Good Calories, Bad Calories Part 16

This is where physiological psychologists provided a viable alternative hypothesis to explain both hunger and weight regulation. In effect, they rediscovered the science of how fat metabolism is regulated, but did it from an entirely different perspective, and fol owed the implications through to the sensations of hunger and satiety. Their hypothesis explained the relative stability of body weight, which has always been one of the outstanding paradoxes in the study of weight regulation, and even why body weight would be expected to move upward with age, or even move upward on average in a population, as the obesity epidemic suggests has been the case lately. And this hypothesis has profound implications, both clinical and theoretical, yet few investigators in the field of human obesity are even aware that it exists.

This is yet another example of how the specialization of modern research can work against scientific progress. In this case, endocrinologists studying the role of hormones in obesity, and physiological psychologists studying eating behavior, worked with the same animal models and did similar experiments, yet they published in different journals, attended different conferences, and thus had little awareness of each other's work and results.

Perhaps more important, neither discipline had any influence on the community of physicians, nutritionists, and psychologists concerned with the medical problem of human obesity. When physiological psychologists published articles that were relevant to the clinical treatment of obesity, they would elicit so little attention, said UCLA's Donald Novin, whose research suggested that the insulin response to carbohydrates was a driving force in both hunger and obesity, that it seemed as though they had simply tossed the articles into a "black hole."

The discipline of physiological psychology was founded on Claude Bernard's notion of the stability of the internal environment and Walter Cannon's homeostasis. Its most famous pract.i.tioner was the Russian Ivan Pavlov, whose career began in the late nineteenth century. The underlying a.s.sumption of this research is that behavior is a fundamental mechanism through which we maintain homeostasis, and in some cases-energy balance in particular-it is the primary mechanism. From the mid-1920s through the 1940s, the central figure in the field was Curt Richter of Johns Hopkins. "In human beings and animals, the effort to maintain a constant internal environment or homeostasis const.i.tutes one of the most universal and powerful of al behavior urges or drives," Richter wrote.

Throughout the first half of the twentieth century, a series of experimental observations, many of them from Richter's laboratory, raised questions about what is meant by the concepts of hunger, thirst, and palatability, and how they might reflect metabolic and physiological needs. For example, rats whose adrenal glands are removed cannot retain salt, and wil die within two weeks on their usual diet, from the consequences of salt depletion. If given a supply of salt in their cages, however, or given the choice of drinking salt water or pure water, they wil choose either to eat or to drink the salt and, by doing so, keep themselves alive indefinitely. These rats wil develop a "taste" for salt that did not exist prior to the removal of their adrenal glands. Rats that have had their parathyroid glands*132 removed wil die within days of tetany, a disorder of calcium deficiency. If given the opportunity, however, they wil drink a solution of calcium lactate rather than water-not the case with healthy rats-and wil stay alive because of that choice. They wil appear to like the calcium lactate more than water. And rats rendered diabetic voluntarily choose diets devoid of carbohydrates, consuming only protein and fat. "As a result," Richter said, "they lost their symptoms of diabetes, i.e., their blood sugar fel to its normal level, they gained weight, ate less food and drank only normal amounts of water."

The question most relevant to weight regulation concerns the quant.i.ty of food consumed. Is it determined by some minimal caloric requirement, by how the food tastes, or by some other physical factor-like stomach capacity, as is stil commonly believed? This was the question addressed in the 1940s by Richter and Edward Adolph of the University of Rochester, when they did the experiments we discussed earlier (see Chapter 18), feeding rats chow that had been diluted with water or clay, or infusing nutrients directly into their stomachs. Their conclusion was that eating behavior is fundamental y driven by calories and the energy requirements of the animal. "Rats wil make every effort to maintain their daily caloric intake at a fixed level," Richter wrote.

Adolph's statement of this conclusion stil const.i.tutes one of the single most important observations in a century of research on hunger and weight regulation: "Food acceptance and the urge to eat in rats are found to have relatively little to do with 'a local condition of the gastro-intestinal ca.n.a.l,' little to do with the 'organs of taste,' and very much to do with quant.i.tative deficiencies of currently metabolized materials"-in other words, the relative presence of usable fuel in the bloodstream.133 The physiological hypothesis of weight regulation and hunger that then emerged in the mid-1970s evolved directly from the work of the French physiological psychologist Jacques Le Magnen, one of the more remarkable figures in the past century of science. Le Magnen was blind, the result of an attack of encephalitis when he was thirteen years old. He compensated by developing what his col eagues described as a "phenomenal" and "encyclopedic" memory, particularly for the nuances of relevant scientific research. "Jacques Le Magnen knew everything," as his obituary in the journal Chemical Senses commented after his death in 2002. He was also "incredibly bril iant," says the University of Cincinnati physiological psychologist Stephen Woods, which seems to be a consensus opinion among those who knew his work. Le Magnen joined the prestigious Col ege de France in 1944, and he remained there for forty years, much of it spent working in the office and laboratory that had original y belonged to Claude Bernard. His Laboratory of Sensory and Behavioral Neurophysiology would eventual y grow to become perhaps the largest in the world focused on issues related to hunger and weight regulation.

Le Magnen's research on eating behavior began in the early 1950s, when he designed a device to monitor food intake in rats over entire twenty-four-hour cycles. This led him to report that rats ate discrete meals separated in time by discrete intervals. He then set out to establish what factors regulated the size of the meals and the length of the intervals between meals.

Le Magnen's research resulted in two fundamental observations, both confirming Adolph's observation that eating behavior in animals, and thus hunger, is driven by those "quant.i.tative deficiencies of currently metabolized materials."

Le Magnen learned that when rats are al owed to eat whenever they want, the size of the meal determines how long rats wil go before they get hungry again. As a new supply of ingested calories is exhausted by the rat's energy expenditure, the animal is motivated to eat again. "Al increase or decrease in the two sides of this balance (calories eaten in meals versus metabolic expenditures) wil lead to an immediate shortening or lengthening of the meal-to-meal interval," Le Magnen explained. And this is "the major and direct agent of the regulation of food intake."

The second observation was one that is obviously true for humans as wel : Rats eat to excess during their waking hours, which means their intake exceeds their expenditure of energy, and so they are hyperphagic while awake, storing fat during this period. While they're sleeping, the rats are in negative energy balance-hypophagic-and they live off the fat acc.u.mulated during the waking hours. Weight peaks as the rats are going to sleep and it ebbs as they awake. In humans, this cycle would explain, among other things, why hunger doesn't (or at least shouldn't) wake us from the depths of a night's sleep so we can raid the refrigerator.

While rats are sleeping, they progressively mobilize more and more fatty acids from their adipose tissue and use these fatty acids for fuel. "The rest.i.tution of these stored fats and their utilization to cover an important part of the current metabolism reduces the concomitant requirement for an external supply of calories by food intake," Le Magnen wrote. When he used insulin to suppress this mobilization of free fatty acids, the rats ate immediately. Fatty acids released from the adipose tissue, Le Magnen concluded, simply replace or "spare" the available glucose and, by doing so, delay the onset of hunger and the impetus to feed. The liberal availability of these fatty acids in the blood promotes satiety and inhibits hunger.

Another way to phrase this is that anything that induces fatty acids to escape from the fat tissue and then be burned as fuel wil promote satiety by providing fuel to the tissues. Anything that induces lipogenesis, or fat synthesis and storage, wil promote hunger by removing the available fuel from the circulation. And so hypophagia and hyperphagia, satiety and hunger, Le Magnen wrote, are "indirect and pa.s.sive consequences" of "the neuroendocrine pattern of fat mobilization or synthesis."

By the mid-1970s, Le Magnen had demonstrated that insulin is the driver of this diurnal cycle of hunger, satiety, and energy balance. At the beginning of waking hours, the insulin response to glucose-the "insulin secretory responsiveness," Le Magnen cal ed it-is enhanced, and it's suppressed during sleep. This pattern is "primarily responsible" for the fat acc.u.mulation during the waking hours and the fat mobilization during the sleeping hours. "The hyperinsulin secretion in response to food" during the period when the animals are awake and eating, and the "opposite train" when they are asleep, he explained, produces "a successive fal and elevation" of the level of fatty acids in the blood on a twenty-four-hour cycle-twelve hours during which the fatty acids are depressed and glucose is the primary fuel, and then twelve hours in which they're elevated and fat is the primary fuel. Both hunger, or the urge to eat, and satiety, or the inhibition of eating, are compensatory responses to these insulin-driven cycles of fat storage fol owed by fat mobilization. Insulin secretion is released in the morning upon waking and drives us to eat, Le Magnen concluded, and it ebbs after the last meal of the day to al ow for prolonged sleep without hunger.

This hypothesis of eating behavior did away with set points and lipostats and relied instead on the physiological notion of hunger as a response to the availability of internal fuels and to the hormonal mechanisms of fuel part.i.tioning. Hunger and satiety are manifestations of metabolic needs and physiological conditions at the cel ular level, and so they're driven by the body, no matter how much we like to think it's our brains that are in control.

Several variations on this hypothesis were published from the mid-1970s onward by Le Magnen and others. The most comprehensive account was published in 1976 by Edward Stricker at the University of Pittsburgh, and Mark Friedman, then at the University of Ma.s.sachusetts and now at the Monel Chemical Senses Center in Philadelphia. Their article, "The Physiological Psychology of Hunger: A Physiological Perspective," should be required reading for anyone seriously interested in eating behavior and weight regulation.

The hypothesis is based on three fundamental propositions. The first, as Friedman and Stricker explained, is that the supply of fuel to al body tissues must always remain "adequate for them to function during al physiological conditions and even during prolonged food deprivation." The second proposition is Hans Krebs's revelation from the 1940s that each of the various metabolic fuels-protein, fats, and carbohydrates-is equal y capable of supplying energy to meet the demands of the body. The third is that the body has no way of tel ing the difference between fuels from internal sources-the fat tissue, liver glycogen, muscle protein-and fuels that come from external sources-i.e., whatever we eat that day.

With these propositions in mind, the simplest possible explanation for feeding behavior is that we eat to maintain this flow of energy to cel s-to maintain "caloric homeostasis"-rather than maintain body fat stores or some preferred weight. If the cel s themselves are receiving sufficient fuel to function, the size of the fat reserves is a secondary concern. As Friedman and Stricker explained, "Hunger appears and disappears according to normal y occurring fluctuations in the availability of utilizable metabolic fuels, regardless of which fuels they are and how ful the storage reserves." In 1993, the Princeton physiological psychologist Bartley Hoebel described the hypothesis in terms that echoed the origins of the theory in the work of Claude Bernard: "The primitive goal of feeding behavior," Hoebel explained, "is to maintain constancy of the nutrient concentration of the milieu interieur."

From this perspective, we're not much more complicated than insects, which wil seek out food and consume it until their guts are ful . External taste receptors signal whether they've come upon something they can benefit from eating; gut receptors signal when sufficient food has been consumed to inhibit the hunger. The role of the brain is to integrate the sensory signals from the gut and the taste receptors and couple them to motor reflexes to initiate eating behavior or inhibit it. In both flies and mosquitoes, if the neural connection between gut and brain is severed, the insect loses its hunger inhibitor and continues to eat until its gut literal y ruptures. As Edward Stricker explained in The New England Journal of Medicine in 1978, hunger is little more than a disturbing stimulus, like an itch, that "feeding behavior removes or attenuates." Satiety, on the other hand, "is more than the absence of hunger; it is the active suppression of interest in food and of feeding behavior."

The primary difference between humans and insects, by this logic, is that we have two primary fuel tanks (three if we include glycogen stored in the liver, and four if we include protein in the muscles), and they effectively have one. In our case, fuel is stored initial y in the gut for the short term, and then in the fat tissue for the medium to longer term. The fat tissue extends the time we can go between meals by hours, days, or more. The fuel supply to the cel s is maintained by the fil ing and emptying of both these energy reserves. "Energy metabolism," Friedman and Stricker wrote, "is maintained by alternating tides of nutrients that sweep in from the intestines or adipose tissue at regular intervals depending on when food consumption occurs." The fat tissue partic.i.p.ates actively in metabolism by acting as an energy buffer: it provides storage for nutrients that arrive with the meal but are not immediately necessary for energy, and then it releases them back into the circulation as this absorptive phase is coming to an end. In effect, the fat tissue prevents dramatic shifts in the energy supply, which would otherwise be unavoidable considering the fact that, unlike cattle or sheep, we don't graze continual y but, rather, eat episodical y in discrete meals.

We can think of eating and satiety as a cycle that begins with the meal and fil s the gastrointestinal reserve-the gut. As nutrients are absorbed into the circulation, some are used for fuel immediately, and the rest restock the fat reserves, the glycogen reserves in the liver, and the protein in the muscles. As the gut empties, and this dietary fuel is either stored or oxidized, the fat reserves become the primary source of fuel. As the fat reserves begin to empty and the fuel flow shows signs of faltering, the inhibition of hunger is lifted, we are motivated again to fil the gut, and the cycle begins anew.

This "harmony of tissue metabolisms" is orchestrated by the hypothalamus, via the central nervous system and the endocrine system of hormones.

These regulate the fil ing and emptying of the various storage depots in response to an environment that might require that we suddenly expend more or less energy, or store more or less fat, to accommodate seasonal variations. The hypothalamus does what the brains of insects do: it integrates sensory signals from the body and the rest of the brain, and couples them to motor reflexes that permit or restrain eating behavior. It also adjusts this fil ing and emptying of the fuel reserves to accommodate the immediate need for fuel and the antic.i.p.ated need for fuel.

According to this hypothesis, weight stability is nothing more than an equilibrium between the fatty acids flowing into the energy buffer of the fat tissue and the fatty acids flowing out. What the body regulates, as Le Magnen suggested, is the fuel flow to the cel s; the amount of body fat we acc.u.mulate is a secondary effect of the fuel part.i.tioning that accomplishes this regulation.

The implication of this hypothesis is that both weight gain and hunger wil be promoted by factors that work to deposit fatty acids in the fat tissue and inhibit their mobilization-i.e., anything that elevates insulin. Satiety and weight loss wil be promoted by factors that increase the release of fatty acids from the fat tissue and direct them to the cel s of the tissues and organs to be oxidized-anything that lowers insulin levels. Le Magnen himself demonstrated this in his animal experiments. When he infused insulin into rats, it lengthened the fat-storage phase of their day-night cycle, and it shortened the fat-mobilization-and-oxidation phase accordingly. Their diurnal cycle of energy balance was now out of balance: the rats acc.u.mulated more fat during their waking hours than they could mobilize and burn for fuel during their sleeping hours. They no longer balanced their overeating with an equivalent phase of undereating. Not only were their sleep-wake cycles disturbed, but the rats would be hungry during the daytime and continue to eat, when normal y they would be living off the fat they had stored at night.*134 Indeed, when Le Magnen infused insulin into sleeping rats, they immediately woke and began eating, and they continued eating as long as the insulin infusion continued. When during their waking hours he infused adrenaline-a hormone that promotes the mobilization of fatty acids from the fat tissue-they stopped eating.

If this hypothesis holds for humans, it means we gain weight because our insulin remains elevated for longer than nature or evolution intended, and so we fail to balance the inevitable fat deposition with sufficient fat oxidation. Our periods of satiety are shortened, and we are driven to eat more often than we should. If we think of this system in terms of two fuel supplies, the immediate supply in the gut and the reserve in our fat deposits, both releasing fuel into the circulation for use by the tissues, then insulin renders the fat deposits temporarily invisible to the rest of the body by shutting down the flow of fatty acids out of the fat cel s, while signaling the cel s to continue burning glucose instead. As long as insulin levels remain elevated and the fat cel s remain sensitive to the insulin, the use of fat for fuel is suppressed. We store more calories in this fat reserve than we should, and we hold on to these calories even when they're required to supply energy to the cel s. We can't use this fat to forestal the return of hunger. "It is not a paradox to say that animals and humans that become obese gain weight because they are no longer able to lose weight," as Le Magnen wrote.

This alternative hypothesis may also tel us something profound about the relationship between nutrition and fertility. That shouldn't be surprising, because reproductive biologists, as we discussed earlier (see Chapter 21), have long considered the availability of food to be the most important environmental factor in fertility and reproduction. By this hypothesis, the critical variable in fertility is not body fat, as is commonly believed, but the immediate availability of metabolic fuels. This was suggested in the late 1980s, when the reproductive biologists George Wade and Jil Schneider described their research on hamsters, which were chosen because of their clockwork four-day estrous cycles. The experiments were remarkably consistent. These animals wil go into heat whether they are fat or lean, and they wil continue to cycle, as long as they can eat as much food as they want.

If both fatty-acid and glucose oxidation are inhibited, however, and they're not al owed to increase their food intake in response, their estrous cycles stop.

They'l remain infertile, whether they are gaining or losing weight at the time. These animals are responding to the general availability of metabolic fuels.

The same observation has been made about pigs, sheep, and cattle. Monkeys wil shut down their secretion of the hormone that triggers ovulation if they go twenty-four hours without food, but they'l re-establish secretion immediately upon eating. The more the monkeys are al owed to eat, the more hormone they'l secrete.

If it is true that fertility is determined by the availability of metabolic fuels, as Wade and Schneider explained, then "it would be expected that ovulatory cycles would be inhibited by treatments that direct circulating metabolic fuels away from oxidation and into storage in adipose tissue." This is what insulin does, of course, and, indeed, infusing insulin into animals wil shut down their reproductive cycles. In hamsters, insulin infusion "total y blocks" estrous cycles, unless the animals are al owed to increase their normal food intake substantial y to compensate. This hypothesis can also explain the infertility a.s.sociated with obesity in both humans and lab animals. If "an excessive portion of available calories" is locked away in fat tissue, then the animal wil act as if it's starving. In such a situation, Wade and Schneider said, "there wil be insufficient calories to support both the reproductive and the other physiological processes essential for survival" reproductive activity shuts down until more food is available to compensate.

This metabolic-fuel hypothesis of fertility has escaped the attention of clinicians. The clear implication is that a woman struggling with infertility or amenorrhea (the suppression of menstruation) wil benefit more from a diet that lowers insulin but stil provides considerable calories-a low-carbohydrate, high-fat diet-and thus repart.i.tions the fuel consumed so that more is available for oxidation and less is placed in storage.

If this hypothesis of hunger, satiety, and weight regulation is correct, it means that obesity is caused by a hormonal environment-increased insulin secretion or increased sensitivity to insulin-that tilts the balance of fat storage and fat burning. This hypothesis also implies that the only way to lose body fat successful y is to reverse the process; to create a hormonal environment in which fatty acids are mobilized and oxidized in excess of the amount stored. A further implication is that any therapy that succeeds at inducing long-term fat loss-not including toxic substances and disease-has to work through these local regulatory factors on the adipose tissue.

If the princ.i.p.al effect of a drug, for example, is to suppress in the brain the desire to eat, and thus reduce food consumption, then the body wil perceive the consequences as caloric deprivation and compensate accordingly. Energy expenditure wil be reduced, and weight loss wil be temporary at best. On the other hand, any drug that works local y on the fat cel s to release fatty acids into the circulation wil inhibit hunger because it wil be increasing the flow of fuel to the cel s. This could also be the case for any treatment that appears to increase metabolism or energy expenditure. A weight-loss drug that works in the brain to increase metabolism wil also increase hunger, unless it also works on the fat tissue to mobilize fatty acids that can supply the necessary fuel.

Consider nicotine, for instance, which may be the most successful weight-loss drug in history, despite its otherwise narcotic properties. Cigarette smokers wil weigh, on average, six to ten pounds less than nonsmokers. When they quit, they wil invariably gain that much, if not more; approximately one in ten gain over thirty pounds. There seems to be nothing smokers can do to avoid this weight gain.

The common belief is that ex-smokers gain weight because they eat more once they quit. They wil , but according to studies only in the first two or three weeks. After a month, former smokers wil be eating no more than they would have been had they continued to smoke. The excess of calories consumed is not enough to explain the weight gain. Moreover, as Judith Rodin, now president of Rockefel er University, reported in 1987, smokers who quit and then gain weight apparently consume no more calories than those who quit and do not gain weight. (They do eat "significantly more carbohydrates," however, Rodin reported, and particularly more sugar.) Smokers also tend to be less active and exercise less than nonsmokers, so differences in physical activity also fail to explain the weight gain a.s.sociated with quitting.

The evidence suggests that nicotine induces weight loss by working on fat cel s to increase their insulin resistance, while also decreasing the lipoprotein-lipase activity on these cel s, both of which serve to inhibit the acc.u.mulation of fat and promote its mobilization over storage, as we discussed earlier (see Chapter 22). Nicotine also seems to promote the mobilization of fatty acids directly by stimulating receptors on the membranes of the fat cel s that are normal y triggered by hormones such as adrenaline. The drug also increases lipoprotein-lipase activity on muscles, and this may explain the steep rise in metabolic rate that occurs immediately after smoking. Al of this fits with the observations that smokers use fatty acids for a greater proportion of their daily fuel than nonsmokers, and heavy smokers burn more fatty acids than light smokers. In short, nicotine appears to induce weight loss and fat loss not by suppressing appet.i.te but by freeing up fatty acids from the fat cel s and then directing them to the muscle cel s, where they're taken up and oxidized, providing the body with some excess energy in the process. When smokers quit, they gain weight because their fat cel s respond to the absence of nicotine by significantly increasing lipoprotein-lipase activity. (There's also evidence that the weight-reduction drug fenfluramine-the "fen" half of the popular weight-loss drug phen/fen, which was banned by the FDA in 1997-works in a similar manner, by decreasing lipoprotein-lipase activity in the fat tissue.) This alternative hypothesis of obesity and its physiological perspective on hunger forces us to rethink virtual y al our cherished notions about how weight changes and why. By this hypothesis, any long-term variations in weight, appet.i.te, and energy expenditure-even our inclination to exercise or go for a walk-are likely to be induced at a fundamental level by changes in the regulation of fat metabolism and the part.i.tioning and availability of metabolic fuels in the body. These in turn are driven, first and foremost, by changes in insulin secretion and how our fat and muscle tissue respond to that insulin. In this sense, insulin becomes what researchers who study hibernation and other seasonal weight variations in animals refer to as the adjustable regulator.

Increase or decrease the circulating levels of insulin, and weight, hunger, and energy expenditure increase or decrease accordingly. It's insulin that regulates the equilibrium between the forces of fat deposition and the forces of fat mobilization at the adipose tissue.

What's been clear for almost forty years is that the levels of circulating insulin in animals and humans wil be proportional to body fat. "The leaner an individual, the lower his basal insulin, and vice versa," as Stephen Woods, now director of the Obesity Research Center at the University of Cincinnati, and his col eague Dan Porte observed in 1976. "This relationship has also been shown to occur in every commonly used model of altered body weight, including...genetical y obese rodents and overfed humans. In fact, the relationship is sufficiently robust that it exists in the presence of widespread metabolic disorder, such as diabetes mel itus, i.e., obese diabetics have elevated basal insulin levels in proportion to their body weight." Woods and Porte also noted that when they fattened rats to "different proportions of their normal weights," this same relationship between insulin and weight held true.

"There are no known major exceptions to this correlation," they concluded. Even the seasonal weight fluctuations in hibernators agree with this correlation; the evidence suggests that annual fluctuations in insulin secretion drive the yearly cycle of weight and eating behavior, although this has never been established with certainty.

This same mechanism might explain the annual patterns of weight fluctuation in humans as wel -heavier in the fal and winter and lighter in the spring and summer-that are commonly attributed to increased physical activity supposedly accompanying the joys of spring or driven by the peer pressure and anxiety of the coming of bathing-suit season. When researchers have measured seasonal variations in insulin levels in humans, they have invariably reported that insulin is highest in late fal and early winter-twice as high, according to one 1984 study-and lowest in late spring and early summer.

Moreover, as the University of Colorado's Robert Eckel has reported, lipoprotein-lipase activity in fat tissue elevates in late fal and decreases in spring and summer; its activity in skeletal muscle fol ows an opposite pattern. This would stimulate weight loss in the spring and weight gain in the fal , whether we consciously desire either or not, and would certainly make it easier to lose weight in the spring and gain it in the fal .

One of the most radical implications of this hypothesis is that even such an intractable condition as anorexia nervosa-which, like obesity, is now universal y considered a behavioral and psychological disorder-may be caused fundamental y by a physiological defect of fat metabolism and insulin.

The behavior of undereating may be a compensatory response to a physiological condition, just as the behavior of overeating can. Any hormonal abnormality that makes it difficult to store calories as fat-the fat cel s, for example, becoming prematurely or abnormal y resistant to insulin-could conceivably induce a compensatory inhibition of eating behavior and/or an increase in energy expended. What appears to be purely a behavioral phenomenon, the anorexia itself (and perhaps even bulimia nervosa), would be the compensatory response to a physiological problem, the inability to store calories after a meal in the energy buffer of the fat tissue. Correctly identifying cause and effect in these conditions would be difficult, if not impossible, without the understanding that there is an alternative hypothesis to explain the observations.

One final point has to be made about this physiological hypothesis of hunger and weight regulation, and it's almost as counterintuitive as it is important.

This is what the hypothesis says about our perception of taste. One seemingly obvious relationship between diet and obesity has always been that the more palatable the food, the more we're likely to overindulge and so grow fat.

In the 1960s and 1970s, obesity researchers referred to this supposed effect of taste on food intake and weight as the palatability hypothesis. But these researchers defined palatability on the basis of how much their experimental animals ate. If their rats or mice ate more of one food than another, the researchers a.s.sumed that they did so because they liked it better. The problem is that this concept of palatability "arises mainly from human experience; its existence in animals is an inference," as the physiological psychologist Mark Friedman explained in 1989. In other words, the animals' preference for certain foods could have been explained by other factors.

In fact, our perception of what tastes good depends very much on circ.u.mstances. Le Magnen made this observation early in his career, and it's one reason why the subject of his own research evolved from olfactory stimuli to food intake. Le Magnen first noted that our a.s.sessment of odor changes with food consumption. The smel of a cinnamon bun baking in the oven wil be considerably more enticing when we're hungry than after we've eaten. Our subjective interpretation of taste changes as wel . With the possible exception of inordinately expensive meals at fashionable restaurants, the memorable meals of our lives are likely to be those we ate when we were particularly hungry-after a day of hard work or a particularly strenuous workout. "It is often said and not without reason," as Pavlov wrote in the 1890s, "that 'hunger is the best sauce.'"

Le Magnen established that an animal's response to a particular food correlates with how depleted the animal happens to be at the time, with the caloric value of the food, and with how rapidly it fulfil s the animal's nutritional requirements. Rats given the choice between caloric sugar solutions and zero-calorie but equal y sweet saccharine solutions initial y drink similar amounts of both, Le Magnen reported. They both taste good. But the rats wil drink more of the sugar solution with each pa.s.sing day-drinking three times as much on day five as on day one-while rejecting the saccharine solution after three or four days, having apparently concluded, metabolical y, that it offers no nutritive value. If the rats drinking the saccharine solution, however, are simultaneously infused with calorie-bearing glucose directly into their stomachs, they wil continue to drink the saccharine solution as long as they get the calories along with it. The taste hasn't changed, but their post-absorption metabolic responses have. Foods that supply calories and other nutritional requirements quickly and efficiently wil come to be perceived as tasting good, and so we learn to prefer them over others.

This offers up an alternative scenario to the common a.s.sumption that we are born with an innate preference for sugar because it would have been evolutionarily beneficial, prompting us to seek out those foods that are the densest source of calories in a world in which calories were supposedly hard to come by. "In evolution," as the Yale psychologist Linda Bartoshuk told the New York Times in 1989, "we needed the energy of sweet-tasting, sugary foods, especial y during times of scarcity." The research of Le Magnen and others suggests that these preferences have little to do with the presence of famine in our evolutionary history (as discussed on Chapter 14) and everything to do with the absence of these refined carbohydrate foods. We come to prefer these foods, according to the alternative hypothesis, because they induce an exaggerated version of the post-absorption responses to natural y occurring sources of glucose and fructose-either plant foods that are difficult to digest (the kinds of roots, tubers, or fruit eaten by Paleolithic populations) or the protein in meat and the relatively slow conversion of its amino acids into glucose.

Since insulin plays the critical role in our post-absorption responses to particular foods, it's not surprising that insulin may play the critical role in our determination of palatability. A little-discussed observation in obesity research is that insulin is secreted in waves from the pancreas. The first wave begins within seconds of eating a "palatable" food, and wel before the glucose actual y enters the bloodstream. It lasts for perhaps twenty minutes. After this first wave ebbs, insulin secretion slowly builds back up in a more measured second wave, which lasts for several hours.*135 The apparent function of the first insulin wave is to prime the body for what's coming. It takes insulin almost ten minutes to have a measurable effect on blood-glucose levels; it takes twice that long to have any significant effect. Meanwhile, glucose is entering the bloodstream from the meal and continuing to stimulate insulin secretion. When blood sugar is at a maximum, the signal to the pancreas to secrete insulin is also highest, but by this time enough insulin has already been secreted to do the necessary job of glucose disposal. "The pancreas has no idea what's going on elsewhere in the body," says University of California, San Francisco, biochemist Gerald Grodsky, who pioneered much of this work. "Al it sees is the glucose." The way we apparently evolved to deal with this systems-engineering problem is the flooding of insulin into the circulation immediately upon beginning a meal; this prepares the body in advance to start taking up the glucose as soon as it appears.

Le Magnen described this first wave of insulin as increasing "the metabolic background of hunger." In other words, this wave of insulin shuts down the mobilization of fat from the adipose tissue and stores away blood glucose in preparation for the imminent arrival of more. This leaves the circulation relatively depleted of nutrients. As a result, hunger increases. And this makes the food seem to taste even better. "In man," suggested Le Magnen, "it is reflected by the increased feeling of hunger at the beginning of a meal expressed in the popular adage in French: L'appet.i.t vient en mangeant"-i.e., "the appet.i.te comes while eating." As the meal continues and our appet.i.te is satisfied, the metabolic background of hunger ebbs with the flood of nutrients into the circulation, and so the perceived palatability of the food wanes as wel . Palatability, by this logic, is a learned response, conditioned largely by hunger, which in turn is a response to the pattern of insulin secretion and the availability of fatty acids and/or glucose in the circulation.

A related observation that has been a part of scientific study since Pavlov's famous research in the nineteenth century is that the smel , sight, or even thought of food wil induce a cascade of physiological reactions. These include the secretion of saliva, gastric juices, and, not surprisingly, insulin. By the 1970s, these cephalic*136 reflexes had been studied in humans, rats, monkeys, cats, sheep, and rabbits. Le Magnen's student Stylianos Nicolaidis had demonstrated that rats wil secrete insulin in response to the mere taste of a sweet substance, and it doesn't matter whether it is sugar or a no-calorie sugar subst.i.tute. The perceived taste of sweetness is sufficient to stimulate insulin secretion. Just as Pavlov demonstrated that dogs wil salivate at the sound of a bel they have learned to a.s.sociate with feeding, Stephen Woods and his col eagues demonstrated that rats wil secrete insulin when confronted with similar eating-related stimuli. (These researchers arbitrarily chose the smel of mentholatum, a mixture of menthol and petroleum jel y, more commonly used as a topical rub for chest colds.) Humans wil do the same. This reflexive release of insulin, Nicolaidis suggested, is "pre-adaptive": it antic.i.p.ates the effects of a meal or a particular food, and so prepares the body. As Mark Friedman describes it, this cephalic release of insulin also serves to clear the circulation of "essential y anything an animal or a person can use for fuel. Not just blood sugar, but fatty acids, as wel . Al those nutrients just go away." Hence, the thought of eating makes us hungry, because the insulin secreted in response depletes the bloodstream of the fuel that the peripheral tissues and organs need to survive.

This cephalic secretion of insulin in preparation for the act of eating provides yet another mechanism that may work to induce hunger, weight gain, and obesity in a world of palatable foods, which could mean, of course, simply those foods that induce excessive insulin secretion to handle the unnatural y easy digestibility of their carbohydrates. The idea was suggested in 1977 by the psychologist Terry Powley, who was then at Yale and is now at Purdue University. Powley was discussing the obesity-inducing effect of lesions in the hypothalamus and speculated that the lesions cause the animal to hypersecrete insulin when just thinking about, smel ing, or tasting food, and this amplifies its perception of hunger and palatability. The result would be what Powley cal ed a "self-perpetuating situation"-i.e., a vicious cycle. "Rather than secreting quant.i.ties of insulin and digestive enzymes appropriate for effective utilization of the ingested material," Powley wrote, "the lesioned animal over-secretes and must then ingest enough calories to balance the hormonal and metabolic adjustments."

Powley did not go so far as to suggest that this same phenomenon was at work in humans, but his then col eague Judith Rodin did. Rodin reported in 1980 that those individuals whose eating behavior is most responsive to the smel or sight of food-a gril ing steak, in her experiments-were those who also had the greatest cephalic-phase insulin response. Insulin had to be considered a "major candidate," Rodin suggested, "for an intervening physiological mechanism that might be responsive to environmental stimuli." By 1985, Rodin was speculating that the chronic hyperinsulinemia of the obese would also exacerbate this phenomenon. "A feedback loop is suggested by these findings in which hyperinsulinemia in turn leads to increased consumption, which, unless compensated for, could lead to further weight gain," she wrote. "Because acute hyperinsulinemia can also be produced in some individuals by simply looking at or thinking about food, it, too, can in turn lead to increased consumption and possible weight gain."

The possibility that insulin determines what Le Magnen cal ed the metabolic background of hunger also explains two observations we discussed in the sections on fattening and reducing diets.

The first is the observation by Ethan Sims that he could stuff his convict subjects with as much as ten thousand calories a day of mostly carbohydrate and they would stil feel "hunger late in the day," and yet subjects fed eight hundred superfluous calories of fat "developed marked anorexia." On a more familiar level: why is it that most of us can imagine eating a large bag (twenty ounces) of movie popcorn-more than eleven hundred calories if popped in oil,*137 as it typical y is-but not so the equivalent caloric amount of cheese: say, fifteen slices of American cheese, or a cup and a half of melted Brie?

The simple explanation is that the insulin induced by the carbohydrates serves to deposit both fats and carbohydrates (fatty acids and glucose) as fat in the adipose tissue, and it keeps those calories fixed in the adipose tissue once they get there. As long as we respond to the carbohydrates by secreting more insulin, we continue to remove nutrients from our bloodstream in expectation of the arrival of more, so we remain hungry, or at least absent any feeling of satiation. It's not so much that fat fil s us up as that carbohydrates prevent satiety, and so we remain hungry.

The second observation is the carbohydrate craving a.s.sociated with obesity. Here the metabolic background of hunger is established by chronic hyperinsulinemia rather than the immediate insulin secretion during a carbohydrate-rich meal. In both cases the insulin induces hunger or prevents satiety.

In the case of hyperinsulinemia and obesity, however, this happens even between meals, when the cel s should be living off a fuel mixture of predominantly fatty acids. Instead, the insulin traps the fat in the fat tissue, and it signals the cel s to burn glucose. As far as the body is concerned, the elevated insulin is the indication that we've just eaten-"high levels of insulin herald the 'fed' state," as George Cahil put it-and the signal that carbohydrates are available to be burned. But in this case, they're not. Now the homeostatic system that evolved to maintain blood sugar in a healthy range establishes an internal environment in which the cel s are primed to burn glucose for fuel, and only glucose can satisfy that demand, yet there's no expendable glucose in the system. High insulin levels even prevent the liver from releasing the glucose that's stored there as glycogen. As a result, it's glucose that we crave. Even if we eat fat and protein-our cheese slices, for instance-the hyperinsulinemia wil work to store these nutrients rather than al ow them to be used for fuel.

The practical implication of this situation is critical to how we perceive the dietary treatment of obesity, or simply the maintenance of a healthy weight, in a world of inexpensive, easily digestible carbohydrate-rich foods. Among the more pessimistic arguments wielded against carbohydrate-restricted diets is that al diets fail eventual y because the subjects inevitably fal of the diet, just as they do calorie-restricted diets. But this argument is based on the a.s.sumption that al diets work by limiting the calories consumed. It also ignores any physiological difference between a craving for carbohydrates and the hunger that results from semi-starvation. The latter is caused by the absence of sufficient calories to satisfy physiological demands. The craving for carbohydrates is more closely akin to an addiction, which is how it was described by the British clinician Robert Kemp in 1963. It is the consequence of hyperinsulinemia, which in turn is caused initial y by the presence of carbohydrates in the diet, just as an addiction to nicotine or cocaine or any other addictive substance is caused by the use of these substances. There is nothing inherently natural about such addictions. The hunger that accompanies calorie restriction is an unavoidable physiological condition; the craving for carbohydrates is not.

Sugar (sucrose) is a special case. Just like cocaine, alcohol, nicotine, and other addictive drugs, sugar appears to induce an exaggerated response in that region of the brain known as the reward center-the nucleus acc.u.mbens. This suggests that the relatively intense cravings for sugar-a sweet tooth -may be explained by the intensity of the dopamine secretion in the brain when we consume sugar. When the nucleus acc.u.mbens "is excessively activated by sweet food or powerful drugs," says Bartley Hoebel of Princeton, "it can lead to abuse and even addiction. When this system is under-active, signs of depression ensue." Rats can be easily addicted to sugar, according to Hoebel, and wil demonstrate the physical symptoms of opiate withdrawal when forced to abstain.

Whether the addiction is in the brain or the body or both, the idea that sugar and other easily digestible carbohydrates are addictive also implies that the addiction can be overcome with sufficient time, effort, and motivation, which is not the case with hunger itself (except perhaps in the chronic condition of anorexia). Avoiding carbohydrates wil lower insulin levels even in the obese, and so ameliorate the hyperinsulinemia that causes the carbohydrate craving itself. "After a year to eighteen months, the appet.i.te is normalized and the craving for sweets is lost," said James Sidbury, Jr., about the effects on children of his carbohydrate-restricted diet. "This change can often be identified within a specific one to two week period by the individual."

If the more easily digestible carbohydrates are indeed addictive, this changes the terms of al discussions about the efficacy of carbohydrate-restricted diets. That someone might find living without starches, flour, and sugar to be difficult, and that there might be physical symptoms accompanying the withdrawal process, does not speak to the possibility that they might be healthier and thinner for the effort. No one would argue that quitting smoking (or any other addictive drug) is not salutary, even though ex-smokers invariably miss their cigarettes, and many wil ultimately return to smoking, the addiction eventual y getting the better of them. The same may be true for these carbohydrates.

It also makes us question the admonitions that carbohydrate restriction cannot "general y be used safely," as Theodore Van Ital ie wrote in 1979, because it has "potential side effects," including "weakness, apathy, fatigue, nausea, vomiting, dehydration, postural hypotension, and occasional exacerbation of preexisting gout." The important clinical question is whether these are short-term effects of carbohydrate withdrawal, or chronic effects that might offset the benefits of weight loss. The same is true for the occasional elevation of cholesterol that wil occur with fat loss-a condition known as transient hypercholesterolemia-and that is a consequence of the fact that we store cholesterol along with fat in our fat cel s. When fatty acids are mobilized, the cholesterol is released as wel , and thus serum levels of cholesterol can spike. The existing evidence suggests that this effect wil vanish with successful weight loss, regardless of the saturated-fat content of the diet. Nonetheless, it's often cited as another reason to avoid carbohydrate-restricted diets and to withdraw a patient immediately from the diet should such a thing be observed, under the mistaken impression that this is a chronic effect of a relatively fat-rich diet.

In 1963, when Robert Kemp discussed his clinical experience with carbohydrate-restricted diets and the apparent problem of carbohydrate addiction, he made the point that the necessary step was to establish beyond reasonable doubt whether carbohydrates indeed were the cause of obesity and overweight. By doing so, we could then make informed decisions about the risks and benefits of our cravings. Many former cigarette smokers would likely stil be smoking today without the certain knowledge that tobacco causes lung cancer. "At least half of our patients, win or lose, cannot be persuaded that they must permanently alter their eating habits to save their lives," Kemp wrote. "This is undoubtedly a battle for the mind where unfortunately the patient is completely unsettled by the confusion of advice offered from both professional and lay sources." This statement is stil true today. Carbohydrate-restricted diets wil always be tempting, if for no other reason than their efficacy at inducing weight loss. But to make a permanent change in diet requires the confidence that we wil be healthier for doing so. For that, we need the support of physicians, nutritionists, and the public-health authorities, and we need advice that is based on rigorous science, not century-old preconceptions about the penalties of gluttony and sloth.

EPILOGUE.

The community of science thus provides for the social validation of scientific work. In this respect, it amplifies that famous opening line of Aristotle's Metaphysics: "Al men by nature desire to know." Perhaps, but men of science by culture desire to know that what they know is real y so.

ROBERT MERTON, Behavior Patterns of Scientists, 1968 The first principle is that you must not fool yourself-and you are the easiest person to fool.

RICHARD FEYNMAN, in his Commencement Address at Caltech, 1974 ON FEBRUARY 7, 2003, THE EDITORS OF Science published a special issue dedicated to the critical concerns of obesity research. It included four essays written by prominent authorities, al communicating the message of the toxic-environment hypothesis of the obesity epidemic and the belief that obesity is caused by "consuming more food energy than is expended in activity." The one article that offered a potential solution to the national and global problem of burgeoning waistlines-other than the promise of future obesity-fighting drugs-was written by James Hil of the University of Colorado, John Peters of Procter & Gamble, and two col eagues. Hil and Peters introduced the concept of an "energy gap" that could purportedly explain the existence of the obesity epidemic and il uminate a path of action by which it might be halted or reversed. By their calculation, the obesity epidemic represented an energy gap of a hundred calories per person among the American public per day that had been consumed but not expended. To undo the epidemic, Hil and Peters suggested, Americans would have to make either comparable increases in daily energy expenditure-walking one extra mile, perhaps-or decreases in energy consumption, such as "eating 15% less (about three bites) of a typical premium fast-food hamburger." Two years later, when the U.S.

Department of Agriculture released the sixth edition of its Dietary Guidelines for Americans, it offered similar advice based on the identical logic: "For most adults a reduction of 50 to 100 calories per day may prevent gradual weight gain."

This proposition should evoke a distinct sensation of deja vu, because it is the precise argument that Carl von Noorden made over a century ago. Hil , Peters, and the USDA authorities, like von Noorden, were treating the regulation of body weight as though it were a purely arithmetical process, in which a smal excess of calories consumed, day in and day out, acc.u.mulates into pounds of flesh and then tens of pounds, and a smal deficit, day in and day out, does the opposite. That this argument is now the cornerstone of the official U.S. government recommendations for obesity prevention made the single caveat in Hil and Peters's Science article al that much more remarkable. Speaking of the hundred-calorie energy gap, they said that their "estimate is theoretical and involves several a.s.sumptions"-in particular, "Whether increasing energy expenditure or reducing energy intake by 100 kcal/day would prevent weight gain remains to be empirical y tested."

The more important point, though, which Hil and Peters did not discuss, was why a century of research had not produced such an empirical test. Two immediate possibilities suggest themselves: Either the acc.u.mulated research and observations on weight regulation in humans or animals had never provided sufficient reason to believe that such a proposition should be true, which is a necessary condition for anyone to expend the effort to test it; or, perhaps, n.o.body cared to test it. In either case, we have to wonder whether the individuals involved in the pursuit of the cure and prevention of human obesity, as Robert Merton would have put it, have the desire to know that what they know is real y so.

In the 1890s, Francis Benedict and Wilbur At.w.a.ter, pioneers of the science of nutrition in the United States, spent a year in the laboratory testing the a.s.sumption that the law of energy conservation applied to humans as wel as animals. They did so not because they doubted that it did, but precisely because it seemed so obvious. "No one would question" it, they wrote. "The quant.i.tative demonstration is, however, desirable, and an attested method for such demonstration is of fundamental importance for the study of the general laws of metabolism of both matter and energy."

This is how functioning science works. Outstanding questions are identified or hypotheses proposed; experimental tests are than established either to answer the questions or to refute the hypotheses, regardless of how obviously true they might appear to be. If a.s.sertions are made without the empirical evidence to defend them, they are vigorously rebuked. In science, as Merton noted, progress is made only by first establishing whether one's predecessors have erred or "have stopped before tracking down the implications of their results or have pa.s.sed over in their work what is there to be seen by the fresh eye of another." Each new claim to knowledge, therefore, has to be picked apart and appraised. Its shortcomings have to be established unequivocal y before we can know what questions remain to be asked, and so what answers to seek-what we know is real y so and what we don't. "This unending exchange of critical judgment," Merton wrote, "of praise and punishment, is developed in science to a degree that makes the monitoring of children's behavior by their parents seem little more than child's play."

The inst.i.tutionalized vigilance, "this unending exchange of critical judgment," is nowhere to be found in the study of nutrition, chronic disease, and obesity, and it hasn't been for decades. For this reason, it is difficult to use the term "scientist" to describe those individuals who work in these disciplines, and, indeed, I have actively avoided doing so in this book. It's simply debatable, at best, whether what these individuals have practiced for the past fifty years, and whether the culture they have created, as a result, can reasonably be described as science, as most working scientists or philosophers of science would typical y characterize it. Individuals in these disciplines think of themselves as scientists; they use the terminology of science in their work, and they certainly borrow the authority of science to communicate their beliefs to the general public, but "the results of their enterprise," as Thomas Kuhn, author of The Structure of Scientific Revolutions, might have put it, "do not add up to science as we know it."

Though the reasons for this situation are understandable, they offer scant grounds for optimism. Individuals who pursue research in this confluence of nutrition, obesity, and chronic disease are typical y motivated by the desire to conserve our health and prevent disease. This is an admirable goal, and it undeniably requires reliable knowledge to achieve, but it cannot be accomplished by al owing the goal to compromise the means, and this is what has happened. Practical considerations of what is too loosely defined as the "public health" have consistently been al owed to take precedence over the dispa.s.sionate, critical evaluation of evidence and the rigorous and meticulous experimentation that are required to establish reliable knowledge. The urge to simplify a complex scientific situation so that physicians can apply it and their patients and the public embrace it has taken precedence over the scientific obligation of presenting the evidence with relentless honesty. The result is an enormous enterprise dedicated in theory to determining the relationship between diet, obesity, and disease, while dedicated in practice to convincing everyone involved, and the lay public, most of al , that the answers are already known and always have been-an enterprise, in other words, that purports to be a science and yet functions like a religion.

The essence of the conflict between science and nutrition is time. Once we decide that science is a better guide to a healthy diet than whatever our parents might have taught us (or our grandparents might have taught our parents), then the sooner we get reliable guidance the better off we are. The existence of uncertainty and competing hypotheses, however, does not change the fact that we al have to eat and we have to feed our children. So what do we do?

There are two common responses to this question, as there wil be to the arguments made in this book. One response is to take into account the uncertainties about the health effects of fats and carbohydrates and then suggest that we simply eat in moderation. This in turn implies eating a balanced diet in moderation. "Perhaps our most sensible public health recommendation should be moderation in al things, and moderation in that," as the University of Michigan professor of public health Marshal Becker suggested back in 1987. But some of us do eat with admirable restraint of the four major food groups and yet are obese or overweight anyway, and presumably have an increased risk of other chronic diseases because of it; some of us are suitably lean, eat balanced diets in moderation, and exercise regularly and yet are insulin-resistant and maybe even diabetic.

The more optimistic response is a compromise position: to take virtual y every reasonable hypothesis from the past fifty years that can coexist with the saturated-fat/cholesterol hypothesis of heart disease and fold them al into one seemingly reasonable diet that might do us good and probably won't do harm. Thus, the current conception of a healthy diet is one that minimizes salt content and maximizes fiber; has plenty of good fats (monounsaturated and omega-three polyunsaturated fats) and minimal bad fats (saturated fats and trans fats); has plenty of olive oil and fish, and little red meat, b.u.t.ter, lard, and dairy products. When meat is consumed, it's lean, which keeps saturated-fat content down and reduces energy density and thus, supposedly, calories.

Dairy is low-fat or no-fat. The diet has plenty of nuts and legumes and good carbohydrates, which are those with copious vitamins, minerals, antioxidants, and fiber (vegetables, fruits, and unrefined grains), but few bad carbohydrates, which are energy-dense and thus contribute to obesity (highly refined carbohydrates and sugars).

It may be true that such a diet is uniquely healthy-but we have no idea if that's real y so. The diet has the advantage of being political y correct; it can be recommended without fear of ostracism from the medical community. Whether it is healthier, however, than, say, a meat diet of 7080 percent fat calories and absent carbohydrates almost entirely, as Stefansson suggested in the 1920s, or any diet of animal products (meat, fish, fowl, eggs, and cheese) and green vegetables but absent entirely starches, sugar, and flour or even sugar alone, is stil anybody's guess. And whether such a diet would prevent us from fattening or reverse obesity, or do it better than a mostly meat diet, has also never been tested. If it doesn't, then it's probably not the healthiest diet, because excessive fat acc.u.mulation is certainly a.s.sociated with increased risk of chronic disease.

I have spent much of the last fifteen years reporting and writing about issues of public health, nutrition, and diet. I have spent five years on the research for and writing of this book alone. To a great extent, the conclusions I've reached are as much a product of the age we live in as they are my own skeptical inquiry. Just ten years ago, the research for this book would have taken the better part of a lifetime. It was only with the development of the Internet, of search engines and the comprehensive databases of the Library of Medicine, the Inst.i.tute for Scientific Information, research libraries, and secondhand-book stores worldwide now accessible online that I was able, with reasonable facility, to locate and procure virtual y any written source, whether published a century ago or last week, and to track down and contact clinical investigators and public-health officials, even those long retired.

Throughout this research, I tried to fol ow the facts wherever they led. In writing the book, I have tried to let the science and the evidence speak for themselves. When I began my research, I had no idea that I would come to believe that obesity is not caused by eating too much, or that exercise is not a means of prevention. Nor did I believe that diseases such as cancer and Alzheimer's could possibly be caused by the consumption of refined carbohydrates and sugars. I had no idea that I would find the quality of the research on nutrition, obesity, and chronic disease to be so inadequate; that so much of the conventional wisdom would be founded on so little substantial evidence; and that, once it was, the researchers and the public-health authorities who funded the research would no longer see any reason to chal enge this conventional wisdom and so to test its validity.

As I emerge from this research, though, certain conclusions seem inescapable to me, based on the existing knowledge: 1. Dietary fat, whether saturated or not, is not a cause of obesity, heart disease, or any other chronic disease of civilization.

2. The problem is the carbohydrates in the diet, their effect on insulin secretion, and thus the hormonal regulation of homeostasis-the entire harmonic ensemble of the human body. The more easily digestible and refined the carbohydrates, the greater the effect on our health, weight, and wel -being.

3. Sugars-sucrose and high-fructose corn syrup specifical y-are particu