Even More Dissonance

A recently published study comparing various weight-loss approaches has been getting a lot of press and Internet buzz, probably because the results contradict mainstream thinking about diet and health. It's pleasantly surprising that this is getting some media coverage - usually such dissonance-inducing results are largely ignored. Regina Wilshire posted an especially amusing blog, showing how different people interpret these results. You can taste the cognitive dissonance, as each individual spins the results according to their own beliefs.

The essence of the study results is that those following a low-carbohydrate diet had greater weight-loss and improvements in blood lipids. The Mediterranean diet did well also. Both of these results are predictable from what we know about metabolic regulation, but for the mainstream, this result clearly induces significant dissonance. I particularly enjoyed Dean Ornish's attempt at reconciling this dissonance. Here's a choice quote:

I'm also very skeptical of the quality of data in this study. For example, the investigators reported that those on the "low-fat" diet consumed 200 fewer calories per day—or 10,000 fewer calories per year—than those on the Mediterranean diet, yet people lost more weight on the Mediterranean diet. That's physiologically impossible.

I think Dr. Ornish needs to bone up on his biochem. We'll hit this point later in the series on Energy Regulation, but the body very definitely has a mechanism to dump excess fat calories in the form of heat. And of course Ornish's calorie-centric focus completely ignores other regulatory effects, such as insulin's effect on fat storage. Ornish does spend plenty of time telling you all about himself, what he believes, why his particular diet flavor is superior, etc. The article reads more like an infomercial than scientific exposition. Comparison of different scientific hypotheses requires inclusion of ALL relevant evidence. Ornish heavily weighs evidence of his own creation, which (not surprisingly) supports his own preconceived notions. If you selectively weigh evidence in this way, you can come to any conclusion you want.

Here's another fun quote from Ornish: "Most people associate an Atkins diet with bacon, butter and brie, not a plant-based diet like the one I recommend." There's that "I" again. Shouldn't the diet be recommended by the evidence, not one individual? I guess Dr. Ornish is smarter than the rest of us. Maybe he would grace us with a more detailed explanation of why he's "right" given our knowledge of metabolic regulation at the molecular and cellular level?

I'm not holding my breath.

Ornish's comment also highlights one of the major origins of dissonance surrounding these recent results: the seemingly unshakable belief that saturated fat ("bacon, butter, and brie") plays a role in a wide range of disease processes. We saw in the original post on cognitive dissonance that there actually exists essentially no evidence of causality (I just confirmed this with an ex-official of the American Heart Association). For example, there may be some statistical association between saturated fat consumption and development of heart disease (particularly if you limit the observational data set), but there's no evidence at all of causality at the molecular and cellular level. Let's look at a some ways in which this association might arise:

• Fast food is often high in saturated fat. It's also often high in total refined carbohydrates, particularly fructose. The damage wrought by increase carbohydrates (fructose is particularly good at this) and the hormonal derangement from repeated insulin spikes (and probably fructose as well) quite logically predicts an increase in heart disease. The likely high consumption of oxidized fats from deep-fried foods is the cherry on top of this sundae. Lipoprotein molecules are composed of a water soluble membrane including both proteins and fatty acids. White blood cells have a specific receptor for oxidized LDL (but not unoxidized LDL), so if your LDL includes some oxidized fat from your French fries, you should expect an increased immune response, which is known to be important in the development of atherosclerosis. So if a population has a high consumption of fast food, not only is their saturated fat consumption higher, so is the consumption of refined carbohydrates and oxidized fats. Which of these actually causes the observed increase in heart disease?
• Grain-fed beef is known to have some nutritional issues. Grains are not the natural food of cattle, who prefer to eat leafy material, which tends to be rich in the omega-3 alpha-linolenic acid. When compared with grass-fed beef, grain-fed has a significantly higher ratio of omega-6/omega-3 fatty acids. There is a biochemical reason to believe this could increase heart disease, due to the pro-inflammatory effect of omega-6 fats. Grain-fed beef is also much higher in saturated fat, so there would be an association between saturated fat intake and increased omega-6/omega-3 ratio.
• Grain-fed beef is also higher in total fat. Guess what - carbohydrates make cows fat too! But this fat is essentially "empty calories" in that the increased fat intake does not bring significant additional micronutrients, probably displacing calories from foods that are nutrient dense. Again, at the molecular/cellular level, there are good reasons to believe these micronutrients (like magnesium) are protective against the development of heart disease.
• Eating a crappy diet like fast food makes people sick. Sick people tend to stay inside. If you don't go outside, in all likelihood you are deficient in Vitamin D. Vitamin D deficiency is implicated in a whole host of diseases, including heart disease. I'll bet saturated fat consumption is correlated with Vitamin D deficiency as well.

I'm sure with a little thought we could come up with several more. The point is this: associating causality with an individual statistical correlation is a very slippery slope. If you have no evidence for causality, making such an association implies that you are ignoring other possible causes WITHOUT EVIDENCE. Attempting to treat sick people based on this association could be expected to be ineffective at best, harmful at worst. And of course you wind up with the precise situation we observe today, which is that some bogus dogmatic belief blocks the advancement of science due to cognitive dissonance.

Energy Regulation 2: Appetite

In Energy Regulation 1, I asserted that the body had many regulation mechanisms for energy intake, storage, and utilization. This regulatory network presumably evolved to maintain health over a wide range of conditions: different seasonally available foods, physical requirements, hot and cold temperatures, etc. Let's start digging in to the details of what is known, which will then should inspire some ideas on what aspects of modern life could potentially knock things askew, resulting in a situation where the body actually defends an unhealthy state like obesity.

A few caveats first. Metabolic regulation is a complex and evolving subject, and much of the knowledge is very recent (if you want to give yourself a headache, check out this spreadsheet I made trying to illustrate the various parts and their relationships). Even if you were to consider all of the available science I doubt the picture is anywhere near complete, and of course I've probably only been exposed to some smallish subset of what is known. If anybody out there finds gaps in this presentation, please fill them in via the comments. Additionally, much of the research on metabolic regulation is done on animals and extrapolated to humans. Nobody is going to do experiments where, say, they directly infuse oleic acid into the brains of people. Some of the published reviews are unfortunately vague as to whether the mechanisms discussed have been studied in humans.

One final issue is that the reviews are very focused on dietary fat, and to a lesser extent carbohydrates. But protein is essential for life, so there must be appetite and metabolic controls regulating protein intake, but this is largely not discussed. For instance, I'm guessing somewhere in the body there's something that detects amino acids and influences appetite, particularly preference for protein-rich food.

With that in mind, we'll start at the beginning. Animals eat when they're hungry. In a healthy organism, hunger is a signal that available and/or stored energy is getting low and need to be replenished. Humans have three primary energy stores: the stomach, glycogen (starch) in muscle and liver tissue, and fat (triglycerides) in adipose tissue. Now, if this system is working right, low available energy should be equivalent to low stored energy. But we're going to see it's quite plausible that conditions can arise where the body thinks available energy is low, yet excess energy is in storage.

The brain acts as a central controller, receiving various signals from the body and adjusting many different "knobs" to maintain a healthy state. Peripheral tissues also exercise some independent controls as well, e.g. the pancreas will secrete insulin in response to rising blood glucose without nervous system control. This combination of central and peripheral controls provides for both robustness and responsiveness.

The major nervous system player in metabolic regulation is the hypothalamus, an area at the base of the brain, roughly the size of an almond. The hypothalamus is the main connection between the rest of the brain and the various hormone systems of the body, sharing a private circulatory system with the pituitary gland, and projecting nerve connections to various other endocrine organs as well. The hypothalamus is also well situated to sample various chemical concentrations in the blood. Most of the brain is protected by the "blood-brain barrier" (BBB), closely-packed cells which tightly control what substances pass from the blood to the brain. But the hypothalamus is located near a region where the BBB is incomplete. It's leaky, in a sense, so the hypothalamus gets a taste of much of what's in the blood. The hypothalamus can be further divided into "nuclei", which have different sensory and control functions. Of particular interest here are the arcuate nucleus (ARC), the ventromedial nucleus (VMN), and the dorsomedial hypothalamus (DMH).

The brainstem is a close neighbor of the hypothalamus, sharing lots of neural connections. The particular region called the nucleus of the solitary tract (NTS) is the termination of the afferent fibers of the vagus nerve (afferent nerves cause signals to arrive at the brain; efferent nerves allow signals to exit the brain). The vagus nerve connects to many different organs, including those of the digestive system. The NTS appears to integrate different signals (both hormonal and nervous) and send them along to the hypothalamus. The hypothalamus does some additional integration, and projects to other brain areas involved in behaviors like finding food and eating it.

I've used the term "integrate" a couple of times. What does that mean? The neurons in the brainstem and hypothalamus receive many different signals: from other nerves, from hormones like insulin, and can directly sense nutrients like glucose. The "decision" of whether the neuron fires or expresses certain proteins must factor in all of these signals. For example, the brain requires a certain blood glucose concentration to function properly. If glucose falls, regardless of the level of insulin, the brain should take some action (like stimulating appetite), because otherwise you'll die.

The ARC in particular contains two populations of special neurons. One of these expresses cocaine- and amphetamine-related transcript (CART) along with pro-opiomelanocortin (POMC). These neurons seem to be associated with appetite suppression. For instance, POMC can be chopped up to yield alpha-melanocyte-stimulating hormone (alpha-MSH), which in turn binds to the melanocortin-4 (MC-4) receptor. Genetic problems causing defects in the MC-4 receptor result in obesity characterized by overeating. The other population expresses agouti-related protein (AgRP) and neuropeptide-Y (NPY), both of which increase appetite. If NPY is infused into rat brains, they respond with a several-fold increase in food intake that lasts 6-8 hours, similar to rats that have been fasted for 36-48 hours.

Having two opposing systems (as opposed to just one that gets turned up or down) allows for rapid fine-tuning of metabolism; this idea of opposing systems which maintain balance is found elsewhere, e.g. the sympathetic and parasympathetic endocrine systems. Both classes of neurons appear to "detect" both available energy in the blood as well as hormonal levels and probably nerve signals, with opposing results. Energy nutrients go through part of the same cycle used to actually generate energy, and the resultant metabolic products appear to trigger opening/closing of ion channels on the cell membrane. Hormones like leptin and insulin have similar effects, hence the "integration" of these signals. Changing the balance of ions inside and outside the neuron affect the "action potential", make it more or less susceptible to firing, expressing proteins, etc.

NPY neurons, for example, are glucose inhibited (GI), meaning the more glucose is around, the less active they beome. If blood sugar falls, the NPY neurons become more active, and as we saw above, NPY appears to strongly stimulate appetite. So blood sugar falls, and you get hungry. Similarly if insulin or leptin falls, these neurons are activated, and again you get hungry. But what if insulin is high AND glucose is low? Well, the brain needs a certain glucose level to operate, so I would guess that the low glucose wins, because the alternative is a hypoglycemic coma and death. Have you ever had a major blood-sugar crash a few hours after a large carbohydrate-laden meal? It's the "Chinese food makes you hungry an hour later" thing (see e.g. Teriyaki Stix Beef Bowl: 102g of carbohydrate, probably all highly refined). I would bet the extreme feelings of hunger (kind of like you were starved for 36-48 hours) is the result of increasing NPY concentrations in the hypothalamus, in turn triggered by low blood glucose, even though your insulin is still elevated. Rats show a preference for high-carbohydrate meals when stimulated with NPY. If the same is true for humans, then we shouldn't be surprised that a blood-sugar crash sends us scurrying for the vending machine to fearlessly slay and consume a candy bar, regardless of how much energy is stored in the stomach or fat. So we begin to see how the system can be broken to store excess energy, mainly fat.

The scenarios described above relate more to the instantaneous availability of energy in the blood as opposed to the amount stored. The major energy store (in terms of calories) is white adipose tissue (WAT). Fat cells, or adipocytes, are not passive buckets, but rather metabolically active both in the storage/release of fatty acids as well as the secretion of hormonal signals relating to appetite and metabolic regulation. The best-known of these is leptin, a hormone whose secretion is proportional to the amount of stored fat. Leptin suppresses appetite, probably via multiple actions. Leptin inhibits the NPY/AgRP neurons (which stimulate appetite) and excites POMC/CART neurons (which decrease appetite). Leptin also slows gastric emptying, the rate at which food leaves the stomach and enters the small intestine. So more leptin (everything else being constant) should keep the stomach fuller for a longer time, and the stomach of course sends it's own signals relating to appetite and satiety. Leptin may also increase base metabolic rate via diet-induced thermogenesis, a topic we'll explore later. There is a genetic defect that causes people to secrete little or no leptin. Individuals with this genetic problem tend to overeat considerably, and extrapolating from rats may additionally have a lower metabolic rate, with the result of extreme obesity. Administration of leptin to these individuals substantially aids this condition.

Fat cells secrete other hormones as well. Adiponectin secretion is inversely correlated with stored fat: more fat, less adiponectin, and vice versa. Adiponectin has potentially influences many things, including appetite, insulin sensitivity, inflammation, and vascular function. Interleukin-6 (IL-6) causes insulin resistance in fat cells, which tends to make them release fat instead of store fat. The hypothalamus also expresses and contains receptors for IL-6, particularly in areas controlling body composition. Fat cells also express tumor necrosis factor alpha (TNF-alpha), which inhibits lipoprotein lipase (the enzyme required to get fat out of lipoproteins and into fat cells), stimulates breakdown and release of triglycerides in fat cells, and may also induce insulin resistance.

So we see mechanisms in place to control fat storage through appetite. As more fat is stored, more leptin is secreted, which should blunt the appetite. As fat is lost, leptin levels drop, which should promote appetite. Leptin (and other hormones from fat cells) may additionally modulate metabolic rate, to encourage fat burning when there is an excess, and discourage it during a deficit. So again there's a lot of knobs to turn, all aimed at maintaining fat storage in a particular range.

Our final stop is the gastrointestinal (GI) tract along with the closely related pancreas. When we eat, food hits the stomach, which does a nominal amount of digestion both mechanical and chemical. The stomach represents short-term energy storage, more or less the "gas tank" for the body, and so it's no surprise that the stomach is involved in appetite as well. Indeed, most people think of appetite in terms of "my stomach is full/empty", but we've seen above that many other factors come in to play as well. The stomach signals the full/empty state both through nerves and hormones. Stretch receptors on the stomach wall send signals via the vagus nerve indicating fullness. The stomach also secretes the hormone ghrelin, which strongly stimulates appetite. Empty stomach means more ghrelin, full stomach means less. Increasing ghrelin increases brain concentrations of NPY. So an empty stomach definitely tends to increase your appetite, but gastric signals must be integrated with the variety of other signals to actually determine the degree of appetite stimulation.

Most of the hormonal action occurs in the small intestine and pancreas, and indeed there is some interplay between these organs. The pancreas is not only an endocrine organ (which sends hormones into the blood), it is also exocrine, emitting various substances like enzymes and bile salts require to break down food so it can be absorbed through the small intestine. The small intestine itself secretes a several hormones in various quantities, depending on the total caloric content as well as the individual levels of carbohydrate, protein (really amino acids), and fat. These hormones have a wide variety of effects, including stimulation/inhibition of pancreas endocrine and exocrine functions, modification of the rate at which food passes through the GI tract, metabolic control, and of course appetite. I'm not going to cover nearly all of these hormones or their effects. Check out the spreadsheet, or this paper and this paper for details.

A major hormone secreted by the small intestine is cholecystokinin (CCK, and no, I don't know how to pronounce it). Dietary fat and protein more potently stimulate of CCK release than does carbohydrate, and long-chain fatty acids seem to have a greater effect than short-chain. CCK affects a number of systems, e.g. inducing gallbladder contraction (to release the bile needed to digest the fat which stimulated CCK release in the first place). CCK also slows gastric emptying. Again this makes sense from a regulatory standpoint. Once the small intestine has received some energy nutrients, CCK signals the stomach to stop sending more until the present batch is done processing.

CCK also strongly suppresses appetite. In rats, administering CCK reduced food intake in a dose-dependent manner: more CCK, less food eaten. The exact mechanism is unclear, but it seems to be a combination of reduction in gastric emptying (stomach stays full) and detection by the nervous system. In both monkeys and humans, the fullness of the stomach seems to modulate the appetite suppression of CCK. The afferent fibers of the vagus nerve as well as the brainstem express CCK receptors. The Otsuka-Long-Evans-Tokushima fatty rat (try saying that 3 times fast) is a genetic variant which lacks the CCK-1 receptor, and both overeats and becomes obese.

A few notes on other GI hormones. PYY-36 is released in proportion to calories and meal composition, with fat resulting in higher concentrations than protein or carbohydrate, and may inhibit food intake. Glucagon-like peptides GLP-1 and GLP-2 are cleavage products of preproglucagon. GLP-1 increases insulin secretion and suppresses glucagon release. It also slows gastric emptying and inhibits food intake. Key areas of the brain such as the ARC express GLP-1 receptors. GLP-2 release is potently stimulated by fat and carbohydrates, and may enhance the digestive and absorptive capabilities of the small intestine. Oxyntomodulin (OXM) is released in proportion to calories ingested. It suppresses appetite and gastric motility, enhances insulin secretion, decreases food intake, and possibly increases metabolic rate.

So the takeaway here is that the GI tract sends numerous hormonal signals indicating energy is present and being absorbed, please don't send any more. One interesting side-note is that the levels of some of these hormones, notably PYY-3-36, GLP-1, and OXM, all increase after gastric bypass surgery. The effect of this should be to suppress appetite, and possibly increase metabolic rate, which would explain the success of such surgeries to reduce obesity. I find this interesting, because by itself I would guess reduction in stomach size should probably have little effect on overall food intake because of the other mechanisms regulating appetite based on stored and available energy. But diddle the relevant hormones, and voila, sustained appetite reduction and weight-loss. Hopefully the increasing understanding of these regulatory mechanisms will give rise to better treatments, since surgery seems an extreme way of accomplishing the desired effect.

Finally, we come to the pancreas. The best-known pancreatic hormone is insulin, arguably the Big Mama of metabolic regulation. It is interesting to note that the protein structures of both insulin and NPY are remarkably conserved across evolution. If you look at a primitive animal like a hagfish, it's insulin and insulin receptors are fairly similar to that of humans, so much so that hagfish insulin significantly stimulates human insulin receptors. The implication is that the role of insulin is central in metabolism and development, and fairly successful as relatively drastic changes across species required little mutation of insulin. We're most familiar with insulin's role in controlling blood sugar, both by increasing tissue uptake of glucose and by regulating glucose output from the liver. Insulin also regulates many other aspects of metabolism, like fat storage and cell division. Subsequent posts will visit these in greater detail.

Insulin is manufactured by the pancreatic beta-islet cells (B-cells). When glucose enters the B-cell, it is metabolized to ATP, the primary short-term "energy currency" of the body. But rather than using that ATP for energy, some of it closes potassium ion channels. This depolarizes the cell membrane, allowing calcium ions to enter the cell and causing stored insulin to be released. The presence of glucose in the cell additionally signals the cell to manufacture more insulin. Amino acids also trigger insulin release to varying degrees, depending on the particular flavor, as do ketone bodies. The effect of fatty acids is complex and not well understood. It appears that fatty acids are necessary for normal glucose-stimulated insulin secretion. Increasing fatty acid concentrations in the short term (1-2 hours) will cause more insulin to be released for a given glucose concentration. But long term, elevated fatty acids impair insulin secretion. Both the nervous system and other hormones also affect the amount of insulin released.

Insulin affects appetite, both directly and indirectly. The indirect path involves sensitization of the body to other satiety signals like CCK (a role shared with leptin). Insulin also appears to directly signal the hypothalamus, increasing activity of POMC/CART neurons and decreasing activity of NPY/AgRP neurons. We all know that the pancreas secretes insulin in response to blood glucose, but insulin secretion is also modulated by a number of other factors. We saw above how some GI hormones potentiate greater insulin release (the so-called incretin effect). Insulin levels are also a function of body-fat: the more fat that is stored, the higher insulin is in all states (fed, fasting, etc.) So insulin signals both energy availability and energy storage, but the primary effects indicate that over the long term insulin (along with leptin) signal how much fat is stored.

If insulin is infused directly to the brain (of a rat, presumably), the result is a decrease in food intake and loss of body weight in a dose-dependent manner. If insulin receptors are blocked, food intake and body weight increase. When insulin levels in the brain are held constant over long time periods via slow infusions, animals modify their diet and body composition until a certain body weight is achieved, and that weight is subsequently defended at a level determined by the insulin concentration.

We saw an example above where high insulin could be overridden by low blood glucose to cause hunger. Insulin suppresses appetite only when blood glucose is maintained at a proper level. Insulin-induced hypoglycemia (whether from a high-carbohydrate meal or administration of insulin) triggers an override mechanism in the brain, inducing hunger and eating to avoid going into a coma. Type 1 diabetics have the opposite problem: high blood glucose and low insulin. Type 1 diabetics are typically ravenously hungry despite high glucose, again showing the integrative capacity of the brain; yet they will fail to gain weight regardless of how much they eat, as the lack of insulin disrupts other metabolic functions.

The pancreatic B-cells also co-secrete another hormone called amylin. Insulin and amylin a secreted in a fixed molecular ratio of about 10 to 100 to one. Various disease states (including obesity) and pharmacological interventions increase the amount of amylin relative to insulin. While insulin appears to primarily signal stored fat levels, amylin signals both the amount of stored fat and energy availability from food intake. Amylin is secreted in proportion to body fat and meal size. Giving rats a does of amylin prior to a meal reduces meal size. Blocking amylin receptors produces a long-lasting increase in food intake and fat storage. Amylin appears to act in the area postrema (AP) of the hindbrain. AP neurons activated by amylin are also activated by glucose, CCK, and GLP-1, and the AP projects to the NTS, which in turn projects to areas of the hypothalamus regulating appetite and metabolism.

Type I diabetes occurs due to destruction of the pancreatic B-cells, so Type I diabetics also lack amylin, which is thought to contribute to their large appetites. Type II diabetics treated with insulin often gain more weight (duh), but this can be mitigated be treatment with an amylin analog. Some doctors are prescribing amylin analogs in obese patients who are not being treated with insulin. Since amylin serves both as a satiety an adiposity signal, this works as expected: these people both eat less and lose fat. But just as most obese people are insulin resistant, they're also amylin resistant. Administration of amylin to an already overtaxed system is, I think, a questionable long-term strategy. Additionally we know the body wants to keep the insulin/amylin ratio fixed, probably for a good reason. Adding exogenous amylin to the mix perturbs this balance even more than it already is, rather than helping to restore it to a healthy state.

Last, but not least, is glucagon, manufactured and secreted by pancreatic alpha-islet cells (A-cells). Metabolically, glucagon tends to counter the effects of insulin, e.g. increasing glucose output from the liver. Glucagon secretion is stimulated mainly by protein, possibly by fat, and not at all by carbohydrate; indeed, glucose inhibits A-cell glucagon secretion. Pancreatic hormones are dumped into the portal vein, so the liver gets first shot at them. Apparently the liver removes most of the glucagon, and rather little makes it into systemic circulation. Even so, glucagon acts as a satiety signal. Rather than acting directly in the brain, glucagon's action probably occurs in the liver, which then sends a signal to the brain via the vagus nerve. Animals whose afferent vagal nerves have been blocked do not have their feeding inhibited by glucagon.

So let's see how some different meals may affect appetite. We'll revisit these later, after we've gone through the other aspects of metabolic regulation and can look at the big picture; but the isolated effects on appetite are still interesting. These are my guesses, not proven by any scientific research. Feel free to add your own scenarios to the comments.

We discussed above what may happen after a high-carbohydrate low-fat meal, like the Teriyaki Stix Beef Bowl (102g carbohydrate, 33g protein, 7g fat). The stomach fills, reducing ghrelin secretion and sending the "full" signal to the brain. The large amount of refined carbohydrates should elicit a large insulin and amylin response, further potentiated by the release of hormones like GLP-1 and OXM. The protein in particular stimulates CCK release, which along with insulin, amylin, and other GI hormones suppress appetite. But the major insulin release induces hypoglycemia. The initial effects probably are an increase in gastric emptying via nervous system control to try and balance out the blood sugar, but of course this tends to raise insulin even more. Sooner or later the depressed blood glucose causes an increase in brain NPY, and powerful hunger, despite the fact that rather little of the meal may actually have been used for energy.

How about a "healthy" low-calorie meal, maybe a really big salad, lots of veggies and fat-free dressing. The conventional wisdom is that the large fiber load (and amount of water) fills up the stomach, contributing to satiety. That's true, to a certain extent, as filling the stomach triggers both the stretch receptors and reduces ghrelin. But the relative lack of any energy nutrients implies correspondingly low secretion of appetite control hormones like CCK. The brain also will not detect much rise in blood sugar or fatty acids. In turn, gastric emptying and intestinal motility is not inhibited and may in fact be accelerated, so the stomach empties faster than it would in a high-calorie meal. Appetite suppression from stomach distension rapidly fades, and you're hungry again.

How about a "cardiac arrest" meal of a big steak smothered in mushrooms and butter? This is a calorically dense meal, probably occupies considerably less stomach volume than the big salad, so maybe we don't get as much from stretching the stomach. But once this hits the small intestine, we get should get lots of hormones like CCK and glucagon to suppress appetite and gastric emptying. Some insulin and amylin are secreted as well. The glucagon helps keep blood sugar stable, and the additional protein from the steak may temporarily bump up blood sugar as well. The fat makes it into the circulation more slowly, and should help to both suppress appetite and gastric emptying over the longer term. Additionally, fat sensing by the hypothalamus also help the liver regulate blood sugar, so we don't get the "low glucose" override.

So to summarize:

• The high-carbohydrate high-calorie fast-food meal makes you get hungry faster due to insulin-induced hypoglycemia. This happens despite consumption of plenty of energy.
  
• The low-calorie low-glycemic salad fills you up in the short term, but you get hungry again quickly simply due to lack of available energy.
• The high-fat high-calorie meal suppresses appetite for a longer time, both by avoiding adverse conditions like hypoglycemia, as well as providing a measured release of energy into the blood via the small intestine.

Now I ask you, which of these meals is the most likely to cause fat gain?

These examples are interesting (so I think), but again must be considered in the larger context of metabolic regulation. Obesity is not a simple result of overeating, fat-loss not the simple result of undereating. Both are a combined effect of different regulatory mechanisms. Appetite is just one piece of the puzzle. Genetically-modified rats, for example, illustrate different behavioral and physical outcomes depending on the nature of the mutation. Some overeat and maintain normal body weight. Some eat normally and get fat, and some both overeat and get fat. Conversely, to lose fat almost certainly requires restoration of the proper regulatory balance. By itself, the recommendation to "eat less and move more" is meaningless. We need to consider the effect on the hormonal and nervous system mechanisms, which require detailed thinking about the effects of food and exercise on human biochemistry.

Dissonance Redux

Michael Eades' most recent blog gives an outstanding example of cognitive dissonance in action. In short, a recent study found that obesity in China was correlated with higher intake of vegetable foods. But "everybody knows" that vegetables are healthy, right? So the authors conclude it can't be the vegetables causing obesity, it must be the vegetable oil the Chinese cook them in. The funny (but simultaneously sad) thing is that their own published data not only refutes this hypothesis, but also clearly supports the alternative hypothesis that refined carbohydrate consumption leads to hormonal imbalances which in turn lead to obesity. It's right there on the page. Talk about cognitive dissonance.

Dr. Eades did an excellent job hitting the big points, so I just want to add a few thoughts. I can't get access to the original paper (I have no interest in handing Nature any of my money for this paper, especially given that someone was clearly asleep at the wheel to let it past peer-review), but I would infer that it is an epidemiological study. So we can't give it a lot of weight, any more than we should give much weight to the mostly epidemiological evidence that support current mainstream dietary recommendations. That said, the authors' conclusion is clearly goofy, and ignores considerable information. The differences in fat consumption between less and more obese groups was fairly minimal: essentially zero in men, and about 6g in women. The statistical measure of the "trend" (indicating correlation between quantities) indicates lack of signficance in correlating fat intake with obesity for both men and women. But here's a list of items whose trend was indicated at greater than 99.9% confidence (the "+" and "-" indicate positive or negative correlation):

• Fresh vegetables (+)
  
• Fruits (+)
• Rice (-)
• Wheat flour (+)
• Whole grain (+)
• Root vegetables (+)
• Pickled vegetables (+)
• Fish (+)
• Milk (+)
• Eggs (+)
• Calories (+, women only)
  
• Protein (+)
• Carbohydrate (+)
• Plant food fats (+)
• Animal food fats (-)
  
• Vegetable oil (+, women only)
• Physical activity (+)

Thus, people who ate more vegetables were more obese, people who ate more fat from animal sources were less obese, etc. Indeed, if you look at the actual amounts of food consumed, what we find between the least and most obese quartiles are major increases in wheat flour (5x men, 20x women), whole grain (18x men, 22x women), root vegetables (4x men, 4.7x women), and milk (75x men, 92x women). Physical activity in the most obese quartile was somewhat less than two times greater that in the least obese. In other words, those people following a diet and lifestyle (at least given the presented data) similar to that recommended by the USDA were the most obese, on average. The focus on vegetable consumption is actually a little weird, being only about 50% higher in the most obese quartile, compared to the least obese, considerably less variation than than that for wheat etc. I guess it's more dissonance: "everyone knows" that wheat, whole grains, etc. are healthy, so why even go there?

The ultimate scientific test of a theory is its predictive power. The theory underlying USDA recommendations basically says if you eat like the food pyramid and exercise more, you should be at lower risk of obesity. When confronted with data which contradicts the theoretical predictions, you have two choices: question the data, or question the theory. These guys did neither, instead waving their hands and adding an additional hypothesis which still failed the predictive test for one study group (men), but which I guess let them sleep at night.

Let's now consider an alternative hypothesis: that most obesity is a symptom of an underlying hormonal imbalance caused by overconsumption of refined carbohydrates. This theory predicts precisely the results seen, without any bogus ad hoc additions. Carbohydrates drive insulin drive fat storage. For that matter, milk proteins may also have a larger effect on insulin than other proteins, and of course milk does add to the carbohydrate load. There's even evidence supporting Gary Taubes' hypothesis on the connection between caloric intake and physical activity: those with higher caloric intake were, on average, more physically active. There's no evidence of causality: it may be that eating more calories increases activity, or that those with increased activity get hungrier, or both. While the weight supplied by this study is rather thin, it does at least provide further confirmation of what we would expect given current knowledge of metabolic regulation, which is considerably better than the nonsensical conclusions put forth by the authors.

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:

• Reviews on Appetite: a group of 14 papers on the topic
• Neuronal Glucose Sensing: What do we know after 50 years?: A nice (but technical) discussion of how the nervous system can directly detect blood glucose levels, and how this influences other regulatory systems.
• Central Administration of Oleic Acid Inhibits Glucose Production and Food Intake: Similar to the above, but evidence of how the brain detects fatty acids in the blood, and again what effects this has on other aspects of metabolism.
• Attenuation of Insulin-Evoked Responses in Brain Networks Controlling Appetite and Reward in Insulin Resistance: some discussion of how insulin affects reward behavior associated with eating, which in turn informs as to why foods that strongly affect insulin are labeled "comfort foods" and may be addicting.
• Why Zebras Don't Get Ulcers, Third Edition by Robert M. Sapolsky: Good info on endocrine systems, particularly related to stress. Also provides some understanding of how different systems interact and affect each other.
  
• Good Calories, Bad Calories by Gary Taubes
  
• Metabolic Regulation: A Human Perspective by Keith Frayn

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.

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.
  

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.