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.

Recall from Part 1 that the set point idea basically says that the body will attempt to defend some body weight (or body fat) level (or perhaps range) by adjusting things such as metabolic rate, activity, hunger, etc. in response to changes in weight or fat.

I’d mention, and I’ll come back to this in a future blog post that it’s most likely body fat levels that are being regulated, more than absolute body weight per se.

This almost suggests that any attempt to alter body weight or body fat levels is futile because of the body’s defenses (and some have interpreted the concept in exactly that fashion). This is especially true when it comes to weight/fat loss as the human body appears to defend against weight/fat loss much moreso than against weight/fat gain.

In contrast, the essential idea of a settling point is that bodyweight/body fat levels will ‘settle’ at a given point based on the environment. The availability (or lack thereof) of food (and how tasty it is), the amount of activity done, all work to adjust where the body will settle.

So if you take the average human being and put them in America, with tasty inexpensive food readily available and very little activity required on a daily basis, their body weight will ‘settle’ at a certain point that may be somewhat high.

Now change their diet, or enforce a large amount of exercise, presumably their body weight will settle at some lower point (regardless of set point). At least assuming that the intervention to diet/activity is maintained.

Now take that same person and put them in a third world country where massive amounts of food aren’t available and high amounts of activity have to be done daily to obtain it; bodyweight will presumably settle at the lowest level.

This would tend to occur absolutely regardless of any biological set point.

And, as usual, there is data to support both concepts. And, given recent understanding that a variety of systems regulate body weight (including homeostatic and hedonic), it seems pretty obvious to me that both set point and settling point concepts are working to regulate body weight/fat levels.

Nobody can deny that the body fights back (to relatively greater or lesser degrees) when weight/fat levels change, especially when weight/fat is lost.

At the same time it’d be asinine to think that humans are little more than automatons driven by a homeostatic drive to eat with no control over what goes into their mouth.

As well, clearly the environment plays a huge role in eating behavior. Increasing portion sizes, exposure to food advertising and a host of other factors all impact on eating behavior regardless of homeostatic systems.

An excellent synthesis of these ideas came in a 2002 paper titled “Putting behavior back into feeding behavior: a tribute to George Collier.”

Quoting from the abstract:

“The combination of these data with George’s insightful idea, has merged into a modification of the popular Set-Point Theory of the regulation of body weight. The alternative “Settling Zone” Theory suggests that whereas biology may determine a range of body weights (adiposity) that are maintained fairly constant for long periods of time, within this “zone”, the behaviors responsible for controlling energy intake and energy expenditure are influenced primarily by environmental and cognitive stimuli.”

Essentially, while the set point may be working to keep people within some range of body fat levels, even within that range individual behaviors and environment will affect where within that range folks will end up. This model manages to tie pure biology in with pure psychology which, as I noted earlier, is a false separation in the first place.

And, I’d note again, it’s becoming abundantly clear that, regardless of set points or settling points or whatever you want to call it, the prevailing environment and individual behaviors can overcome either.

For most people given the current environment (which researchers are now terming obesigenic, meaning that it generates obesity), this means maintaining a much higher bodyweight/body fat level than you’d expect based on the set point concept (note again that any homeostatic system defending against weight gain appears to be pretty weak).

I’d note also, and this is a contentious issue, that some evidence suggests that the set point can go up (apparently permanently) with the maintenance of chronic obesity. Other things such as pregnancy, puberty and a couple of others may be able to permanently move the set point up as well.

However, there are clearly subgroups of dieters and athletes who, through various behavioral means (generally involving dietary choice and activity) can clearly maintain bodyweight and bodyfat levels that are presumably below (or at least at) their biological setpoint.

Of course, contest dieters (bodybuilders, figure competitors) often work like to hell to diet down far below their set point. Fighting against hunger, metabolic slowdown, etc. these individuals clearly can and do reach the extreme lower limits of human body fat levels (roughly 3-5% for men and 7-9% for women). Few maintain that in the long-term of course and most suffer from the post-starvation hyperphagia I mentioned in Friday’s post.

Horror stories of competitors gaining weight rapidly and massively following a strict 12-16 week diet are plentiful, many people will finish their contest preparation and go on month-long food binges (with no training) afterwards. Some of this is clearly physiological, some of it is psychological and, again, there are overlaps in the system.

I’ll continue with some of the physiology behind this system next time and (finally, really, I promise) move into psychological stuff after that.

A long standing debate in the world of obesity research revolves around the idea that bodyweight (or perhaps body fat) is regulated. What does that mean exactly?

Think about your thermostat (yes, this is the example I always use): you set it to keep the house at 80 degrees and it continually senses the temperature (via a thermometer). If the temperature goes above 80 degrees, the air conditioning comes on; if it drops below 80, the heat comes on. This is a regulated system. Your cruise control in the car works the same way: you set the speed you want to maintain and it either gives more or less gas to the engine in an attempt to maintain that level.

For some 50 odd years, it’s been thought that bodyweight/body fat are regulated similarly; that is the body is attempting to maintain some set level (called the set point) and is adjusting things like appetite, behavior, movement, etc. to do so.

A great deal of animal research supports this model: starve a rat and its metabolic rate slows, it moves around less (conserving energy), it’s appetite goes up such that when you give it free access to food again it will eat until it reaches its starting weight at which point things go back to normal. The same occurs when you fatten it up, metabolic rate goes up, activity goes up, appetite/hunger go down and it rapidly returns to its starting weight when you stop force feeding it. The rat is, somehow, trying to maintain weight at a set level.

Quick note: and this ties into that research review I did on homeostatic vs. hedonic pathways a few weeks back: exposed to certain types of diets (in rat lingo, this is called a cafeteria diet and consists of calorically dense tasty foods), most rats will readily maintain a weight that is above their set point (when exposed to a more typical rat diet). That is, the tastiness of the food can overcome any homeostatic attempts to prevent weight gain. This is important and something I’ll come back to later in this series.

Some research has found a similar effect in humans although the studies tend to be very mixed on this (I’ll address why in a later blog post): when you diet down a human being, often you see metabolic rate decreasing far more than you’d expect based on the loss of body weight alone. That is, based on the weight loss, say you expected metabolic rate to drop by 200 calories; but when you measure it it really drops by 300. That extra 100 calories is more than predicted and suggests that the body is ‘adapting’ to the weight loss in an attempt to not only slow further fat loss but also to get bodyweight/body fat back up when food becomes available again.

There are other adaptations, folks often decrease their activity levels (conserving energy), fat burning goes down and fat storage goes up, appetite often goes up so that people eat more when food is made available. In common parlance, this is often referred to as the ‘starvation response’ and, yes, there is something to it. Unfortunately, it’s basically the price that has to be paid for losing body fat to any significant level. People talk constantly about avoiding the starvation response and things of that nature but the only way to avoid it completely is to never lose fat.

In any case, perhaps the classic study in this regards is the Minnesota semi-starvation study, a 6 month study undertaken during the mid 20th century where a number of lean male war objectors were placed on 50% of their maintenance calories for the entire time while forced to engage in quite a bit of daily activity (5-6 miles walking per day).

In that study, after reaching the lower limits of human body fat levels (about 5%) and showing a host of adaptations (including an obsession with food), the men showed uncontrolled hunger when food was made available and rapidly ate themselves back up beyond their initial body fat level.

This has been termed post-starvation hyperphagia (a technical word that means overeating). Of course, it’s crucial to realize just how lean these men got; the response to less severe diets or fat loss is exactly that: less severe. A lot of this also depends on the nature of the intervention (e.g. type of diet) and the population studied. Initial body fat percentage plays a huge role here for reasons you’ll learn about in future blog posts.

Unlike in rats however, in humans, overfeeding doesn’t have nearly as reliable an impact in terms of increasing metabolic rate and it looks increasingly like any bodyweight regulation system present in humans is assymetrical: that is it protects against weight loss far more so than it protects against weight gain.

Put a bit differently and most realize this on some level: for most it’s far harder to lose weight than it is to gain it.

The reasons for this are a bit obscure but it’s thought that since humans never had any real evolutionary pressure to not get fat (e.g. we had no real predators and, during evolution, few could have gotten or stayed fat for extended periods), the body never had to develop defenses against weight gain. In contrast, starving to death was a very real reality in our evolutionary past and the body developed a number of ways of ‘defending’ against weight loss.

Moved into modern times (where food is readily available and activity levels continue to drop), this is a bad bad thing.

For completeness, I should note that there are exceptions, some people appear to show a pronounced response to overfeeding which is now being called NEAT (non-exercise activity thermogenesis) or SPA (spontaneous physical activity); some folks ramp these up to high levels when subjected to increased caloric intakes, burning off the excess calories instead of storing them as fat.

These are the people for whom gaining weight is often difficult: invariably when they try to increase food intake, not only do they sub-conciously start moving around more (burning off the excess calories), their hunger shuts off. You probably had one of these guys in your high school, the one who was always fidgeting and bouncing his leg and all of that; it turns out that the caloric expenditure from that type of activity adds up significantly over a day.

Hunger also seems to shut off more rapidly in these folks as well. They are often the folks who also claim “I eat a ton and can’t gain weight” but when you look at their food intake, they either aren’t eating much at all or they eat a single big meal and get so full that they don’t eat much else for the rest of the day (or next day).

Unfortunately, NEAT seems to be quite genetic and researchers still haven’t really figured out the exact causes or if this can be applied to help in any practical way. It probably has to do with not only the various hormones involved in all of this (which I’ll discuss in a later blog post) but how the brain responds to them.

In any case, all of the above supports the basic idea of a set point in humans: human metabolic rate, etc. clearly adapts (and does so more than weight loss alone would predict) to caloric restriction and weight/fat loss.

Unfortunately, it doesn’t appear to adapt nearly as well to overfeeding and weight gain.

Even more unfortunately, this isn’t the end of the story and determining exactly what sets the setpoint or whether or not it can change in the long-term is an area of continuing debate. Most of what I’ve seen suggests that, if setpoint can change, it only goes up. I’ve seen nothing to suggest that it ever comes back down, even over years of maintaining a lowered body weight.

Additionally, not everyone agrees with the idea of a biological setpoint anyhow, some researchers feel that a settling point is a better description of what’s going on.

Stay tuned for Part 2.

But before doing that I need to make something very clear: the distinction I’m making between psychology and physiology is simply for convenience, it’s not one that really truly exists.

That is to say, psychology impacts on physiology and physiology impacts on psychology and the days of pretending the body and mind are separate non-interacting entities are long, long gone. Again, I’ll make the separation primarily for reasons of convenience, it will save me some needless complexity in the upcoming discussion. Just keep in mind that it’s an artificial and non-existent separation in reality.

Modern science, for example the field of psychoneuroimmunology, recognizes that the brain and body are in a constant state of interaction and involvement with one another. This is sort of the basis for the idea that you can think yourself sick, or for the idea that people with a more positive attitude are more likely to survive certain diseases (such as cancer). Your thought processes can impact on such workings of your body as immune function.

Put more simply, how you think affects how your body works and how your body works can affect how you think or feel.

Incidentally, for anybody who is interested in this topic, I would highly, highly, highly recommend almost any of the books by science writer Robert Sapolsky, especially his book Why Zebras Don’t Get Ulcers where this topic is discussed in some detail (primarily wrt: cortisol and stress). This is literally one of my top-5 books ever and I cannot recommend it too highly.

Anyhow, while you’re sitting there reading this, I want you to start thinking about something that really makes you angry. Taxes, gas prices, my inability to blog consistently, take your pick. Really get a good anger going. Now stop for a second and pay attention to your body: odds are that your heart rate is up, if we measured blood pressure it would be increased too, you might be breathing a little bit harder, you get the idea. The mere act of thinking about something that upset you had a strong physiological effect throughout your body.

Here’s another example in the reverse direction: everybody knows how they get really lethargic and lazy when they are sick with something like the flu or a bad cold or what have you. It’s as if when you are sick your body is deliberately trying to get you to lay around all day and rest. This turns out to basically be the case.

When you are sick, your body releases short-lived chemicals called cytokines, some of which are inflammatory. Inflammatory cytokines, in addition to making you feel like warmed over crap when you have the flu or something, they also directly impact on the brain and your motivation to move around.

I’d note that a similar mechanism has been suggested as a primary cause of overtraining; called the cytokine hypothesis of overtraining I think it ties together a lot of conflicting and contradictory data on the topic. It explains changes in performance along with behavior and ties together the previous held (but wrong idea) of local versus central overtraining. It turns out that they are the same thing and local effects (tissue damage) is causing central effects (behavior and motivation changes).

Essentially constant/chronic/excessive inflammation locally (in the muscles you’re training) causes an increase in inflammatory cytokines and this is responsible for the lack of motivation to train and lethargy that often sets in. Essentially, your body (your muscles) are trying to ‘tell’ your brain to give it a rest and take some down-time. Of course, humans, being the stubborn folks that we are, often choose to ignore or over-ride these signals.

This has a lot of relevance to the issue of dieting failure which is what I’ll be talking about next.

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.