Saturday, June 28, 2008

Energy Regulation 1: Do Calories Count? And Who's Counting?

In the last post discussing acylation stimulation protein, I made several references to the various regulatory mechanisms that control energy intake, utilization and storage. My claim is that if all of these are working correctly, the body will more or less maintain itself in a healthy state, as that is presumably the evolutionary point of all this stuff. "Healthy state" includes not becoming obese. My guess is that unless you break one or more of these mechanisms, you would find it very difficult to store much excess body fat, because the body doesn't want that, and tries very hard to avoid it by influencing behavior and metabolism.

As we'll see, there are lots of possible things to break and ways to break them: genetic defects, drugs, disease. But for most of us, the major influence is probably diet, mainly through it's influence on insulin. Insulin is arguably the "master hormone" in charge of energy balance. As we'll see, insulin not only controls of blood sugar, but also acts as a signal to start or stop eating, and signals the amount of stored energy in the form of body fat. Insulin interacts with many other hormonal and nervous system mechanisms, and screwing up insulin balance also potentially fouls up a lot of other things as well; take a look at all of the problems inherent in "metabolic syndrome", and you'll get the picture.

I don't believe obesity is a disease in itself, but rather the symptom of an underlying metabolic problem. To "cure" obesity, you really need to restore the appropriate balance, so that the regulatory systems can operate properly. For instance, some obese people have a genetic defect that causes them to make little or no leptin, a hormone secreted by fat cells which is involved in control of both appetite and fat storage. Once you know somebody has this problem, it can be treated by giving them leptin to make up for their deficit. Type I diabetics (who are not obese) lack insulin, so they are treated with insulin. But Type II diabetics have too much of both leptin or insulin, and reduced response to both. Treating them with either leptin or insulin would not be expected to succeed in restoring their metabolic balance and thus normal bodyweight, an expectation borne out by experience. If you're going to fix a problem, you'd better have some idea of the root cause.

So this is the first in a series of posts to delve into the broad topic of "energy regulation", including feeding behavior, energy utilization, and energy storage. Considerable scientific progress has been made on these topics in recent years, but the understanding is far from complete. I'm going to try and touch on the high points, and hopefully avoid too many technical details (which honestly, I don't completely understand myself). Part 1 will be mostly a setup to the subsequent discussion. At the end of this post, I'll put some links to scientific publications or textbooks used, so you can delve into the details if desired.

There's been a lot of discussion lately about whether or not "calories count" in weight gain or weight loss. Much of the argument surrounding this point seems to be unfortunately misguided, with people taking absolute positions on either side. The reality is more complicated. The short answer to the first question is "Yes, calories do count", but is qualified by the fact that many hormonal and nervous system mechanisms regulate caloric intake, storage, and output. Roughly speaking, these are influenced by caloric content of food, but greater influence is exerted by the composition of those calories. As we go through this series, we'll see several examples where macronutrient composition plays a much larger role in influencing the biological response than does simple calorie content. In short, as far as metabolic regulation is concerned, the oft-repeated phrase "a calorie is a calorie" does not apply.

Thinking about the question "Who's counting calories" starts us down the path of understanding. After all, what organisms in nature consciously count the calories they eat or expend? That's easy: humans, and humans alone. Clearly an animal like a rat isn't keeping a tally like "I ate 5 extra grams of rat chow this morning, did 20 minutes on the exercise wheel to compensate" etc. Somehow, they "just know" how much to eat and be active, and their body adjusts accordingly. It is often stated that humans become obese due to an overabundance of readily available food. But in their natural environment, animals will not become obese regardless of food abundance UNLESS there is some other biological imperative to do so. Foxes don't get fat when there's lots of rabbits around, they make more baby foxes. Storage of excess body fat is again clearly regulated by other mechanisms. Mice, for instance, will lay on bodyfat as winter approaches in anticipation of hibernation. Further, they will store excess fat largely independent of how much or little they are fed. Bears similarly lay down fat stores for winter hibernation. Yet once they pass a certain age, they lose the ability to store enough fat for the winter, regardless of how much food is consumed. So the amount of input calories would not seem to be the major controlling factor in fat storage or loss.

Many recommendations for diet and health are based on a grossly oversimplified view of how food intake is regulated. The fullness of the stomach is widely thought to be the primary regulator. You eat until the stomach is full, food moves into the intestines, where your body sucks up whatever it can at a fixed rate until the stomach is more or less empty. Then you get hungry and eat again. This supposedly happens about once every four hours, leading to the idea of three meals a day during waking hours. This oversimplification spawns silly ideas like drinking lots of water or eating high-fiber foods to make you feel more full on less calories, or even sillier interventions like bariatric surgery. Just a little thought shows these ideas can't be right. If it were, a rat would happily eat wood chips and water until it felt full, and would ultimately starve to death from a lack of energy nutrients. Clearly the rat "knows" the energy content of possible food items, and thus avoids the wood chip diet. And we'll see later that surgery such as gastric bypass does more than simply shrink stomach capacity: it also causes measurable and significant changes in the levels of hormones associated with appetite and energy regulation.

The oversimplified view is part of the web of flawed thinking underlying diet. Obesity is not simply a result of being gluttonous, and weight-loss is not simply a process of curtailing caloric intake. "Willpower" is unlikely to enter in to the equation, unless your plan for avoiding or reducing obesity requires that you fight against millions of years of evolutionary programming, life-preserving impulses, and mechanisms regulating appetite and metabolism. Rats and bunnies and bears don't need willpower if fed their natural diet; but feed them something outside of their evolutionarily defined diet, and their bodies often go haywire, with obesity as one possible outcome. One presumes the same holds for humans. Similarly, I think it's pretty easy to poke holes in the idea that higher brain functions (e.g. "willpower") have the capability to override behavior which is key for survival of the organism. Next time somebody blabbers at you about having "willpower" to lose or keep off excess fat, ask them if they have the willpower to hold their breath until they pass out. Fighting against hunger is, I think, the same thing: you can do it for awhile, but the body isn't going to let itself die, and will sooner or later induce behavior it thinks is necessary for survival. This will hopefully become more clear as we delve into the regulation of diet and metabolism.

Before diving into some of the biochemical details, it might be useful to think of a simple model system which requires similar regulatory capabilities. The hybrid electric vehicle (HEV) seems to be a good one, and has some nice similarities with the body. An HEV takes fuel (usually gasoline or diesel) from an external source, and stores it in the gas tank. It also can store energy in a battery, and when moving also "stores" kinetic energy (the energy of motion). Energy can be used from these various sources as demanded by the usage of the car. When accelerating, gasoline is burned in an internal combustion engine and/or electricity from the battery is used to power an electric engine. Energy can be converted amongst it's different forms. The internal combustion engine can be used to either accelerate the car (increasing kinetic energy) or charge the battery. Kinetic energy can be converted to stored electrical energy through regenerative braking.

All of this requires some regulation, so that you don't store/use too much energy, possibly causing inefficient use or damage. One mechanism is simply mechanical: the gas tank has a maximum capacity. If you try to put in more gas than it can hold, gasoline spills out all over your shoes. The battery has a maximum capacity as well: charge it too much, and it may explode. The car's "brain" (a computer and related electronics) monitors the various systems as well as the energy requirements based on your usage. Thus, if the battery registers as not full, applying the brakes will generate electricity which charges the battery. If the battery is full, then that energy must be "wasted" as heat, because there's no place else to put it. If power requirements exceed that of the electrical motor or if the battery is empty, then the internal combustion engine needs to be turned on.

The human body has many parallels. Fuel is supplied externally, but we can take in multiple types: carbohydrate, fat, protein, and alcohol (though obviously the latter is not recommended). This fuel is stored in the stomach, much like the gas tank. Rather amazingly, unlike an HEV, the body needs only one power plant for all different fuel types: the mitochondria. The body has "batteries" as well. Fat cells can store fat, muscles and the liver store glycogen (the storage form of sugar), and lean tissue throughout the body contains protein, though this is generally used for energy only in emergency situations. Different fuel types can be interconverted: carbohydrates can be changed to fat, protein to glucose, fats to ketones. Excess energy can be wasted as heat. And all of this is monitored and regulated by a combination of the nervous system and glands, to maintain the body in a healthy state over a wide variety of usage conditions, whether sleeping or avoiding becoming a bear's lunch. As humans are omnivores, the system can also deal with a very wide range of different macronutrients from plant and animal sources.

The differences between people and HEV cars are informative as well. An HEV can't go get it's own fuel. Instead, it reports on the fuel status to the driver via the fuel gauge. Humans of course need to obtain their own fuel. The "fuel gauge" is ultimately appetite, which is driven by a complex system of hormones and several parts of the brain. An HEV also uses fuel for only one thing, which is to generate energy. While energy is one main purpose of food intake in humans, humans are also constantly regenerating new tissue and other functional substances like hormones and enzymes. Food provides the raw material for this as well. As we'll see in a bit, these functions, most importantly including growth in children, are also closely tied in to the same systems which regulate food intake and energy metabolism.

The cycle of food intake and energy usage/storage can be broken into several steps. Each of these tends to have several interacting regulatory mechanisms, both hormonal and nervous. The steps are:
  • Appetite stimulation, which in turn stimulates food-seeking behavior.
  • Initiation of the meal (start putting stuff in your mouth).
  • Termination of the meal (stop putting stuff in your mouth).
  • Movement of food from the stomach to the small intestine for digestion and absorption.
  • Utilization or storage of nutrients.
  • When everything eaten is used up, start again.
If the regulation of any step is disrupted, we have the possibility of non-optimal health, the most outward symptom of which is obesity. For instance, researchers use several strains of rats and mice which have been genetically modified to be predisposed to obesity. The modified genes affect different regulatory systems, with various different outcomes like overeating, underactivity, increased storage of fat over lean tissue, etc. (the "willpower" gene has yet to be identified.) But the main outcome is the same: obesity. When you break a regulatory mechanism, the animal exhibits some combination of behavioral and/or metabolic changes that cause it to become obese. Conversely, if you repair whatever is broken, or compensate for it's effects, the animals generally lose their obesity and normalize metabolism. Why would it be any different in humans?

Subsequent posts will delve into these regulatory mechanisms more deeply, and explore some possible implications for diet and health. Again, much is unknown in this field, so the best we can do is take what is known and apply rational inference; but I think we'll see that some knowledge of how eating and energy storage are controlled provides a powerful explanatory framework for much of what is observed in terms of obesity, weight-loss, and just general health.

Here are some links to the science papers, if you want to get a head start:

Wednesday, June 25, 2008

Petition the NIH to Weigh All Scientific Evidence

A recent comment from Lauri Cagnassola asked for support on a petition to the National Institutes of Health (NIH). Dr. Cagnassola is the managing editor of the journal Nutrition and Metabolism, and the petition is basically asking the NIH to consider all scientific evidence surrounding the issue of blood sugar control in Type 2 diabetics. Particular focus is on an NIH statement about the ACCORD study: "Intensively targeting blood sugar to near-normal levels ... increases risk of death." What makes this statement somewhat brain-dead is that it is not qualified by "using the methods for blood sugar control employed in the ACCORD study", which I believe were largely intensive drug therapy, possibly including insulin. There are plenty of good reasons to think that intensive insulin therapy could shorten your life, and this sort of blanket conclusion is dangerous, obviously, since the implication is that we should just give up on controlling blood sugar in diabetics, since presumably the cure is worse than the disease.

There is plenty of evidence, however, both anecdotal and clinical, that Type 2 diabetes is often effectively controlled through diet. See, for example, this recent study, as well as the excellent documentary "My Big Fat Diet". Proper testing of a hypothesis requires that all relevant evidence be included in evaluating that hypothesis, and the NIH appears to be only considering the narrowly defined evidence admitted by current dogmatic beliefs. The usual complaint when diet is brought up to this group of people is something like "we don't know the long term effects of a low-carbohydrate diet in patients with Type 2 diabetes." Of course you don't, because you've neither looked at the currently available evidence, nor attempted studies to gain your own evidence.

The petition is asking to change that. Of all scientific organizations involved in studying human health and making treatment or lifestyle recommendations, the NIH is one of the very few truly public institutions. It is funded by your tax dollars, and is supposed to represent the best interest of the general population, not of specific interests such as drug or food companies. Their responsibility is to consider all available evidence, since getting it wrong can literally be the difference between life and death. If you feel similarly, please sign the petition, and also consider contacting your congressional representatives. Elected officials are more sensitive to the public voice than bubble-world bureaucrats, and they hold the purse-strings for funding the NIH.

Tuesday, June 24, 2008

Reading List and Gratuitous Commentary

A reader recently asked for recommended reading, and I thought it would be good to just post it to the blog rather than burying in comments.

Some of the stuff listed is fairly technical. But one thing that is important to realize is that a lot of the technicality in biochemistry is big words. Don't get scared off by terms like "fructose-1,6-bisphosphatase", instead try to grasp the big picture. Similarly, biological systems are "complex", in the sense of having a lot of interacting parts. But in the end, it's pretty much "the leg bone is connected to the hip bone". You don't need to build a radically new mental framework to think about this stuff, as you might with something like quantum field theory. And the details of many processes aren't really so important in making health-related decisions, e.g. knowing the precise chemical reactions by which lipoprotein lipase cleaves fatty acids from triglycerides isn't as important as knowing that in the neighborhood of fat cells, insulin makes it occur more.

Enough babbling. Here's the list (with more specific babbling), roughly ordered from easiest to hardest:
  • The Protein Power Lifeplan by Michael R. Eades and Mary Dan Eades: Packed with very readable accounts of the relevant science. The Eades are good about delineating what appears clear from available scientific evidence, and what they've inferred "makes sense".
  • Life Without Bread by Christian B. Allan and Wolfgang Lutz: Another readable account, complementary in many ways to what is presented in other books. The discussion on hormonal balance is pretty interesting by itself.
  • Nutrition and Physical Degeneration by Weston A. Price, DDS, and Price-Pottenger Nutrition Foundation: After you read this, you'll never look at someone's face the same way. Nutritional information is largely observational, but at least some of Price's conclusions are being borne about by more detailed biochemical research. Price guessed a lot of stuff we seem to be rediscovering today. Also has lots of anthropological information, particularly illustrating connections between food and culture.
  • Good to Eat: Riddles of Food and Culture by Marvin Harris: Very entertaining and thought-provoking, and should start you thinking about the interrelationships of food and culture.
  • Why Zebras Don't Get Ulcers, Third Edition by Robert M. Sapolsky: A detailed but funny and readable account of how the body's hormonal systems work, with a particular accent on stress.
  • Good Calories, Bad Calories by Gary Taubes: Very detailed and dense accounting both of how several "sacred cows" of modern nutrition came to be, as well as the (largely ignored) scientific evidence against them. A great read both for the sociology and the science, and packed with info. Worth reading more than once, and required reading before diving into any textbooks.
  • Cholesterol and Health Website by Chris Masterjohn: Very thorough and detailed write-ups of various nutritional topics, mostly centered around lipid metabolism. About the same level as Taubes. Definitely read Masterjohn's discussion of The China Study for a good example of bad science.
  • Metabolic Regulation: A Human Perspective by Keith Frayn: A good stepping stone to the more detailed textbooks. Reading Frayn after Taubes is recommended, since they cover a lot of the same ground, Frayn in more technical detail. Frayn tries to connect the biochemical details to current nutritional dogma. Ignore this and draw your own conclusions.
  • Advanced Nutrition and Human Metabolism by Sareen S. Gropper and Jack L. Smith: The hard stuff. Similar comment applies in following the science to your own conclusions.
  • Nutrition and Metabolism Society Website: All about including knowledge of metabolism into health-related decisions. See also their open-access journal, Nutrition and Metabolism.
  • Reviews on Appetite: An entire issue of the Philosophical Transactions of the Royal Society B devoted to the details how hormones and the central nervous system control energy intake. Great stuff, and hopefully the subject of my next blog post.

Thursday, June 12, 2008

A Swift Kick in the ASP

Gary Taubes' Good Calories, Bad Calories provided a nice and readable description of the current understanding of fat metabolism, in particular the major mechanism of how dietary calories wind up in fat cells, and how stored fat is made available for energy. The mechanism is fairly simple, and is a scientific "fact" as much as there ever can be one (lots of supporting evidence, no alternative hypotheses). Dietary fats, as well as those created in the liver from carbohydrates, are transported around the body in large molecules called lipoproteins. We've all been inundated with propaganda about lipoproteins, e.g. low-density lipoprotein (LDL) is "bad cholesterol", high-density lipoprotein is "good cholesterol", very low-density lipoprotein (VLDL) is "triglycerides", which are also "bad". The popular nomenclature is terrible and confusing.

Lipids are substances like fat and cholesterol which are not water soluble. To be carried in the blood (which is mostly water), lipids are carried inside of large lipoprotein molecules, which basically wrap up a droplet of lipids in a protein coat. Protein is water soluble, problem solved. The specific proteins on the surface of the lipoprotein allow it to bind to various receptors, so different lipoproteins can perform different functions, depending on receptor binding. Thus, cellular LDL receptors grab LDL from the blood so the cells can extract cholesterol, while HDL bind to receptors that allow it to take away "used" cholesterol for recycling in the liver, e.g. when cells die.

Most of the fat transported by lipoproteins is in the form of triglycerides (more technically known as triacylglycerol), a largish molecule consisting of three fatty acids attached to a "backbone" molecule of glycerol. Two kinds of lipoproteins carry most of the triglycerides: chylomicrons and VLDL. Chylomicrons are manufactured in the intestinal lining, packaging up digested fatty acids and cholesterol. The chylomicrons are (for reasons unknown to me) transported through the lymphatic system and dumped into the blood via the thoracic duct. Cells then have the opportunity to grab fat or cholesterol from the chylomicron, and some other changes happen to the surface proteins which rather quickly render it a chylomicron remnant. The liver vacuums up chylomicron remnants and repackages any lipids as VLDL (which also carries fat created by the liver from excess glucose). The VLDL then returns to the blood, and again cells can grab fats as necessary.

The triglyceride molecules carried by chylomicrons and VLDL are too large to pass across the cell membrane. In order to get some fat into a cell, the individual fatty acids must be released from the tryglyceride; fatty acid molecules can cross the cell membrane. The primary enzyme which performs this tasks is lipoprotein lipase, or LPL.

So that (long-winded) explanation gets us through part one of how fat is stored: LPL frees fatty acids from triglycerides in lipoproteins so they can get inside of the fat cells. Now, fat cells don't store fatty acids directly, but instead create their own triglycerides. However, the glycerol molecule itself also cannot cross the cell membrane. Instead, the fat cells ultimately make their own glycerol (actually a substance known as alpha glycerol phosphate) from glucose, which in turn must be supplied by the blood. Fat storage thus requires two crucial ingredients: action of LPL on chylomicrons or VLDL to free fatty acids, and availability of glucose including the ability to transport that glucose from the blood into the fat cell, which requires some specialized molecules called glucose transporters, or GLUTs.

Now Taubes points out that the primary control mechanism for both LPL activity and glucose transport is the hormone insulin. More insulin means more LPL and more glucose transport, thus more fat storage. Additionally, inside the fat cell lives an enzyme called hormone sensitive lipase, or HSL. HSL performs the same essential task as LPL, but from inside the fat cell: it frees fatty acids from stored triglycerides, so they can be made available to the blood (being carried away bound to the blood protein albumin). HSL response to insulin is opposite of LPL: less insulin means more HSL activity. So when insulin is high, fat tends to be stored, and when it is low, fat tends to be released. It's a nice tidy story, and gives a biochemical basis for the hypothesis that overconsumption of carbohydrates is what drives most obesity. Eating carbs not only raises insulin, it also makes available lots of glucose, thus supplying both of the critical ingredients for fat storage, while simultaneously suppressing the release of fat from fat cells.

I like this story, but have long had the nagging suspicion it is not complete. Consider, for example, the Inuit, whose traditional diet consists almost entirely of protein and fat. Protein does raise insulin. Insulin is the sort of the "key" for opening cells the macronutrients (protein, fats, and carbohydrates). Even if you don't eat any carbs, you need insulin to go up in response to protein consumption so your cells can take up the constituent amino acids and use them for building tissue, making functional proteins like hormones, etc. Protein consumption also triggers the pancreas to secrete another hormone called glucagon, which amongst other things blocks the entry of glucose into cells.

So, naively, a meal containing only fat and protein is somewhat blocked from having the fat stored, because glucagon inhibits the fat cells from taking in the glucose required to build triglycerides. But you do need to store some fat. Fat cells are a sort of energy reservoir, providing a steady source of energy between meals, so even if you eat zero carbohydrates, there should be a mechanism for storing a bit of fat. My guess was that this was accomplished through a precise balance of insulin, glucagon, and blood glucose. And it has to be precise, because too little storage and you run out of gas, but too much and you get fat and slow, making it more likely that you become polar bear food. But biological systems are rarely precise, rather achieving balance through robustness rather than precision. It also seemed like there should be some dose dependent mechanism for fat storage, e.g. eat more fat, store more fat. We certainly evolved that mechanism for storing away energy from carbohydrate-rich meals, and it seemed that something similar should be in place to take advantage of fat-rich meals, like bone marrow.

So this post at the Emotions for Engineers blog caught my attention, because at one point it mentions an alternative metabolic pathway fat storage. Sounded juicy, so I dropped a comment asking for elaboration, and was directed to information on acylation stimulation protein, or ASP. There seems to be a fair amount of confusion both in the scientific literature and on the Internet as to exactly how/why ASP did it's thing, and the implications for obesity. I did a big of digging, and though I certainly haven't solved the mystery, I did uncover some clues. This paper, in particular, provides a lot of useful information.

Fat tissue is increasingly recognized as an endocrine organ, generating several hormones related metabolism. You've probably heard of leptin. When fat cells expand from storing fat, they release leptin. Leptin does several things, most notably sensitizing other parts of the body such as the hypothalamus to the effects of hormones affecting satiety and gastrointestinal activity (see this excellent review for more). In short, when fat cells store more fat, they release more leptin, which makes you less hungry, until the fat cells shrink causing them to release less leptin, allowing you to get hungry again. There are many different such mechanisms regulating energy storage, metabolism, and hunger, forming a robustly controlled system, one that works well across a wide variety of input conditions.

ASP is another hormone secreted by fat cells, with several effects. First, ASP can increase LPL activity, making fatty acids available for transport into the fat cells. Second, ASP increases the expression of glucose transporters in fat cells, allowing them to bring in the glucose required to store fat. So ASP plays roughly the same role as insulin in fat storage, but rather than being generated by the pancreas in response to carbohydrates, is generated by the fat cells themselves. Better yet, ASP stimulates the production of triglycerides inside the fat cells. But what causes ASP to be secreted?

The answer, at least in test-tubes, is chylomicrons. When fat cells are exposed to chylomicrons they generate lots of ASP. By contrast, exposing the same cells to glucose, fatty acids, VLDL, HDL, or LDL elicits little ASP response. Further, the ASP response exhibits both a time and concentration dependence on chylomicron concentration.

This is an important clue. As discussed above, chylomicrons are the first step in transporting dietary fats into the body. When you eat a lot of fat, you make more chylomicrons, which causes the fat cells to make more ASP, which stimulates greater fat storage. But the chylomicrons only hang around for a relatively short time, being converted in the liver to VLDL. The receptor for VLDL (VLDL-R), when activated, does increase LPL activity, but to my knowledge does not stimulate glucose transport into fat cells. Thus the fat in VLDL is available to be used for energy, because the LPL frees the fatty acids for transport across cell membranes; but without some other hormonal signal (e.g. insulin), rather little of this fat can be stored in adipose tissue.

Two questions then arise in the context of a low-carbohydrate/high-fat diet. The most obvious one is "can I get fat by eating too much fat?" Taubes lays out the case that overconsumption of carbohydrates drives fat storage through the action of insulin, but can overconsumption of fat do the same via the action of ASP? When viewed with the most narrow lens, the answer is clearly "yes". While insulin's effects on LPL and glucose transport are considerably stronger than ASP, ASP does ultimately trigger the same conditions leading to fat storage. So if you eat enough fat for a long enough time, in principle you will become obese.

But if we take a step back, things are not so simple. The body has many feedback mechanisms for regulating energy content, such as leptin secretion by large fat cells, leading to suppression of appetite. These mechanisms regulate feelings of hunger, metabolic rate, how fast the stomach empties, etc. The system has presumably evolved to be robust over a wide range of environmental and nutritional conditions, allowing us to have enough energy to make it through times between meals while not having to carry so much that physical performance and other health aspects are compromised. The whole chain of events described above provides a nice example. Eat lots of fat, intestines create lots of chylomicrons. Chylomicrons stimulate fat cells to make ASP, which in turn increases fat storage. As fat cells store fat, they release leptin, which suppresses appetite and sensitizes the body to other satiety signals. But chylomicrons are fairly quickly turned into VLDL, which do not stimulate fat storage, but do make fat available for energy. The brain can detect VLDL levels, and regulate gastric emptying, appetite, etc. until the fat in the VLDL is used up. And that's just one of a complex web of interactions between hormones, the nervous system, metabolism, and digestion.

To become obese (at least without trying really hard), some key regulatory mechanism needs to be broken. For instance, there is a genetic defect which causes the fat cells to not produce leptin. People (or mice) with this defect have an unstoppable appetite, and become extremely obese. Treating them with leptin can reverse this condition. Another example is Cushing's disease, which is a small tumor on the pituitary. The net effect of Cushing's disease is that it causes the body to have high levels of the hormone cortisol. I had a friend with Cushing's disease. He ran five miles every day, and by any measure ate a healthy diet, yet continued to gain weight. Why? Increased cortisol (from the sympathetic endocrine system) can cause compensatory secretion of insulin (from the opposing parasympathetic endocrine system). Chronically high insulin will make you fat no matter how much you exercise or how little you eat. Keep insulin high, and you can literally starve to death while remaining obese.

But it appears the big hitter is carbohydrate consumption, particularly refined carbohydrates. These cause both drastic increases in insulin levels and make available lots of glucose for triglyceride storage. Though insulin nominally acts to suppress appetite and GI motility, high levels drive energy nutrients out of the blood and into the cells, ultimately leading the brain to "override" other mechanisms such as leptin, because low levels of energy nutrients in the blood basically signal imminent starvation; indeed, the brain itself needs a certain level of blood sugar to be maintained for proper operation. So eating carbs not only causes you to efficiently store fat, it also drives you to eat more food, and that food is typically more carbs to stabilize your blood sugar, leading to a vicious cycle.

I don't see a similar issue when eating a high-fat/low-carb diet. Fat ingestion does not cause hormonal derangement. Energy levels in the blood are maintained, allowing the various appetite regulation mechanisms to operate normally without getting an emergency override to eat more food despite available energy in the body. ASP production is stimulated only by chylomicrons, which are relatively short-lived, allowing a limited amount of dietary fat to be stored, while the rest is made available as energy. In principle, you could get fat by eating enough fat, but in practice it would probably be very difficult. You would have to force yourself to eat even though you felt extremely full, and continue to do so over a long time period. Not impossible, but definitely an uphill battle against a whole host of hormonal and nervous control systems, very much the analog of trying to lose weight on a low-fat/high-carbohydrate diet.

While it may be hard to gain fat through a high-fat diet, it is likely possible to keep on a certain level of body-fat. Low-carbohydrate diets are known to "stall", where the last 20 or so pounds just won't come off, regardless of carbohydrate restriction. I suspect our friend ASP plays a crucial role here. The low insulin levels on a low-carb diet will allow the fat cells to free fatty acids, but if you are consuming enough fat, at some point this effect will be balanced by that of ASP, and voila, no more fat loss.