sensitivity is a huge factor influencing how changes in caloric intake affect metabolism. Someone with good leptin sensitivity will tend to stay naturally lean and have an easy time dieting; folks with worse leptin sensitivity (leptin resistance) won’t.

Now, as I pointed out in my last book, injectable leptin is a pipe-dream at this point, an effective dose costing nearly $1000/day (not to mention requiring twice daily injections). Using bromocriptine or other dopamine agonists seemed to fix at least part of the problems by sending a false signal to the brain, making it think leptin levels were normal. Recent studies that have given injectable leptin to dieters show that that fall in leptin is one of the primary signals in initiating the adaptation to dieting. However, unlike in rats, injecting leptin into humans doesn’t fix all of the problems.

This is because, in humans, there is more of an integrated response to both over and underfeeding. To make this easier to understand, let’s look at some of the major things that occur when you cut calories. To understand this better, I want to take a snapshot of what happens when you either reduce or increase calories.

Continued in Calorie Partitioning: Part 2.

This leaves us with other approaches (e.g. nutritional, supplements, training) to attempt to manipulate either leptin levels or signaling.

There are basically three places where dieters might impact leptin levels and/or activity in terms of fighting off the adaptations to dieting.

1. Production at the fat cell

2. Signaling in the brain

3. Transport into the brain

Leptin production in the fat cell
I talked a little bit about #1 in a previous post, when I talked about refeeds. At this point, and this topic is discussed to some degree in nearly every book I’ve written at this point, interjecting high carbohydrate, high calorie refeeds of varying lengths (anywhere from 5 hours to 3 days) is (currently) the best way to raise leptin while dieting.

One of the interesting (and often missed points) is that, as dieters get leaner (and leptin drops more and more), refeeds need to become larger and/or more frequent. That is, rather than necessarily dieting harder as they get leaner, some people are actually doing better by ‘breaking their diet’ (with specific high-carb refeeds) more frequently.

I’d note again that leptin production is related primarily to carbohydrate intake in the short-term, high-fat refeeds aren’t the best way to raise leptin levels. I’d also note that single ‘cheat’ meals won’t impact on leptin levels significantly as leptin doesn’t really change on a meal to meal basis.

Tangent: I’d note that, in this regards, some of the work being done with intermittent fasting and every other day refeeds has relevance here as some data suggests that leptin may be maintained better with that approach to dieting. But until I get Martin Berkhan in here from LeanGains for an interview and dig into it more, I’m not going to talk much about IF’ing as a dietary strategy other than to say: there’s some compelling shit going on here.

An additional strategy, talked about in some detail in my Guide to Flexible Dieting is the idea of full diet breaks, periods of 10-14 days in-between periods of active dieting where calories are brought back to maintenance (and carb intakes brought back to at least moderate levels).

Not only does this provide a psychological break from the grind of continuous dieting, it helps to ‘reset’ some of the metabolic adaptations that occur with dieting. Leptin levels will come up, thyroid conversion in the liver is improved, etc. Assuming dieters have no strict time constraints, I strongly feel that inserting full diet breaks every so often (how often depends on body fat levels) is important for long-term success. Again, for both physiological and psychological reasons.

There are at least two other regulators of leptin levels here, both zinc and Vitamin E intake appears to regulate leptin production and I have suggested supplementation of both in the past to try to help raise leptin. How much (if any) impact this actually has I can’t say.

Leptin action in the brain
Although it seems a bit out of order, I want to jump next to leptin activity in the brain. This is part of the area that gets generally referred to as ‘leptin sensitivity’ in the literature and is, unfortunately, poorly studied and even more poorly characterized.

What causes it, what (if anything) can be done about it is a huge question mark although finding ways to improve leptin sensitivity would probably also have huge benefits. Similar to improving insulin sensitivity, increasing leptin sensitivity would mean that the same level of hormone sends a larger signal. A supplement or drug that increased leptin sensitivity would be expected to do some very nice things.

I would mention that there is indirect evidence that regular exercise improves leptin sensitivity. I say indirect because measuring leptin sensitivity in humans is very difficult. Improved leptin sensitivity is being inferred from the fact that endurance athletes often have leptin levels below what you’d expect given their body fat level; this suggests increased sensitivity. Again, it’s hard to measure in humans.

It does appear that increasing levels of leptin induce resistance to itself (I’ll spare you the mechanism) so it’s conceivable that reducing leptin levels (e.g. with a diet) could transiently reduce leptin resistance/improve leptin sensitivity. How much of an effect or how long this would take is currently unknown.

If this were the case, would provide more support for cyclical dieting approaches such as my Ultimate Diet 2.0. During dieting periods, leptin levels would go down (but sensitivity would go up); during periods of deliberate overfeeding, improved leptin sensitivity (until such time as it went down again) could possibly be taken advantage of.

A similar logic could be applied to weight gain, eventually chronic overfeeding/weight gain might potentially induce leptin resistance; inserting periods of dieting to deliberately lower leptin might offset this.

While I’m on the topic, I should mention that leptin resistance can occur at other tissues such as skeletal muscle (I haven’t talked much about leptin’s actions there).In animals at least, both exercise and fish oils increase skeletal muscle leptin sensitivity.

Leptin transport into the brain
The final topic I want to talk about is that of leptin transport into the brain, something else I haven’t really talked about in this series. But it’s thought that leptin transport issues at the blood brain barrier may be part of the overall ‘leptin resistance syndrome’ and impaired leptin transport into the brain may be part of the problem. It’s thought that leptin transport into the brain can become saturated, that is, once leptin gets above a certain level in the bloodstream, no more can be transported into the brain.

But leptin transport into the brain is also actively regulated by the blood brain barrier, by a variety of things, let’s look at a few:

High blood triglycerides tend to reduce leptin transport and it’s interesting to note that, despite being high in fat, low-carbohydrate diets often reduce blood TG levels; is enhanced leptin transport part of the often observed appetite blunting effect that is often seen (along with other potential mechanisms of course)?

In a similar vein, high-carbohydrate diets, especially combined with low levels of activity often raise blood triglyceride levels, probably hindering leptin transport into the brain.

Both insulin and epinephrine increase leptin transport into the brain. Tying in with my comments above, this might be another reason that high-carbohydrate refeeds ‘work’ after a period of dieting; between (potentially) increased leptin sensitivity in the brain and insulin increasing leptin transport, there is a brief period where leptin signalling should be increased.

The supplements ephedrine and synephrine would be expected to increase leptin transport, ephedrine by raising epinephrine levels and synephrine by directly binding to beta-receptors.

And, of course exercise raises levels of epinephrine and, at least transiently should increase leptin transport into the brain. In that vein, quite a bit of research suggests that the body better regulates food intake when exercise is performed, increased leptin transport (and signalling) might be part of the mechanism.

And while I can’t find the paper now, I seem to recall a rat study suggesting that long-term (4 months if my memory isn’t failing me) fish oil supplementation could increase leptin transport into the brain. But it would likely take a very very long time to occur in humans.

And, at least for the time being that’s pretty much all I have to say about leptin. Next time, I’ll take a quick look at some of the other hormones involved in this system before (finally) moving onto some psychological issues that play a role in dieting.

1. Human bodyweight appears to be biologically regulated, that is it makes some attempt (that can be overcome by environment, of course) to maintain body fat within some range or level.

2. The system regulating body fat is assymetrical, for most people it defends against fat loss much more strongly than against weight gain.

3. For proper regulation, the body needs a way of ‘knowing’ two things: how much fat you’re carrying and how much you’re eating; a variety of hormones play a role here.

4. At least in terms of indicating the amount of body fat is present, the hormones leptin and insulin appear to play a major role. Leptin scales with subcutaneous body fat levels (higher in women), insulin scales with visceral fat levels (usually higher in men); there is some indication of a gender difference in response to the different hormones.

Leptin and insulin also both change with changing food intake; leptin levels can drop significantly within a few days of dieting even with no change in body fat levels. Insulin changes meal to meal.

5. When people reduce calories and lose fat, leptin levels drop, and this appears to be a major part of the overall adaptations to dieting in terms of metabolic rate, hunger, etc.

While leptin certainly isn’t the only hormone involved it appears to be one of the major ones not only having direct effects but also impacting how well or how poorly other hormones (such as CCK) work in the brain.

6. While studies have found that raising leptin in overweight individuals typically does little (for reasons related to either leptin resistance or insufficiency in the brain), preventing leptin from dropping during a diet (or raising it) appears to reverse many of adaptations that occur.

Point 6 raises a question that someone actually brought up in the comments: why can’t I find leptin for sale?

And the answer is that it has never (and I suspect will never) been made available outside of research. When I originally wrote my Bromocriptine booklet, an effective dose of leptin came in around $1000 PER DAY. The last time I looked (about a month ago), it’s down to about $500 per day. That’s assuming a chemical company would sell it to you.

That’s not a typo mind you, leptin makes growth hormone look cheap.

For various reasons, it simply hasn’t been developed for human use outside of research applications. Why? I can’t say for sure. I suspect it’s because drug companies primarily want weight loss drugs that cause weight loss and leptin doesn’t do that.

They don’t seem to want drugs that simply make dieting work better. I’d note that the average dieter isn’t looking for that type of compound either. Drugs that generate weight loss without the person having to change their behavior patterns are the real goal.

There is also the issue of leptin being a peptide hormone, meaning it would have to be injected. Injectable drugs are a bitch practically and there’s been a huge push to develop diabetic solutions not involving injectable insulin for that reason; the odds of the typical person injecting leptin twice daily while dieting are slim.

Bodybuilders would, of course, but that small percentage of people trying to get to 5% body fat are not the target market of the drug companies.

End result: nobody is developing leptin for commercial use so far as I can tell and I doubt this will change.

But for dieters and especially the very lean, injectable leptin would be a godsend fixing a majority of the problems that occur with dieting. Unfortunately, it’s a pipe dream at this point.

Where does that leave us?

So when you are in an energy deficit and/or losing body fat, leptin levels drop.

Although I haven’t talked much about the role of exercise here I’d only note that whether or not the deficit comes from caloric restriction or exercise per se doesn’t appear to have much of an effect on how much leptin drops.

Basically, the body appears to be sensing ‘energy availability’ (defined as energy intake minus expenditure) and adjusting things based on that. I’d, of course, note that exercise still plays plenty of other crucial roles (including psychological, which I am getting back to slowly but surely) in terms of dieting and fat loss.

In any case, what happens now?

Well, a bunch of stuff. Leptin interacts with various part of the brain but the hypothalamus (where the setpoint is primarily thought to be regulated) appears to be the key aspect. In conjunction with the other hormones I haven’t talked much about yet, when leptin drops a bunch of other neurochemicals change. These all have complicated names like Neuropeptide Y (NPY), Agouti Related Peptide (AgRP), Pro-opiomelanocortin (POMC) and Cocaine Activated Receptor Transcript (CART). The names are not that important practically. When these hormones change, they cause other changes further downstream that affect all aspects of metabolism.

There are other regulators as well, in my little Bromocriptine booklet, I pointed out that brain dopamine levels go down when leptin goes down and this appears to play a role in the overall metabolic adaptation to dieting. The whole idea in that booklet was to use a dopamine agonist to ‘trick’ the brain into thinking it was fed, it worked for about half of the people who tried it; I’m still trying to determine what the cause of the variance was.

Lowered dopamine has a secondary effect that low leptin makes animals (mice and rats at least) more likely to addict to drugs when you starve them (there are other mechanisms at work here, of course): they need something to drive the dopamine/reward system. There is also evidence that obese individuals have impaired dopamine signalling in the brain.

In any case, POMC/AGRP/NPY/CART have further downstream effects and regulate things like metabolic rate (which drops when you diet), appetite/hunger (which go up when you diet), activity levels (you tend to get lethargic, burning less calories in daily activity), hormone levels (including thyroid via TRH/TSH and reproductive hormones via LH/FSH), etc. Testosterone and thyroid generally go down as does nervous system output, cortisol goes up. You get the idea.

Please note again that the extent of these changes depends to a great degree on the extent of the diet and the body fat level of the individual: someone dropping from 35% to 30% body fat might see only small changes (or almost none at all) in these parameters, someone who is getting leaner at the 15% range is seeing bigger problems and someone at 5% body fat (e.g. a natural male bodybuilder) is undergoing massive adaptation.

This is a big part of why dieting gets so much harder as people get leaner, muscle loss accelerates, hormones are crashing, etc. My Ultimate Diet 2.0 goes into much more detail on this topic.

Basically, the body undergoes an overall adapatation that attempts to slow fat/weight loss (via reductions in metabolic rate and activity) and seek out food, these adaptations become stronger the leaner the individual gets (you’ll see that this has implications for how to fix it). I’d note that there is more to the overall adaptation to dieting than just the central effects in the brain; for example, impaired conversion of T4 to T3 in the liver is a well known effect of dieting.

Of course, various hormones have other peripheral effects in terms of energy balance and fat loss; for example leptin directly stimulates fat oxidation in skeletal muscle and a known adaptation to fat loss is a decrease in fat oxidation.

There is also that post-starvation hyperphagia I talked about in an earlier post, whereby signals from fat cells drive hunger to extreme levels when food is made available. Which, I’d note is pretty much always in modern society.

Note again (this ties in with my comments above) that the original observation of post-starvation hyperphagia was made in males who were kept on 50% maintenance calories for 6 months, ultimately reaching a body fat percentage of ~5% (that is, the lower limits of human body fat levels). Someone going from 35% to 30% isn’t going to experience nearly that effect and there’s going to be a continuum of responses from fatter to leaner that’s going to occur.

Finally (ok, probably not finally), leptin also impacts on how well or how poorly other appetite hormones in the body send their signals to the brain (that’s in addition to those other hormones sending a signal to the hypothalamus). For example, cholecystokinin (CCK) is a hormone released from the gut primarily in response to protein or fat intake; it’s involved in making you feel full after a meal. As is turns out, in rats at least, CCK doesn’t work as well when leptin is low.

Hardcore dieters (e.g. contest bodybuilders and figure/fitness competitors) are well aware of this: when they start getting very lean, even if they do everything ‘right’ at a given meal (i.e. lots of lean protein, moderate fat, fiber, moderate amounts of low GI carbs), they simply don’t stay full very long. Because all of the short-term fullness signals just aren’t working as well.

That’s because leptin is essentially setting the overall ‘tone’ of the brain in terms of how it responds to other signals. The various hormones that determine when you get hungry or full aren’t working as well when leptin is lowered from dieting and fat loss. Leptin certainly isn’t the only hormone involved in all of this; but it’s definitely one of the most important ones.

Finally, next time, what to do about all of this (short of not dieting and just staying fat and happy).

Here’s the long answer:

Like most hormones in the body, leptin has effects nearly everywhere in the body. In skeletal muscle, it’s involved in promoting fat oxidation, it impacts on fat cell metabolism directly, liver metabolism, is involved in immune system function (which may be why dieters get sick when they get very lean) and more recent research is implicating effects on brain function, neurogenesis, breathing and a whole host of other stuff.

Of some interest, leptin levels are crucially involved in both puberty and fertility, it’s been known for decades that a certain level of body fat was required for puberty to hit and achieving critical levels of leptin appears to play a role in allowing puberty to begin.

The handful of folks who don’t produce leptin never hit puberty, for example and it’s thought that some of the reason children may be hitting puberty sooner is because increasing childhood obesity is causing them to hit that critical level sooner.

In a similar vein, leptin is a key factor in regulating fertility, essentially it ‘tells’ the body and brain that it’s well fed enough to spend calories on things like reproduction and making babies. This at least partly explains why dieters are very low levels of body fat lose both sex drive and the ability to function.

Loss of menstrual cycle is a well known effect of dieting and intensive training and while it was always thought to be related to body fat levels per se, it appears that energy availability (which, remember, leptin tells the body about) is a bigger factor. Essentially, when the body ‘senses’ that energy availability is insufficient, it shuts down what are essentially ‘extra activities’ such as reproduction.

In this vein, the most recent ideas about what leptin ‘does’ in the body are that it acts as an adipometer, a measurement of energy stores that tells the brain whether there are sufficient calories available to spend them on things like making bone, maintaining immune function, etc. Essentially the same concept I’m describing here.

My point being that leptin does a lot of stuff in the body, but that’s not mainly what I want to talk about here. Rather, in keeping with the theme of this blog series, I want to talk about leptin’s potential roles in bodyweight/bodyfat regulation.

When it was originally discovered, leptin was originally conceived as an ‘anti-obesity’ hormone, it was thought that leptin should act to prevent weight gain. This led one researcher to quip (and I’m paraphrasing here) that “If leptin is meant to act as an anti-obesity hormone, it has to go down in history as the most ineffective hormone in the human body” or something roughly to that effect.

As I mentioned in previous blog posts, obese individuals invariably have high levels of leptin, raising levels in those folks does little to generate weight loss and because of that failure, everyone sort of moved on in terms of using leptin as a treatment for weight loss.

The problem is that early ideas about leptin were conceptually incorrect; rather than acting as an ‘anti-obesity’ hormone per se, leptin appears to act as more of an ‘anti-starvation’ hormone. That is, leptin doesn’t act to prevent weight gain, it acts to keep you from starving to death.

This reconceptualization would go a long way towards explaining the apparent assymmetry in the bodyweight regulation system I discussed previously: the body doesn’t defend against weight gain very well, it defends tenaciously against weight loss.

Various research found that the drop in leptin was a key aspect triggering (or at least mediating) the effects of starvation (dieting is just starvation on a smaller scale) in humans. In that vein, several studies had individuals diet before replacing leptin to pre-diet levels. This raised metabolic rate, normalized thyroid and increased fat loss. For example.

Basically while trying to raise leptin in overweight individuals is pretty much a bust, preventing leptin from dropping on a diet (or raising it back to normal levels after weight has been lost) is where the real action is.

In this vein, recent work has found that females suffering from amenorrhea (a loss of menstrual cycle) respond to replacement levels of leptin with improvements in reproductive function, bone health, thyroid and overall hormonal axes, etc. Without weight gain.

So now you know basically what leptin ‘does’ in the body at least conceptually: it signals the brain about energy stores (both body fat levels and energy intake) and appears to act primarily as an anti-starvation hormone. Next time I’ll look at mechanistically some of what it does (e.g. impact on appetite, etc) and then about how to go about dealing with this on a diet.

Leptin is a protein hormone released primarily from fat cells although skeletal muscle, the gut and possibly the brain releases it too. But, in terms of overall quantity, fat cells are the primary place where leptin is synthesized and released.

Note: those of you still laboring under the false idea that fat cells are simply inert storage cells need to get out of the 1970′s and get up to date. Fat cells are turning out to be an endocrine organ in their own right, releasing a host of hormones and chemicals that have effects all over the body; leptin is but one of them.

Quite in fact, leptin scales scarily well with body fat percentage, as I noted on Wednesday, primarily with subcutaneous body fat percentage. The higher the level of body fat, the higher the leptin level and vice versa. Males below 10% body fat may have no detectable leptin in their bloodstream.

I’d note that, probably for hormonal reasons, women generally have 2-3 times as much leptin as men at any given level of bodyfat. There is also some evidence for gender differences in how leptin responds in women versus men to things like diet and exercise; more importantly, women’s brains may respond to leptin differently than men.

Tangentially, I suspect that this may be part of what’s involved in terms of why women generally have a harder time losing fat (a topic I discussed in some detail in my Bromocriptine booklet and that I’m delving even more heavily into right now).

However, leptin doesn’t only scale with body fat percentage, it is also related heavily to food intake, specifically carbohydrate metabolism in the fat cell.

In response to both over- and under-feeding, leptin changes quite rapidly.

When someone starts a diet, leptin may drop by 30-50% within about a week, obviously they haven’t lost that much of their body fat. After that rapid initial drop, drops in leptin are much slower scaling with body fat loss.

By the same token, with even short-term overfeeding, leptin can come up far more quickly than body fat is gained. This latter fact is part of the basic premise behind refeeding and cyclical dieting; short-term very high carbohydrate/caloric intakes can raise leptin without causing significant fat gain.

I’d note that, in the short-term, only carbohydrate intake affects leptin leptin levels; fat overfeeding has no effect. In addition, changes in fat mass per se don’t regulate leptin in the short-term (less than 48 hours). Rather, it’s the effect of glucose metabolism within the fat cell that is affecting leptin synthesis and release.

This is why my diets always base refeeds around periods of high-carbohydrate intakes, acutely this is the only way to affect leptin levels in the short-term.

In essence, leptin is telling your body two different things:

1. How much fat you’re carrying.

2. How much you’re eating.

From the standpoint of bodyweight regulation and physiology, these are important things for the body to know about.

I want to note again that, as I mentioned in the last post, insulin is also a player in bodyweight regulation, scaling primarily with visceral fat and there is evidence that men’s and women’s brains are relatively more or less sensitive to the two hormones.

Women’s brains appear to respond more to changes in leptin while men’s respond more to insulin. As you’d expect, these effects are probably mediated by differences in hormone levels and it appears that estrogen improves the sensitivity of the brain to leptin. While not tested in humans, estrogen injected into male rats increases the response to leptin.

As I discussed in a previous research review, there is also evidence that estrogen exerts a leptin like signal in the brain as well.

I’d mention that, from a practical standpoint (regarding refeeds), this doesn’t particularly matter in that both leptin and insulin will primarily be increased via high-carbohydrate refeeds.

In any case, leptin (and insulin and, of course, the other hormones I mentioned last time) are sending a signal to the brain about body fat levels and food intake, making them likely candidates for bodyweight regulation. So how are they working exactly?

That’s what I’ll talk about next time (still focusing on leptin but starting to address some of the other hormones as well).

With early research (I’m talking the 1950′s) having established the existence of some type of setpoint (again, primarily in animal models), early researchers had to sort of guess what might be going on in terms of regulating body fat levels.

Essentially they postulated that the brain of the animal must be responding in some form or fashion to a hormone that scaled with body fat levels. They could only postulate what it was and it would take another 40 years before a major candidate would make itself known.

In 1994, the gene for a hormone that would eventually be called leptin (from the Greek “leptos” for thin) was discovered in the OB (OB stands for obesity) mouse. The OB mouse had been studied for decades and was spontaneously overweight with a low resting metabolic rate, low levels of activity, etc. It ate a lot, put on fat easily, etc. Here’s what it looks like compared to a normal lean mouse.

Superficially, the OB mouse appeared to be similar to obese humans (except furrier).

It turns out that the OB/OB mouse doesn’t produce leptin at all, it has a gene defect and makes zero leptin.

Inject it with synthetic leptin and it loses weight rapidly.

After the discovery of leptin, the news was abuzz with thoughts that the cure for obesity was finally here. Companies spent a lot of money getting the rights to leptin, thinking it would fix the global obesity problem and they’d make zillions of dollars.

So researchers went about measuring blood levels of leptin in humans of varying weight expecting obese humans to produce no leptin.

To their dismay, it turned out that obese individuals invariably had very high levels of leptin and it was suggested that, in a similar vein to insulin resistance (where the body no longer responds appropriately to the hormone insulin), the body or brain had become leptin resistant. There was plenty of leptin floating around but it wasn’t sending the right signal to the brain to turn off appetite and reduce body fat.

I’d note in this regards that two other rat strains, the DB (for diabetic) and DIO (dietary induced obesity) rat show varying degrees of leptin resistance (the existence of resistance to the supposed regulating hormone was also postulated back in the 50′s). In the case of the DB rat, it’s complete and genetic; in the DIO rat it develops with increasing obesity.

A variety of things induce leptin resistance including high blood triglyceride levels and even leptin itself; when elevated chronically, leptin induces resistance to itself.

I’d note that it is currently being debated if leptin resistance is truly the cause for what’s going on and other models, such as the leptin insufficiency theory are being discussed as well; in this concept, a lack of leptin in the brain (but not in the body) is the problem. In either case, the signal from leptin isn’t being sent properly. I’ll talk about what that signal is in the next post.

And while a handful of individuals have been found who produce no leptin (and who respond to injectable leptin with massive weight loss and a normalization of metabolic rate), studies which injected leptin levels in the obese showed disappointing or no weight loss.

Which doesn’t make leptin useless, mind you; it was simply being used incorrectly because researchers didn’t quite understand what it was actually doing or supposed to be doing. Many people still don’t.

Before wrapping this up, I want to note that leptin isn’t the only candidate hormone for body weight regulation; as it turns out insulin is also a key player here (insulin also scales with bodyfat). Direct injection of insulin into the brains of animals reliably reduces food intake and bodyweight.

There is also evidence, which I’ll discuss later, that there is a gender difference in how the brain responds to either leptin or insulin. Given that leptin scales mostly with subcutaneous fat (generally higher in women) and insulin scales mostly with visceral fat (generally higher in men), this will turn out to make some logical sense.

Of course, there are other factors here as well. Hormones such as cholecystokinin, peptide YY, ghrelin as well as blood glucose, blood fatty acids, amino acids, and others being discovered damn near daily are all sending an integrated signal to the brain about what’s going on in the body.

As well, varying hormones work on relatively longer or shorter time frames. For example, insulin can change in a matter of minutes, leptin may take hours, ghrelin operates on a meal to meal basis, etc. This makes for a very complicated system. But I’m getting ahead of myself.

Oh yeah, it goes without saying that most of this information is discussed to one degree or another in almost all of my books. There are links to individual ones on the side rail or you can go to the store.

A neural network sensitive to leptin and other energy status signals stretching from the hypothalamus to the caudal medulla has been identified as the homeostatic control system for the regulation of food intake and energy balance. While this system is remarkably powerful in defending the lower limits of adiposity, it is weak in curbing appetite in a world of plenty. Another extensive neural system that processes appetitive and rewarding aspects of food intake is mainly interacting with the external world. This non-homeostatic system is constantly attacked by sophisticated signals from the environment, ultimately resulting in increased energy intake in many genetically predisposed individuals. Recent findings suggest a role for accumbens-hypothalamic pathways in the interaction between non-homeostatic and homeostatic factors that control food intake. Identification of the neural pathways that mediate this dominance of cortico-limbic processes over the homeostatic regulatory circuits in the hypothalamus and brainstem will be important for the development of behavioral strategies and pharmacological therapies in the fight against obesity.

My comments: this isn’t the kind of uber-technical paper I usually like to deal with in the research review because I don’t figure most readers care so much about the detailed neurobiological stuff; they want application. But this will tie in heavily with a future article series examining the physiological and psychological issues that relate to dieting and fat loss and gives some important background to them.

The basic gist of this paper is that the body has two different systems that ‘regulate’ food intake (and by extension, body weight). Those are homeostatic and non-homeostatic systems.

Some definitions are in order:
Regulation simply refers to the idea that a certain system, via feeding back onto itself, will maintain itself within a fairly narrow range. The best example of a regulated system I can give you is that of your thermostat or maybe cruise control. Your thermostat takes input (temperature), runs that through the processor (what you want the temperature to be) and sets up an output (turns on the heat or the air conditioning). So, depending on where you set the thermostat, the temperature in your house stays fairly stable. That’s a regulated system. The idea that bodyweight is regulated has been around for 50 years and the subject of much debate. I’ll write about that at some later date, at this point simply accept that some level of regulation is going on.

The homeostatic system has to do with the idea that the body tries to maintain some specific ‘set point’ in terms of bodyweight or body fat. Basically this system takes incoming signal (from hormones like leptin, insulin, blood glucose, ghrelin, peptide YY and a host of other stuff) and makes adjustments in appetite, hormones, metabolic rate and activity to compensate.

The non-homeostatic system has less to do with internal signaling and more to do with how the body interacts with the external world. So when you are bombarded by food advertising, super size options (lots of food at a low price), appetizers (Awesome Blossom anyone?), and all you can eat buffets, these interact with the non-homeostatic system.

This paper basically lays out a quick review of the different systems before getting into the (complicated) neurobiology of how they work.

The homeostatic generally works better for defending against weight loss than weight gain. There are a bunch of complicated reasons for this, perhaps the simplest of which is that starving to death is very bad, while being fat was never really a bad thing in our evolutionary past. So the body developed a system to fight like hell agains weight loss but work fairly ineffectively against weight gain. Simply, for most people it’s far far easier to gain weight than it is to lose it. I’ll be getting into the details of this system as I continue to talk about leptin in coming issues but the above is the basic gist of it.

The non-homeostatic system has less to do with internal biology and everything to do with external environment. It also ties in with what is described as the hedonic system of eating: simply put, we eat because it is pleasurable. Essentially, the non-homeostatic system deals with issues related to food intake that are not governed by the homeostatic/internal system. The paper goes into the details, I don’t think they are that relevant for most readers, it has to do with how certain parts of the brain (the nucleus accumbens) “provide an interface between motivation and behavioral action.”

And this is where things get kind of interesting. One of the most eye-opening papers I may have read in recent years was by a research named Juan De Castro who looks at real-world eating habits (as opposed to what you might see in a lab or controlled setting). Basically he made the huge point that humans eat for reasons often totally unrelated to hunger. That is, it’s a convenient and easy trap to fall into to think of humans like rats: a gut and a nervous system with appetite being rigidly controlled by the set point. But it’s not that simple. Even rats can be fattened far past their set point with what is called a cafeteria diet (think cookie dough). Give them access to enough high calorie tasty food and they will over-ride any internal set point or homeostatic mechanism.

And the same holds for humans which a point De Castro made and which the non-homeostatic system appears to be involved with. The non-homeostatic system explains why so many humans appear to so easily override any internal homeostatic system that is operating. An abundance of food cues (tv advertising) and the easy availability of highly palatable calorie dense foods (would you like to Supersize that for only 39 cents?) and even the social environment all tend to promote food intakes far outside of any homeostatic system involved.

De Castro’s work has demonstrated this routinely. For example, the amount of food consumed goes up almost linearly with the number of people at an event. Now you know why you eat so much at holiday gatherings. People typically eat more on the weekends than during the weekdays. How much food is presented to you (all you can eat buffet anybody) also affects food intake: the more food on the plate, the more you tend to eat. So does greater food variability: the more variety at a given meal, the more people tend to eat. Think about the next time you are gorging on 18 different kinds of food at Thanksgiving dinner.

To quote one of his papers “Changes in intake can be detected with different levels of the number of people present, food accessibility, eating locations, food color, ambient temperatures and lighting, and temperature of foods, smell of food, time of consumption, and ambient sounds.” None of which has to do with any internally set system one bit.

But goes a long way towards explaining why restaurants (who are in the business of getting you to eat more) do what they do, and why most people in a modern environment have so many problems avoiding weight gain unless they impose a tremendous amount of self-discipline. It may also explain why bodybuilders and athletes, who are typically the most successful at dieting are succeeding: many of their behaviors explicitly avoid much of what De Castro’s work has demonstrated. By eating a low variety of food,s rarely if ever going out (many become social pariahs and refuse to go out with friends for fear of screwing up their near pathological eating patterns), avoiding most places where supersizing or buffet style eating would be a problem, etc they avoid many of the problems. Suggesting that type of approach (become a food obsessed hermit) to the non-obsessed is generally a recipe for disaster but recognizing that there are aspects of eating behavior that are not simply internally determined may be of some use. At the very least, recognizing those types of situations which tend to promote overconsumption is not a bad thing.

A point that I really want to drive home before wrapping this up is this:

I don’t want it to sound like these are completely separate pathways controlling food intake, which would be easy to do.

Rather, the systems are overlapping and integrated and separating them is more a function of convenience (and a reflection that they do represent slightly different things).

Here’s a quick example: the reward system in the brain is primarily dependent on dopamine. So the body releases dopamine in the brain in response to rewarding things (a bit more accurately, it turns out that it’s the expectation of rewarding things that releases dopamine) and this is what makes them rewarding.

Readers may have heard about the famous study were rats had a level wired up to fire the reward pathway in their little rat brains; they would sit there hammering away at the lever over and over, ignoring food, water, etc. That’s how powerful the dopamine/reward pathway can be.

Dopamine is also highly involved in addiction and addicting stimuli (such as drugs) tend to drive dopamine levels.

Now, one of the key hormones involved in the homeostatic system is leptin which I’ve been rambling about variously for damn near 10 years. Leptin does a lot of things in the body but, among them, arguably its primary role is as a signal to the brain about two things: how much fat you’re carrying and how much you’re eating on a day to day basis.

As it turns out, leptin appears to drive dopamine levels in the brain. When leptin drops, so do dopamine levels (this is discussed in more detail in my little book that most don’t even know about, on the drug Bromocriptine).

As it turns out, when you starve rats, they are more likely to become addicted to various substances, because of the drop in dopamine.

My point simply being that changes in the homeostatic system (for example, in response to fat loss or food restriction) are overlapping with the non-homeostatic (or hedonic) system. Everybody has noticed that food seems to ‘taste better’ when you’re hungry and these changes are probably why.

Comparative Medicine, Yale University, New haven, Connecticut, United States.

Obesity, characterized by enhanced food intake (hyperphagia) and reduced energy expenditure that results in the accumulation of body fat, is a major risk factor for various diseases including diabetes, cardiovascular disease and cancer. In the United States, more than half of adults are overweight and this number continues to increase (Flegal et al., 2002). The adipocyte secreted hormone, leptin, and its downstream signaling mediators play crucial roles in the regulation of energy balance. Leptin decreases feeding while increasing energy expenditure and permitting energy-intensive neuroendocrine processes (such as reproduction). Thus, leptin also modulates the neuroendocrine reproductive axis. The gonadal steroid hormone, estrogen, plays a central role in the regulation of reproduction and also contributes to the regulation of energy balance. Estrogen deficiency promotes feeding and weight gain, and estrogen facilitates and to some extent mimics some actions of leptin. In this review, we examine the function of estrogen and leptin in the brain, with a focus on mechanisms by which leptin and estrogen cooperate in the regulation of energy homeostasis. Key words: estradiol, leptin, crosstalk.

My comments: Ok, this is a bit of a technical paper but rather than focus on the detail pieces, I want to use it to try and clear up some big misconceptions that exist in the fitness and dieting world.

First things first, let me talk about leptin and the hypothalamus. I feel like I’ve been thumping on about leptin for years now, probably because I have. In many ways, it is the single most important hormone when it comes to problems with dieting and body recomposition. Released from body fat (and scaling frighteningly well with body fat levels), leptin signals the brain about two things which are

1. How much fat you’re carrying
2. How much you’re eating

This is important because knowing these two things is crucial for your body to be able to adjust things like metabolic rate, appetite, hormones, etc. Now, originally leptin was thought to exist to prevent obesity; this turns out to be incorrect. Rather, leptin exists to prevent starvation and the fall in leptin is what coordinates most of the bad things that happen on a diet.

Metabolic rate falling, dropping T3, increasing cortisol, increased appetite…all coordinated by the fall in leptin when you diet. Towards this end, while studies have routinely shown that increasing leptin in fat people does little, other studies find that replacing leptin to pre-diet levels on a diet raises metabolic rate and thyroid levels and increases fat loss.

Although leptin affects other tissues such as skeletal muscle, fat cells and the liver, most of its central action occurs in the brain, at the level of the hypothalamus. By exerting its signal there, leptin does what I talked about above. Recent work has also found that leptin can ‘rewire’ the brain (at least in rats) to increase the amount of a compound that does help to inhibit appetite. Outside of cases where leptin is massively elevated chronically (causing problems), leptin is one of the good hormones.

Which brings me to estrogen and the topic of this paper. In the world of bodybuilding and dieting, estrogen is usually painted rather broadly with the brush of ‘bad’. The old (and incorrect) idea is that estrogen is responsible for women’s fat problems. Estrogen makes you store fat, estrogen gives you fat legs, estrogen makes you crazy (ok, the last one is partially true). And there’s some truth to all of that. But there’s a lot of non-truth. Women seem compelled to try and banish estrogen (seriously, some use that terminology), figuring if they get rid of it, the fat will melt off.

As it turns out, estrogen is fairly schizophrenic in the female body in terms of how it impacts fat loss. As I discuss in The Stubborn Fat Solution estrogen can both positively and negative affect body fat levels in women. For example, estrogen stimulates fat oxidation during exercise. It can also limit fat mobilization from fat cells (through various mechanisms). The hows and whys of the differences aren’t important here, just realize that estrogen isn’t ‘bad’ in the sense that most think.

Consider for example this simple fact: if estrogen were THE source of women’s dieting problems, then women whose estrogen levels have fallen to very low levels (as occurs with amenorrhea or when they diet to low levels) should have an easier time losing fat. Yet nothing could be further from the truth. Or consider this: when a woman enters menopause (and her estrogen and progesterone levels drop to extremely low levels), she often gains body fat. If estrogen were the problem, neither of these things should be the case.

And this week’s paper goes a long ways towards explaining why. In addition to its schizophrenic effects on other tissues of the body, estrogen affects the brain. And, in the context of this paper, it turns out that estrogen is having a lot of signalling effects in the hypothalamus that are IDENTICAL to leptin’s (which, as I outlined above, are nothing but good). I’d note, tangentially that other studies suggest that estrogen improves the brain’s sensitivity to leptin, meaning that it makes leptin work better.

Of more importance, as stated, estrogen and leptin appear to show a great deal of similarity of the signals that they send in the brain which is what this paper details.

Somehwhat like leptin, estrogen can actually reduce food intake and body fatness levels in both animals and humans. As I noted above, postmenopausal women often gain fat and estrogen replacement causes them to lose that body fat. There is some evidence that metabolic rate may go down after menopause, and this may also be fixed by estrogen replacement.

Of some interest, empirically some contest prep coaches feel that the reason many anti-estrogen drugs (such as Nolvadex) are effective is because they exert a pro-estrogenic effect in some tissues (this little bit of strangeness, whereby a supposed anti-estrogen compound can have pro-estrogenic effects is explained in The Stubborn Fat Solution book).

Additionally, a deficiency in the level of aromatase (the enzyme that converts testosterone to estrogen) has been shown to cause a number of hormonal problems along with infertility in both sexes; clearly estrogen is crucial to normal functioning.

As mentioned above, recent work in rats has found that leptin ‘rewires’ the hypothalamus to express more of the neurons which release the ‘good’ hormones (in terms of appetite control). Estrogen has been found to do the same thing. Both estrogen and leptin also activate those same neurons, increasing levels of the hormone in question (it goes by the abbreviation POMC for pro-opiomelanocortin). I’d note that recent work suggests that it is the drop in estrogen (rather than the increase in progesterone) that is responsible for the increase in appetite during certain parts of the menstrual cycle. That is, normal or high estrogen levels blunt appetite.

The paper gets into a number of molecular details beyond the above but it’s not really relevant. My main point here is that

1. Estrogen and leptin appear to have interacting and overlapping roles in the brain in terms of reducing appetite and body fat.
   Estrogen is certainly not ‘bad’ in any sense in terms of its impact on body weight and body fat regulation. Certainly some of its physiological effects are negative but there are also extreme positives to estrogen in the body. The idea that simply eliminating estrogen will solve women’s fat or weight problems (or solve lower body fat problems) is simply silly, reductive, and nonsensical.

The molecule I want to talk about is called AMP-activated protein kinase or AMPk for short, a compound that is turning out to be one of the major metabolic regulators in the liver, skeletal muscle, fatty acids, and the brain. This is especially true if you’re talking about the regulation of glucose uptake and utilization, fatty acid intake and oxidation, and appetite. Ok, maybe I have your attention again.

What is AMPk and How is it Regulated (1)

I’m not going to bore you with a detail of the structure of AMPk. Sufficed to say that it’s a heterotrimeric compound (translation to nonscientist: contains 3 different parts which are different from each other) which are all regulated differently. Sparing you unnecessary details, AMPk is turned on when the cellular energy state of the cell drops. Basically, anything that causes the cell to use energy (ATP is broken down to produce energy and ADP, and the ATP/ADP ratio is a key activator of AMPk) will activate AMPk. As well, specifically in muscle, levels of glycogen may also regulate AMPk: it appears that high levels of glycogen inactivate AMPk and lowered levels of glycogen activate it.

Ok, let’s get more specific. A number of cellular stresses can activate AMPk. This includes metabolic poisons (DNP anybody?), glucose deprivation, ischemia (decreased blood flow), hypoxia (insufficient oxygen), oxidative stress and hyperosmotic stress. With the possible exception of DNP use, none of these are going to occur in healthy athletes. A chemical activator of AMPk called AICAR (NOT to be confused with acetyl-l carnitine or ALCAR) is being used in research as a chronic activator of AMPk. I thought I had heard rumors that someone was going to try to bring it to market as a fat loss product. As I’m going to explain below, for athletes/bodybuilders, use of such a compound would be a tremendously bad idea.

So what else? Well, I already mentioned that glycogen depletion may play a role (this is probably part of why glycogen depletion increases whole body fat utilization). Probably the most relevant activator of AMPk is exercise and muscular contraction, both of which shift both the ATP/ADP ratio as well as the creatine/phosphocreatine ratio. I should mention that exercise also activates AMPk in liver and fat cells and this appears to result from exercise induced release of certain molecules such as interleukin-6 (released from muscle cells during intense activity, especially when glycogen is depleted). Also, systemic changes in fuel availability during exercise is involved in the activation of AMPk in tissues like liver and fat cells.

AMPk is also controlled by a variety of hormones. Leptin and adiponectin, released primarily from fat cells in response to nutrient surplus, both activate AMPk in peripheral tissues. Leptin also appears to decrease AMPk levels in the brain (I’ll come back to this paradox below) while ghrelin (released from the stomach in response to eating less) increases levels of AMPk in the brain.

What Does AMPk Do?

Although it’s likely that AMPk is involved in cellular control in most cells of the body, I’m going to focus primarily on liver, skeletal muscle fat cells, and the brain (specifically the hypothalamus, which is the area primarily involved in appetite/hunger and bodyweight regulation) with AMPk playing a role in carb, fat and protein metabolism in peripheral tissues and bodyweight regulation in the brain.

With regards to carbs, AMPk activation inhibits glycogen storage and increases glucose uptake, it appears to be very involved in improving insulin sensitivity for this reason. Insulin sensitizing drugs such as metformin and the thiazolidinediones (TZD’s) appear to work at least partially through AMPk activation. Note that the TZD’s tend to increase bodyfat and metformin hasn’t been found to cause a drastic decrease in fat mass by itself either (2) although it seems to improve the results of low-carbohydrate diets in insulin resistant/obese individuals .

So what about fat metabolism? In the liver, AMPk activation decreases fatty acid and cholesterol synthesis. In muscle cells, AMPk activation increases fatty acid oxidation (i.e. you burn more fat). It also appears that AMPk activation is one of the keys to how endurance training causes adaptations such as increased mitochondrial protein synthesis (3). In fat cells, AMPk activation decreases both fatty acid synthesis and lipolysis (by inhibiting hormone sensitive lipase).

Ok, so far so good, right? With the exception of the inhibition of lipolysis, it sounds like AMPk activation is a good thing, increased glucose uptake, increased fatty acid oxidation in skeletal muscle cells. So why not just jack up AMPk levels all the time and get ripped?

The first reason I alluded to in the UD2.0, a low cellular energy state inhibits protein synthesis. And it looks like AMPk activation is part of the mechanism. In a rat model, AMPk activation has been shown to suppress protein synthesis by down regulating another molecular target called the mammalian target of rapomyacin, or mTOR (4) which is heavily involved in protein synthesis.

Although this hasn’t been shown in humans to my knowledge, the general picture is that AMPk activation turns off energetically costly processes (such as protein synthesis) and turns on energy producing processes (such as glucose and fat oxidation). So an AMPk inhibition of skeletal muscle protein synthesis would be consistent in humans. I’ll note that years ago, Dan Duchaine commented how insulin sensitizers (of which metformin was one of the ones in use) caused muscle loss and I have to wonder if this isn’t part of the mechanism.

The second reason has to do with the effects of AMPk activation in the brain where AMPk activation has a rather negative effect, which is to increase appetite. Recall from above that I mentioned that both leptin and ghrelin affect AMPk levels in the brain. Well, it’s time to talk about that. As mentioned, ghrelin, which tends to increase appetite and food intake increases AMPk levels in the brain while leptin, which tends to decrease appetite and food intake (sort-of) decreases AMPk. As well, nutrient availability affects brain AMPk (probably through leptin and ghrelin). Eat more and brain AMPk goes down, eat less and brain AMPk goes up (5). Increased activity of hypothalamic AMPk via AICAR also increases food intake (6). I’ll come back to the ramifications of all of this below.

I want to mention that the mechanism whereby leptin increases AMPk levels in muscle but decreases them in brain is currently unknown (7). That is, leptin has opposite effects on AMPk in muscle/fat/liver cells versus the brain.

Putting it All Together

So now a few things may start to come together in terms of dieting or mass gains or what have you. When you eat less (diet), a lot of things occur. One of those is going to be a decreased cellular energy charge (an effect which may be increased by glycogen depletion and, of course, exercise). Fat oxidation goes up, insulin sensitivity goes up, good things happen in terms of fat loss. But the drawback is that, due to changes in hormone levels and AMPk signaling you get hungry. As well, protein synthesis is inhibited (this is a huge part of why it’s so hard to gain muscle while losing fat at the same time).

AMPk and its function also explains one of the older models of hypertrophy whereby protein synthesis was acutely depressed during exercise. Activation of AMPk during exercise directly inhibits mTOR and protein synthesis. The recovery of cellular energy post-workout allows protein synthesis to increase and growth to occur. Note also the huge push on the provision of amino acids, specifically leucine, post-workout as leucine directly activates mTOR, turning on protein synthesis.

A question that comes to mind (which I have no answer to): can leucine’s activation of mTOR override the AMPk suppression of mTOR either during exercise or while dieting? High dose BCAA may decrease muscle loss on a diet, could this be a potential mechanism?

In reverse, consider what happens when you’re eating above maintenance. AMPk will be inhibited (except during exercise) meaning no inhibition of protein synthesis. Also, assuming decent brain leptin sensitivity, appetite and food intake will be kept under control. However, this comes at the expense of decreased fat oxidation (part of why folks tend to gain fat as they gain muscle).

Basically, AMPk (and, make no mistake, there are multiple other pathways involved) help to explain why it’s so hard to have it all: fat loss with muscle gain. As described in the UD2.0, the mechanisms needed to maximize fat loss are more or less directly antagonistic to those mechanisms involved in muscle gain and vice versa. Which is why the UD2.0 was broken up into discrete fat loss and muscle gain phases which were alternated every few days.

A Few Words About Application

As mentioned in the introduction, this article didn’t really present a whole lot useful, I’m wondering why I’m wasting your time with it. Clearly, the most potent tool we have to activate AMPk and increase fat oxidation and the rest is exercise. Dieting in general probably activates AMPk as well although I can’t recall seeing it directly studied.

The effects of both can be increased by depleting glycogen (ala the UD2) but this comes with the price of inhibited protein synthesis. Which is why I’m so adamant about all diets having a refeed/anabolic phase at some point. You need to turn off diet induced catabolism although I should note that AMPk activation is only one of many mechanisms (including insulin, cortisol, etc, etc.)

Under non-dieting circumstances, although AMPk will be activated during training, impairing protein synthesis, providing nutrients afterwards (i.e. carbs + proteins) is known to reverse the catabolic processes and turn on anabolic processes. Making me wonder if pre- or during-workout nutrition can actually prevent the activation of AMPk in the first place (by limiting the drop in cellular energy charge). To my knowledge, it hasn’t been studied but it would make some logical sense.

A Final Question about AMPk and Fat Loss

From the standpoint of treating obesity and insulin resistance, AMPk appears to be an attractive target. However, the contradiction described above has to be dealt with. Ideally you’d want to activate AMPk in peripheral tissues such as muscle and fat cells while decreasing AMPk in the brain (to reduce or control food intake).

Clearly leptin injections are one way of doing that but leptin injections are unlikely to work in obese individuals, due to leptin resistance, in the first place. Of course, lean athletes and bodybuilders aren’t obese and probably have decent leptin sensitivity. This is probably one of the reasons refeeds ‘work’, by raising leptin, we are activating AMPk in skeletal muscle (explaining why people often lean out after a refeed) and inhibiting it in the brain. Is there any other way? Well, maybe.

One study (again, in rats) found that alpha-lipoic acid ingestion decreased AMPk in the brain while increasing it in skeletal muscle in rats (8). I should note that the doses used were high and a very informal poll on my forum doesn’t seem to indicate that ALA was having any such effect in terms of fat loss or appetite. If anything, people noted an increase in appetite, most likely mediated by a decrease in blood glucose via insulin sensitization. Would consuming ALA while eating sufficient carbs allow us to achieve the same effects without increasing hunger? I don’t know. There is also the dose issue.

But it does point out that increasing AMPk in muscle while decreasing it in the brain is possible and future drugs or nutrient compounds may allow us to get the best of both worlds. Unfortunately, there is still the issue of muscle loss due to the inhibition of protein synthesis that would occur with chronic muscular activation of AMPk. At this point, I have no idea how to sidestep that. Would sufficient amounts of protein, BCAA or even just leucine be sufficient to activate mTOR against the inhibition occurring due to AMPk? Or would another drug or nutrient be required to prevent muscle loss against chronic AMPk activation. At this point, it’s all speculation; hopefully more research will help to answer these questions.

References

1. Kahn, BB. et. al. AMP-activated protein kinase: Ancient energy gauge provides clues to modern understanding of metabolism. Cell Metabolism (2005) 1: 15-25.
2. Ruderman NB et. al. Minireview: Malonyl CoA, AMP-activated protein kinase, and adiposity. Endocrinology (2003) 144: 5166-5171.
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