Good Calories, Bad Calories Part 13

Over the years, a common way to avoid thinking about the paradox of a diet that al egedly restricts calories but does not induce hunger is to attribute the suppression of appet.i.te to a factor that these authorities consider irrelevant to the bigger picture of weight and health-to ketosis, the condition produced when the liver increases its production of ketone bodies to replace glucose as a fuel for the brain and nervous system. Once ketone bodies are produced, "their appet.i.te-depressing activity takes effect," as Richard Spark of Harvard Medical School claimed in 1973. "Substances cal ed ketones wil acc.u.mulate in your bloodstream [during carbohydrate restriction] and can make you slightly nauseated and light-headed and cause bad breath," wrote Jane Brody in the New York Times in 1996. "This state is not exactly conducive to a hearty appet.i.te, so chances are you wil eat less than you might otherwise have of the high-protein, high-fat foods permitted on the diet."

But this, too, fails as a viable explanation. The liver increases ketone-body synthesis only when carbohydrates are unavailable and the body is relying predominantly on stored fat for its fuel. Ketone bodies could be responsible for appet.i.te suppression, as Spark and Brody suggested, but so could the absence of carbohydrates or the burning of fat, or something else entirely. Al of these are a.s.sociated with the absence of hunger. In fact, the existing research argues against the claim that ketone bodies suppress appet.i.te. Individuals with uncontrol ed diabetes, for example, wil suffer from ketoacidosis, during which ketone-body levels can be tenfold or even forty-fold higher than the mild ketosis of carbohydrate restriction, and yet these people are ravenous. "It is not clear why the sensation of hunger subsides [in starvation studies], but the disappearance is apparently not related to ketosis," wrote Ernst Drenick in 1964 about his fasting studies at UCLA. Hunger sensations often disappeared in his subjects before ketone bodies could be detected in their blood or urine, "and it did not reappear" in those periods when ketone body levels were low. The same dissociation between ketone bodies and hunger was reported in 1975 by Duke University pediatrician James Sidbury, Jr., in the treatment of obese children.

Another common explanation for the absence of hunger on carbohydrate-restricted diets is that fat and protein are particularly satiating-"these foods digest slowly, making you feel satisfied longer," as Brody has explained in the Times. (Even those investigators who published studies supporting Yudkin's idea that carbohydrate-restricted diets work by restricting calories would invariably comment that high-protein, high-fat diets stil induced the least hunger and the greatest feeling of satiation. "There is a good reason to believe that the satiety value of such diets is superior to diets high in carbohydrate and low in fat, and hence, may be a.s.sociated with better dietary adherence," the metabolism researcher Laurance Kinsel wrote in an influential 1964 article ent.i.tled "Calories Do Count.") But this is also unsatisfying as an explanation. The statement that fat and protein satisfy us longer is equivalent to the statement that carbohydrates are less satisfying-they either make us experience hunger sooner than fat and protein or perhaps induce hunger, whereas fat and protein suppress it. This leads us back to the now familiar question: what is it about carbohydrates, or about the speed with which we digest them, that accelerates or exacerbates our sensation of hunger and our desire to eat?

Even Yudkin had struggled with the question of why people would wil ingly semi-starve themselves on a carbohydrate-restricted diet. "For reasons I do not clearly understand," he wrote, there must be something unique about carbohydrates that either stimulates our appet.i.tes or fails to satiate us. "It would seem from this that carbohydrate does not satisfy the appet.i.te," he noted; "it may even increase it...."

This conclusion is simply hard to avoid, considering the half century of experimental observations on these diets. It leaves us with two seemingly paradoxical observations. The first is that weight loss can be largely independent of calories. The second is that hunger can also be. Even if we could establish that weight loss on these diets is universal y attended by a decrease in calories consumed-no bread, no b.u.t.ter-we then have to explain why the subjects of these diets don't manifest the symptoms of semi-starvation. If they eat less on the diets, why aren't they hungry? And if they don't eat less, why do they lose weight?

"It is better to know nothing," wrote Claude Bernard in An Introduction to the Study of Experimental Medicine, "than to keep in mind fixed ideas based on theories whose confirmation we constantly seek, neglecting meanwhile everything that fails to agree with them." In the study of human obesity, that fixed idea has been what Yudkin cal ed "the inevitability of calories," which in turn is based on the ubiquitous misconception of the law of energy conservation. If we believe that conservation of energy-calories in equal calories out-implies cause and effect, then we wil refuse to believe that obese patients can lose significant weight without restricting their energy intake beneath some minimal expenditure. Any reports to the contrary wil be rejected on the basis that they cannot possibly be true. "Claims that weight loss occurs even with high-caloric intake, but no carbohydrate, are absurd," as the American Medical a.s.sociation insisted in 1974. "Although authors of popular diet books frequently say that loss of body fat can occur regardless of high-calorie intake, this is not supported by evidence and, in fact, is refuted by the laws of thermodynamics."

Because such a possibility is not refuted by the laws of thermodynamics, we should take such claims seriously, as Alfred Pennington did. Although several of Pennington's articles appeared in journals that were widely read, including The New England Journal of Medicine, they would have little influence on the thinking about obesity. A few practicing physicians took his work seriously-George Thorpe and Herman Tal er, a Brooklyn obstetrician who published a 1961 best-sel er based on Pennington's science ent.i.tled Calories Don't Count-but they only lost professional credibility by doing so.

The great majority of clinicians and nutritionists would not go against the conventional wisdom.

Nonetheless, Pennington was on to something. He set out to understand why his DuPont patients lost weight on a calorie-unrestricted diet that they enjoyed. He knew it contradicted the conventional wisdom but was determined to pursue the evidence. First he read what he cal ed the "voluminous experimental literature on obesity." He concluded that only "meager and conflicting" evidence existed to support the popular contention that calorie restriction would induce long-term weight loss, or even that it should induce long-term weight loss. He came to believe that experts who invoked the first law of thermodynamics to defend their beliefs did great damage. "These tended to distract the general attention from examination of the evidence on the real question, whether or not common obesity arises from a metabolic defect," he wrote.

Pennington based his a.n.a.lysis of the obesity problem on one fundamental premise that he adopted from the research on homeostasis in the 1930s and early 1940s: Because fuel is ultimately used by the cel s themselves, the relationship between fuel supply and demand at this cel ular level determines both hunger and energy expenditure. The less fuel available to supply the metabolic demands of our cel s, the greater the hunger and the less energy we wil expend. The greater the fuel available to the cel s, the greater the metabolic activity and perhaps physical activity also. This was something Francis Benedict had suggested in the 1920s and Eugene Du Bois believed. Energy expenditure, wrote Pennington, is an "index of calorie nutrition at the cel ular level."

Pennington considered two facts about obesity to be particularly revealing. One was Hugo Rony's observation that an obese individual wil spend much of his life in energy balance-in the "static phase" of obesity, to use Rony's term-just as the lean do. "His caloric intake, like that of people of normal weight, is dictated by the energy needs of his body," Pennington wrote. "His appet.i.te, far from being uncontrol ed, is precisely and delicately regulated."

The second fact was that when obese individuals try consciously to eat less-when they go on a low-calorie diet-their metabolism and energy expenditure inevitably decrease, just as they do when lean individuals are semi-starved. Benedict had observed this diet-induced decrease in energy expenditure in his lean subjects in his 191718 semi-starvation studies. Frank Evans and Margaret Ohlson had made the same observation of the obese.

Pennington believed, as Benedict, the Cornel nutritionist Graham Lusk, and others had suggested, that this was the natural response to a diminished supply of energy. Less energy is available to the cel s, and so they expend less. On a calorie-restricted diet, Pennington suggested, the obese and the lean become hungry and lethargic for identical reasons-"their tissues are not receiving enough nutriment."

This presented a dilemma. That the tissues of the lean are semi-starved by calorie restriction is easy to imagine; they don't have a lot of excess calories to spare. But why would this happen with the obese, who do? Pennington found his answer in a 1943 article by the Columbia University biochemist DeWitt Stetten, who reported that the rate at which fatty acids were released from the fat deposits of congenital y obese mice was significantly slower than it was in lean mice. Stetten had suggested that obesity in these animals was caused by a suppression of the flow of fat from the adipose tissue back into the circulation and its subsequent use by the tissues for fuel.

Pennington proposed that the same thing causes obesity in humans. The adipose tissue ama.s.ses fat calories in a normal manner after meals, but it doesn't release those calories fast enough, for whatever reason, to satisfy the needs of the cel s between meals. This was the metabolic defect that causes obesity, he said, and it could apparently be corrected or minimized by removing carbohydrates from the diet.

By hypothesizing the existence of such a defect, Pennington was able to explain the entire spectrum of observations about obesity in humans and animals simply by applying the same law of energy conservation that other obesity researchers had misinterpreted. The law applies to the fat tissue, Pennington noted, just as it does to the entire human body. If energy goes into the fat tissue faster than it comes out, the energy stored in the fat tissue has to increase. Any metabolic phenomenon that slows down the release of fat from the fat tissue-that r.e.t.a.r.ds the "energy out" variable of the equation-wil have this effect, as long as the rate at which fat enters the adipose tissue (the energy in) remains unchanged, or at least does not decrease by an equal or a greater amount. Fat calories acc.u.mulating in the adipose tissue wouldn't be available to the cel s for fuel. We would have to eat more to compensate, or expend less energy, or both. We'd be hungrier or more lethargic than individuals without such a defect.

Pennington suggested that as the adipose tissue acc.u.mulates fat its expansion wil increase the rate at which fat calories are released back into the bloodstream (just as inflating a bal oon wil increase the air pressure inside the bal oon and the rate at which air is expel ed out of the bal oon if the air is al owed to escape), and this could eventual y compensate for the initial defect itself. We wil continue to acc.u.mulate fat-and so continue to be in positive energy balance-until we reach a new equilibrium and the flow of fat calories out of the adipose tissue once again matches the flow of calories in. At this point, Pennington said, "the size of the adipose deposits, though larger than formerly, remains constant: the weight curve strikes a plateau, and the food intake is, again, balanced to the caloric output."

By Pennington's logic obesity is simply the body's way of compensating for a defect in the storage and metabolism of fat. The compensation, he said, occurs homeostatical y, without any conscious intervention. It works by a negative feedback loop. By expanding with fat, the adipose tissue "provides for a more effective release of fat for the energy needs of the body." Meanwhile, the conditions at the cel ular level remain constant; the cel s and tissues continue to function normal y, and they do so even if we have to become obese to make this happen.

This notion of obesity as a compensatory expansion of the fat tissue came as a revelation to Pennington: "It dawned on me with such clarity that I felt stupid for not having seen it before." By working through the further consequences of this compensatory process, Pennington said, al the seemingly contradictory findings in the field suddenly fit together "like clockwork."

This defect in fat metabolism would explain the sedentary behavior typical y a.s.sociated with obesity, and why al of us, fat or lean, wil become easily fatigued when we restrict calories for any length of time. Rather than drawing on the fat stores for more energy, the body would compensate by expending less energy. Any attempt to create a negative energy balance, even by exercise, would be expected to have the same effect.

Clinicians who treat obese patients invariably a.s.sume that the energy or caloric requirement of these individuals is the amount of calories they can consume without gaining weight. They then treat this number as though it were fixed by some innate facet of the patients' metabolism. Pennington explained that this wasn't the case. As long as obese individuals have this metabolic defect and their cel s are not receiving the ful benefit of the calories they consume, their tissues wil always be conserving energy and so expending less than they otherwise might. The cel s wil be semi-starved, even if the person does not appear to be. Indeed, if these individuals are restraining their desire to eat in an effort to curb, if possible, stil further weight gain, this inhibition of energy expenditure wil be exacerbated.

Consider the kind of young, active men Ancel Keys had employed in his starvation experiments. These men might normal y expend thirty-five hundred calories a day, and this was what they would eat from day to day to maintain their weight. In a healthy state, the supply of fuel to their cel s would be unimpeded by any metabolic defects, and so the cel s would have plenty of energy to burn, and their metabolism would run unimpeded. Every day, the calories temporarily stored in their fat deposits would be mobilized and burned for fuel. But imagine that one of these men develops a metabolic defect that r.e.t.a.r.ds the release of fat from the adipose tissue. Now more energy enters his fat tissue than exits. If this amounts to a hundred calories a day, he'l gain roughly one pound every month. After a while, he's likely to go on a diet to rid himself of this excess fat. He might try to reduce his consumption to three thousand calories. In a healthy state, this would have worked, but now he is dogged by a defect in fat metabolism. Fat stil acc.u.mulates in his fat tissue. Rather than remedy the imbalance between the calories coming to and going from the adipose tissue, this self-imposed calorie restriction further decreases the fuel available to the cel s, because now fewer calories have been consumed. He's even hungrier, and if he doesn't give in to the hunger, his body has to get by on even less fuel than before. His metabolic rate slows in response, and he finds himself lacking the desire to expend energy in physical activity. If he wants to inhibit this acc.u.mulation of fat in his adipose tissue, he might further restrict his diet. If he does, however, this wil further diminish the amount of calories his cel s can expend.

To Pennington, this explained the observation that some obese patients can maintain their weight consuming as little as seventeen hundred calories a day, as Keys had reported. It would also explain why malnutrition and obesity could coexist in the same populations and even the same families, as we discussed earlier (see Chapter 14). The chronic, long-term effect of such a defect in fat metabolism, combined with a diet that continues to exacerbate the problem, would so constrain the energy expenditure of adults that they could conceivably gain weight and grow obese on a caloric intake that would stil be inadequate for their children.

"What happens when low calorie diets are applied is that the starved tissues of the obese are starved further," Pennington wrote. Since the consequences of this food deprivation are likely to be the same in the obese as in the lean, they had already been adequately described by the semistarvation experiments of Benedict and Keys. "The first noticeable effect of such a calorie shortage is limitation of the voluntary activities of leisure hours,"

Pennington wrote. "The various avenues of caloric expenditure are al contracted in adjustment to the diminished food intake...and thus deflect the purpose for which low calorie diets are prescribed."

"A more rational form of treatment," Pennington suggested, would be one that makes fat once again flow readily out of the fat cel s, that directs "measures primarily toward an increased mobilization and utilization of fuel" by the muscles and organs. Pennington believed that this is what carbohydrate restriction accomplished and this was why the diets worked. The cel s would respond to this increased supply of fuel by accelerating the rate of metabolism-utilizing the fuel. Now the body would have to establish a new equilibrium between the three variables of the energy-balance equation -energy storage, intake, and expenditure. This new equilibrium, however, would be commensurate with a healthy-i.e., uninhibited-flow of fat from the adipose tissue.

If Pennington was right, a high-protein, high-fat diet that was restricted in carbohydrates but not calories would correct the metabolic fault. The adipose tissue (i.e., energy storage) would shrink, because fat would no longer be trapped in the fat tissue. It would flow out at an accelerated rate, and this would continue until a healthy equilibrium was reestablished between fat storage and fat release. Appet.i.te (i.e., energy in) would adjust downward to compensate for the increased availability of fuel from the fat tissue. Edward Adolph of the University of Rochester and Curt Richter of Johns Hopkins had repeatedly demonstrated that laboratory animals wil increase or decrease their food intake in response to the available calories. Slip nutrients into their drinking water or deposit them through a tube directly into their stomachs, and the animals compensate by eating less. Dilute their food with water or indigestible fiber, and the animals compensate by consuming a greater volume to get the same amount of calories. There is no reason to think that this adjustment in caloric intake wil not occur if the increase in available nutrients comes from the internal fat stores, rather than external manipulations-no reason to think that the body or its cel s and tissues could tel the difference. "Mobilization of increased quant.i.ty of utilizable fat, then, would be the limiting factor on the appet.i.te, effecting the disproportion between caloric intake and expenditure which is necessary for weight reduction," Pennington wrote.

If the fat can be mobilized from the adipose tissue with "sufficient effectiveness," Pennington suggested, "no calorie restriction would be necessary" on a carbohydrate-restricted diet. A greater share of the energy needs would be supplied by the calories from the fat tissue, and the appet.i.te would natural y adjust. "Weight would be lost, but a normal caloric production would be maintained." A person would be eating less because his appet.i.te would be reduced by the increased availability of fat calories in his circulation, not because the diet somehow bored, restricted, or revolted him. He would be eating less because his fat tissue was shrinking; his fat tissue would not be shrinking because he was eating less. "The result would appear to be a 'negative energy balance,'" Pennington said, "because so much of the energy needs would be supplied from stored amounts."

Energy expenditure would also increase on such a diet. The now unconstrained flow of fat calories from the adipose tissue would increase the fuel available for cel ular metabolism. The cel s would no longer be undersupplied, as though living in a constant state of semi-starvation, and their metabolism would no longer be inhibited. Metabolic rate would increase, as would the impulse to physical activity-the urge to expend some of the energy now freely available. That such an effect is possible in humans, Pennington said, had been one of the observations reported by Du Bois and his col eagues in their yearlong al -meat-diet experiment with Stefansson and his col eague Anderson. These investigators had measured Stefansson's and Anderson's metabolism on a balanced diet and then measured their metabolism repeatedly during the yearlong trial. Both men lost some weight while eating the meat diet; both increased their basal-metabolic rate-7 percent for Stefansson and 5 percent for Anderson. Such an increase in energy expenditure could account for a weight loss of twenty pounds or more over the course of a year. If this change in expenditure went in the other direction when the diet included carbohydrates, it could easily account for the slow development of obesity.

When the obese or overweight go on a carbohydrate-restricted diet, Pennington theorized, there wil be an increase in metabolic and physical activity as their bodies expend this newly available energy, and an attendant weight loss. The naive a.s.sumption would be that the physical activity caused the weight loss, and it would be wrong. They wil final y be burning off their acc.u.mulated fat stores and putting that energy to use.

Under these conditions, the energy expenditure of the obese individual might rise to what it otherwise would have been in a healthy state. It was not out of the question, as Frank Evans had reported and Sidney Werner had speculated, that this might be more than four thousand calories a day for someone who was definitively obese. Such an individual might easily eat over three thousand calories a day and stil lose a pound or two a week.

This brings us back to the questions we asked earlier: If people eat less on carbohydrate-restricted diets, why aren't they hungry. And if they don't eat less, why do they lose weight? If the restriction of carbohydrates works to ameliorate this defect in fat metabolism, as Pennington speculated, then weight wil be lost, hunger wil be absent, and calorie consumption may decrease, while energy expenditure wil increase. This is no more than the consequences of the law of energy conservation applied to a biological system that works to conserve body composition and maintain a healthy flow of fuel to the cel s and tissues.

In an ideal world, Pennington's metabolic-defect hypothesis of obesity would have been tested directly. Instead, it was ignored. Pennington made this easier by speculating that the root cause of obesity was an inability to metabolize properly a compound cal ed pyruvic acid. This made physiological sense, but further research quickly refuted it. Pennington's error al owed his contemporaries in nutrition and obesity research to dismiss him as just another renegade who refused to accept the reality of energy conservation. He deserved far better, as it wouldn't be long before researchers pinned down the precise nature of the metabolic-hormonal defect that appears to be the driving force in the acc.u.mulation of excess fat.

Chapter Twenty-one.

THE CARBOHYDRATE HYPOTHESIS, I: FAT METABOLISM.

Looking at obesity without preconceived ideas, one would a.s.sume that the main trend of research should be directed toward an examination of abnormalities of the fat metabolism, since by definition excessive acc.u.mulation of fat is the underlying abnormality. It so happens that this is the area in which the least work has been done.

HILDE BRUCH, The Importance of Overweight, 1957 IN JUNE 1962, EDWIN ASTWOOD OF Tufts University gave the presidential address to the annual meeting of the Endocrinology Society in Chicago. Although Astwood was not known as an obesity researcher, he nonetheless took the opportunity to present what he considered the obvious explanation for its cause. A physician who had spent thirty years studying and treating hormone-related disorders, Astwood had discovered the reproductive hormone luteotropin (now known as luteinizing hormone), and he had created the standard technique for purifying pituitary hormones. He had performed what The New England Journal of Medicine would cal a "bril iant series of experiments" to demonstrate that hyperthyroidism could be control ed with anti-thyroid drugs. By 1976, when Astwood died, three dozen of his former students had become ful professors; eight were department chairmen-"a record perhaps unequaled in medicine," according to his obituary in the journal Endocrinology. He was a man who knew what he was talking about, even when he was speculating, as he was in his 1962 address, ent.i.tled "The Heritage of Corpulence."

Astwood believed that obesity and a disposition to fatten are genetic disorders. If genes determine stature and hair color, the size of our feet, and a "growing list of metabolic derangements," he asked, then "why can't heredity be credited with determining one's shape?" Although it's possible to fatten animals by stuffing them, "and doubtless we could do the same thing to ourselves if we put our minds to it," Astwood did not consider this a cause of overweight. "Not many people try to get into the circus this way," he said-"they become candidates spontaneously." He also considered inactivity to be of dubious importance. "Many of our moderately fat patients sit like b.u.mps on a log," he said, but that could be an effect, not a cause. "It would be interesting to know whether adiposity and inertia go together for some reason common to both. If fatty acid is needed for energy, a deficit could indeed promote lethargy and indolence."

Astwood then described what had been learned over the past thirty years about the hormonal regulation of fat metabolism. "To turn what is eaten into fat, to move it and to burn it requires dozens of enzymes and the processes are strongly influenced by a variety of hormones," he explained. s.e.x hormones, for instance, determine where fat is stored, as evidenced by the differences in fat distribution between men and women. Thyroid hormones, adrenaline, and growth hormone accelerate the release of fatty acids from fat depots, as does a hormone known as glucagon, secreted by the pancreas.

"The reverse process," Astwood said, "the reincorporation of fat into the depots and the conversion of other food to fat, tends to be reduced by these hormones, but to be strongly promoted by insulin." Al of this demonstrated "what a complex role the endocrine system plays in the regulation of fat."

Final y, Astwood speculated on what he considered the simplest possible explanation for obesity, and here he echoed Alfred Pennington, although, if he had read Pennington's work, he neglected to mention it. "Now just suppose that any one of these (or other unlisted) regulatory processes were to go awry," Astwood said.

Suppose that the release of fat or its combustion was somewhat impeded, or that the deposition or synthesis of fat was promoted; what would happen? Lack of food is the cause of hunger and, to most of the body, [fat] is the food; it is easy to imagine that a minor derangement could be responsible for a voracious appet.i.te. It seems likely to me that hunger in the obese might be so ravaging and ravenous that skinny physicians do not understand it.

There is no reason to suppose that only one of these mechanisms ever goes wrong.... There are so many possibilities here that I am wil ing to give odds that obesity is caused by a metabolic defect. I would not want to wager about how many enzymes determine the shape of voluminous pulchritude.

This theory would explain why dieting is so seldom effective and why most fat people are miserable when they fast. It would also take care of our friends, the psychiatrists, who find al kinds of preoccupation with food, which pervades dreams among patients who are obese. Which of us would not be preoccupied with thoughts of food if we were suffering from internal starvation? Hunger is such an awful thing that it is cla.s.sical y cited with pestilence and war as one of our three worst burdens. Add to the physical discomfort the emotional stresses of being fat, the taunts and teasing from the thin, the constant criticism, the accusations of gluttony and lack of "wil power," and the constant guilt feelings, and we have reasons enough for the emotional disturbances which preoccupy the psychiatrists.

For the past century, the conspicuous alternative to the positive-caloric-balance hypothesis has always been, as Pennington, Astwood, and Hilde Bruch suggested, that obesity is caused by a defect in the regulation of fat metabolism. At the risk of repet.i.tion, it is important to say this is, by definition, a disorder of fat acc.u.mulation, not a disorder of overeating. For whatever reason, the release of fat or its combustion is impeded, or the deposition or synthesis of fat is promoted, as Astwood said, and the result is obesity. That in turn wil cause a deficit of calories elsewhere in the body-Astwood's "internal starvation"-and thus a compensatory hunger and sedentary behavior.

This alternative hypothesis differs in virtual y every respect from the positive-caloric-balance/overeating hypothesis. It implies a cause of weight gain and a treatment that stand in contradiction to virtual y everything we have come to believe over the past fifty years. For this reason, it's a good idea to compare the basic propositions of these two competing hypotheses before we continue.

The positive-caloric-balance/overeating hypothesis dictates that the primary defect is in the brain, in the "regulation of ingestive behaviors, particularly at the cognitive level," as it was described by the University of California, Santa Cruz, biologist M.R.C. Greenwood in 1985. This defect purportedly causes us to consume more calories than we expend, and thus induces weight gain. Overeating and sedentary behavior are defined (tautological y) as the causes of obesity. The treatment is to create a caloric deficit by eating less and/or expending more. This hypothesis presupposes that excess calories acc.u.mulate in the body and thus are effectively "pushed" into the fat cel s, which play a pa.s.sive role in the process. And the calories remain bound up as fat only because we never expend sufficient energy to require their use.

Implicit in this hypothesis is the a.s.sumption that energy expenditure and energy intake are independent variables. Because they are independent, one of these variables can be manipulated, consciously or unconsciously, so that the primary result wil be an increase or a reduction in energy stores-i.e., the amount of fat we carry-without the other responding. It is almost impossible to overstate the extent to which this hypothesis now pervades al thinking and research on obesity and weight, and underlies every accepted method of treatment and prevention. As Greenwood observed, "The vast majority of the notoriously unsuccessful weight control programs are predicated on this a.s.sumption."

By contrast, the alternative hypothesis proposes that the primary defect is hormonal and metabolic-in fat storage and/or the burning of fat for fuel (oxidation)-and is in the body, not the brain. This defect causes the excessive acc.u.mulation of calories as fat and compensatory urges to eat more and expend less energy. In this hypothesis, overeating and inactivity (hunger and lethargy) are side effects of this underlying metabolic defect; they are not causes. The hypothesis presupposes that calories are effectively "pul ed" into the fat cel s, rather than pushed, with our fat tissue playing a very active role in this process. It a.s.sumes that energy intake and expenditure are dependent variables: a change in one induces a compensatory change in the other, because the body constantly works to maintain a healthy body composition and a dependable flow of energy to the cel s. Immoderate eating and physical inactivity do not induce obesity, because the body adjusts intake to expenditure and expenditure to intake. Neither eating less nor exercising more addresses the cause of the problem, and that's why these approaches fail. The only effective treatments, according to this hypothesis, would be those that remedy the fundamental regulatory defect.

The only thing missing from this hypothesis as it was original y conceived a century ago, or as reconceived by Pennington and then Bruch and Astwood, was an explanation for the epidemiological observations. In other words, obesity may be caused by a hormonal or metabolic defect determined primarily by genetic inheritance, but the epidemiology tel s us that this defect is triggered by environmental factors. Genetics determines our propensity to put on weight, but those genes (nature) have to be triggered by an agent of diet or lifestyle (nurture) to explain the a.s.sociation of obesity with poverty, the present obesity epidemic, and the emergence of obesity in recently Westernized populations. A change in the environment is also necessary to explain why man alone seems to grow chronical y obese, not other species of animals. "Something has happened in the past twenty, thirty, forty years in the incidence of obesity, and that has to be environmental," as George Cahil has said about the present obesity epidemic.

The likely explanation is the effect of diet on this regulation of fat metabolism and energy balance. Since insulin, as Astwood noted, is the hormone responsible for promoting the incorporation of fat into our adipose tissue and the conversion of carbohydrates into fat, the obvious suspects are refined carbohydrates and easily digestible starches, which have wel -doc.u.mented effects on insulin. This is what Peter Cleave argued, albeit without understanding the underlying hormonal mechanisms at work, and what the geneticist James Neel, father of the thrifty-gene hypothesis, came to believe as wel . And it's the effect of these carbohydrates on insulin that would explain the dietary observations-the futility of calorie restriction, the relative ease of weight loss when carbohydrates are restricted, and perhaps two centuries of anecdotal observations that sweets, starches, bread, and beer are uniquely fattening.

In this hypothesis, obesity is another variation on the theme of insulin dysfunction and diabetes. In Type 1 diabetes, the cause is a lack of insulin. The result is an inability to use glucose for fuel and to retain fat in the fat tissue, leading to internal starvation, as Astwood put it, excessive hunger, and weight loss. In obesity, the cause is an excess of insulin or an inordinate sensitivity to insulin by the fat cel s; the result is an overstock of fuel in the adipose tissue and so, once again, internal starvation. But now the symptoms are weight gain and hunger. In obesity, the weight gain occurs with or without satisfying the hunger; in Type 1 diabetes, the weight loss occurs irrespective of the food consumed.

This alternative hypothesis of obesity ultimately vanished in the 1980s, a casualty of the official consensus that fat was the dietary evil and carbohydrates were the cure. Ironical y, it disappeared just as al the relevant physiological mechanisms had been worked out and a causal path established from the carbohydrates in the diet through insulin to the regulatory enzymes and molecular receptors in the adipose tissue itself.

This alternative hypothesis of obesity const.i.tutes three distinct propositions. First, as I've said, is the basic proposition that obesity is caused by a regulatory defect in fat metabolism, and so a defect in the distribution of energy rather than an imbalance of intake and expenditure. The second is that insulin plays the primary role in this fattening process, and the compensatory behaviors of hunger and lethargy. The third is that carbohydrates, and particularly refined carbohydrates-and perhaps the fructose content as wel , and thus the amount of sugars consumed-are the prime suspects in the chronic elevation of insulin; hence, they are the ultimate cause of common obesity. These latter two propositions-that insulin regulates fat deposition and carbohydrates regulate insulin-have never been controversial, but they've been dismissed as irrelevant to obesity, given the ubiquitous belief that obesity is caused by overeating. That, I wil argue, was a mistake.

Through the beginning of World War I , the notion that a defect in fat metabolism causes obesity was known as the lipophilia hypothesis. "Lipophilia"

means "love of fat." The term was invoked in 1908 by the German internist Gustav von Bergmann to explain why areas of the body differ in their affinity for acc.u.mulating fat-a vital y important phenomenon, one would think, since obesity is a malady of fat acc.u.mulation. Bergmann considered the energy-balance hypothesis of obesity to be nonsensical: "It seems just as il ogical," he wrote, "to say: Child, you shoot up in height because you eat too much or you exercise too little-or you have remained smal because you play sports too much. What the body needs to grow, it always finds, and what it needs to become fat, even if it's ten times as much, the body wil save for itself from the annual balance."

Just as we grow hair in some places and not typical y in others, Bergmann noted, there are places more or less p.r.o.ne to fatten, and some biological factor must regulate that. Some regions of the body are more or less lipophilic than others. This is the kind of observation that can obsess us individual y: Why do we have love handles or a double chin? Why fat ankles, thighs, or b.u.t.tocks? Why is it that some men acc.u.mulate excessive fat in the abdomen (a beer bel y) and yet are lean elsewhere? Why do some women have significant fat deposits in their b.r.e.a.s.t.s and so are considered voluptuous, whereas other women have little or none? These are al variations on the question of which biological factors determine the regional and local distribution of fat.

The example commonly cited in discussions of the nature of this localized lipophilia was that of a twelve-year-old girl in the early 1900s who burned the back of her hand. Her doctors used skin from her abdomen as a graft over the burn. By the time this girl turned thirty, she had grown fat, and the skin that had been transplanted to the back of her hand had grown fat as wel . "A second operation was necessary for the removal of the big fat pads which had developed in the grafted skin," explained the University of Vienna endocrinologist and geneticist Julius Bauer, "exactly as fatty tissue had developed in the skin of the lower part of the abdomen." Some biological factor must regulate this, Bauer believed.

Several clinical conditions also demonstrate this phenomenon of local lipophilia. Benign fat ma.s.ses a few inches in diameter characterize a condition known as lipomatosis, and there are fatty tumors known as lipomas. In both cases, these ma.s.ses of fat appear unaffected by any weight loss by the patients themselves; whatever it is that causes fat to acc.u.mulate in localized ma.s.ses seems to be independent of the fat content of the body itself.

There's also a rare condition known as lipodystrophy, characterized by the inability to store fat in subcutaneous tissue. Those who suffer from it appear abnormal y emaciated; lipodystrophy, too, can be localized, and even progressive. In one case reported in 1913, a ten-year-old girl first lost fat from her face; then, over the next three years, this emaciation gradual y extended down her trunk and arms. "Adiposity of the lower body," as the report described it, began at age fifteen and eventual y became "lower body obesity." By the time she was twenty-four, the patient, who was five foot four and weighed 185 pounds, had effectively al of her body fat localized below her waist.

A case of progressive lipodystrophy with lower-body obesity. If emaciation above the waist is followed by obesity below it, can the quant.i.ty of calories consumed have anything to do with it?

Bergmann and Julius Bauer, the "noted Vienna authority on internal diseases," as the New York Times cal ed him, were the two most prominent proponents of the lipophilia hypothesis, but only Bauer wrote about the hypothesis in English, attempting to influence how obesity would be perceived by physicians in the United States. Bauer's expertise was in the application of genetics and endocrinology to clinical medicine, a field he arguably pioneered in a 1917 monograph ent.i.tled Const.i.tution and Disease. Bauer had taken case histories from 275 obese patients and reported that nearly 75 percent had one or both parents who were also obese. He considered this compel ing evidence that the condition had a genetic component, which in turn implied the existence of genetical y determined hormonal and metabolic factors that would bestow a const.i.tutional disposition to put on excessive fat.

"The genes responsible for obesity," Bauer wrote, "act upon the local tendency of the adipose tissue to acc.u.mulate fat (lipophilia) as wel as upon the endocrine glands and those nervous centers which regulate lipophilia and dominate metabolic functions and the general feelings ruling the intake of food and the expenditure of energy. Only a broader conception such as this can satisfactorily explain the facts."

Lipophilia, as Bauer observed, has nothing to do with energy balance. Where we acc.u.mulate fat is regulated by something other than how much we eat or how little we exercise. Someone who has a double chin, fat ankles, or large b.r.e.a.s.t.s but is lean elsewhere, or the women of African tribes who have the characteristic fat deposits of the b.u.t.tocks known as steatopygia, did not develop these fat deposits by eating too much. Rather, as Bauer wrote, "A local factor must exist which influences the fat deposition in particular regions independently of the general energy balance or imbalance." If a person becomes emaciated above the waist and then, a few years later, obese below it, as in these cases of progressive lipodystrophy, how can the obese half be blamed on overeating? And, if not, why does overeating become the cause when the obesity exists above the waist as wel ? The difference between local lipophilia and generalized obesity, Bauer observed, is one of distribution and not quant.i.ty.

Whatever mechanisms lead some parts of the human body to be more or less lipophilic, Bauer argued, exist to different extents in individuals as wel .

Those of us who seem const.i.tutional y predisposed to fatten simply have adipose tissue that is general y more lipophilic than that of lean individuals; our adipose tissue may be more apt to store fat or less wil ing to give it up when the body needs it. And if our adipose tissue is so predisposed to acc.u.mulate excessive calories as fat, this wil deprive other organs and cel s of nutrients, and wil lead to excessive hunger or lethargy. "Like a malignant tumor or like the fetus, the uterus or the b.r.e.a.s.t.s of a pregnant woman, the abnormal lipophilic tissue seizes on foodstuffs, even in the case of undernutrition," wrote Bauer in 1929. "It maintains its stock, and may increase it independent of the requirements of the organism. A sort of anarchy exists; the adipose tissue lives for itself and does not fit into the precisely regulated management of the whole organism."

In 1941, when Bauer turned to the question of which biological factors might determine or regulate this lipophilia, the understanding of the function of hormones and enzymes in regulating metabolism was stil in its infancy. Bauer based his understanding, as Astwood would twenty years later, largely on clinical observations. Local factors in the adipose tissue itself have to be involved, he thought. How else to explain the lipophilic skin graft? Surely something attached to the skin and the adipose tissue determines how much fat it wil hold. Hormonal factors have to be involved. Male s.e.x hormones seem to inhibit the kind of fat formation typical y seen in women-men who are castrated or whose t.e.s.t.i.c.l.es are destroyed by disease often develop a fat distribution that is more typical y feminine. This type of fat distribution, Bauer wrote, is also present in "obese boys in whom the physiologic production of the testicular hormone is not yet sufficient to prevent the acc.u.mulation of adipose tissue of the female type. The larger the quant.i.ty of fat deposited, the more striking is the resemblance to the female type...." Female s.e.x hormones do not appear to play a major role in determining where fat appears on the body-women who have their ovaries removed put on fat very much like other women. These hormones do, however, seem to affect the quant.i.ty of fat, which would explain the tendency of women to gain weight after menopause. Bauer also suggested that insulin plays a role, by enhancing the deposition of glucose in the adipose tissue, a phenomenon first demonstrated in the 1920s, and by increasing the general affinity of the adipose tissue for acc.u.mulating fat. The nervous system plays a role as wel , Bauer said: researchers had demonstrated that they could increase the amount of fat in fat deposits by severing the nerve fibers that run to the relevant tissue.

Through the 1920s, discussions of the lipophilia hypothesis were confined to the German and Austrian research communities. The relevant research appeared almost exclusively in the German medical literature. Clinicians in the United States began to take notice only in 1933, after Eugene Du Bois convinced Erich Grafe, director of the Clinic of Medicine and Neurology at the University of Wurzburg in Germany, that the American medical community could benefit from an English translation of Grafe's textbook, Metabolic Diseases and Their Treatment. By that time, as Hugo Rony noted, the hypothesis was "more or less ful y accepted" in Europe. "It seems to me this conception deserves attentive consideration," Russel Wilder of the Mayo Clinic wrote in 1938. "The effect after meals of withdrawing from the circulation even a little more fat than usual might wel account both for the delayed sense of satiety and for the frequently abnormal taste for carbohydrate encountered in obese persons.... A slight tendency in this direction would have a profound effect in the course of time."

Knowledge and research on the hypothesis, though, remained largely confined to the German and Austrian research community. When this school of research evaporated with the rise of Hitler and World War I , the notion of lipophilia evaporated with it. Anti-German sentiments in the postwar era may have contributed as wel to the disappearance.*106 In 1955, the year Bergmann died, the primary German textbook on endocrinology and internal medicine included a lengthy discussion of the lipophilia hypothesis in its chapter on obesity, but it was never translated into English. By that time, English had become the international language of science, and the belief that researchers had at least to read German to keep up with the latest advances no longer held sway. (This disappearance of the German and Austrian influence on obesity research is conspicuous in the literature itself. In Rony's Obesity and Leanness, published in 1940, 191 of 587 references are from German publications; in the 1949 manual Obesity..., written by the Mayo Clinic physicians Edward Rynearson and Clifford Gastineau, only thirteen of 422 references are from the German literature, compared with a dozen from Louis Newburgh alone. By the 1970s, when George Bray, John Garrow, and Albert Stunkard wrote and edited the next generation of obesity textbooks and clinical manuals, this German research was treated as ancient history and entirely absent.) Bauer published three articles on lipophilia in English: in 1931 (with Solomon Silver, an endocrinologist at New York's Mount Sinai Hospital), 1940, and 1941, the latter two after he fled to the United States fol owing the German annexation of Austria. By then, however, Bauer was a scholar without an inst.i.tution. He eventual y took a position with the Col ege of Medical Evangelists in Los Angeles, which was affiliated with the Seventh-day Adventist Church, and he became a senior attending physician at Los Angeles County General Hospital. But these were not inst.i.tutions that bestowed credibility.

Meanwhile, Newburgh's seminal paper establishing a perverted appet.i.te as the definitive cause of obesity was published in 1942, and Newburgh rejected the lipophilia hypothesis with the alacrity with which he rejected any explanation that didn't implicate gluttony as the primary cause.

What made the disappearance of the lipophilia hypothesis so remarkable is that it could easily be tested in the laboratory, in animal models. These experiments should have settled the issue. Instead, they generated two distinct interpretations of the same evidence. The scientists who study weight regulation in animals came to conclude that obesity is caused by a defect in the regulation of fat metabolism, just as Bauer would have predicted. Their interpretation influenced Pennington and informed his metabolic-defect hypothesis of obesity. The clinicians, nutritionists, and psychologists concerned with human obesity, however, concluded from this same work that the cause of obesity is overeating, as Newburgh would have predicted, or sedentary behavior, as Mayer would, although they had to ignore considerable contrary evidence to do so. When these latter researchers were confronted by results inconsistent with their beliefs, the matter was reconciled by rejecting the relevance of obesity in animals to obesity in humans. As George Cahil explained in 1978, it was "indubitable" that animals had evolved a regulatory system of fat metabolism and energy balance that had to be crippled or dysregulated before these animals could gain an unhealthy amount of weight. Such a system "is also probably present in man," Cahil acknowledged, "but markedly suppressed by his intel ectual processes."

The value of these animal models of obesity, ideal y, is to see if they can refute or exclude one of the two competing hypotheses. For instance, these models can be used to test the hypothesis that obesity is caused by eating too many calories. We have only to ask a simple question: when laboratory animals grow obese, do they require more food to do so than lean animals would normal y eat? If they grow excessively fat even when their calorie intake is restricted, then that refutes the notion that obesity (at least in these animals) is caused by consuming too many calories. The restriction controls for overeating. The explanation we'd be left with is that they're redistributing the calories they do eat. The fundamental defect would seem to be in the body, not in the brain. Overeating would be a side effect of the fattening process. And this might wel apply to humans.

In 1934, the Harvard physiologist Milton Lee reported that when rats had their pituitary glands removed and were injected with growth hormone (a product of the pituitary gland), they gained "significantly more weight" than their untreated littermates, even when eating identical quant.i.ties of food. The implication was that the weight gain was caused by the effect of growth hormone, independent of calorie consumption. The treated rats grew heavier, larger, and more muscular, Lee reported; the rats found the calories to do so by consuming what fat they had and by expending less energy in physical activity.

As for genetical y obese mice, it is invariably the case, as Jean Mayer discovered in the early 1950s, that these animals wil fatten excessively regardless of how much they eat. Their obesity is not dependent on the number of calories they consume, although al owing them to consume excessive calories may speed up the fattening process. "These mice wil make fat out of their food under the most unlikely circ.u.mstances, even when half starved,"

Mayer had reported. And if starved sufficiently, these animals can be reduced to the same weight as lean mice, but they'l stil be fatter. They wil consume the protein in their muscles and organs rather than surrender the fat in their adipose tissue. Indeed, when these fat mice are starved, they do not become lean mice; rather, as Wil iam Sheldon might have put it, they become emaciated versions of fat mice. Francis Benedict reported this in 1936, when he fasted a strain of obese mice. They lost 60 percent of their body fat before they died of starvation, but stil had five times as much body fat as lean mice that were al owed to eat as much as they desired.

In 1981, M.R.C. Greenwood reported that if she restricted the diet of an obese strain of rats known as Zucker rats (or fa/fa rats in the genetic terminology), and did it from birth onward, these rats would actual y grow fatter by adulthood than their littermates who were al owed to eat to their hearts'

content. Clearly, the number of calories these rats consumed over the course of their life was not the critical factor in their obesity (unless we are prepared to argue that eating fewer calories induces greater obesity). What's more, as Greenwood reported, these semi-starved Zucker rats had 50 percent less muscle ma.s.s than genetical y lean rats, and 30 percent less muscle ma.s.s than the Zucker rats that ate as much as they wanted. They, too, were sacrificing their muscles and organs to make fat.

The most dramatic of these animal obesity models is known as hypothalamic obesity, and it served as the experimental obesity of choice for researchers from the 1930s onward. It also became another example of the propensity to attribute the cause of obesity to overeating even when the evidence argued otherwise. The interpretation of these experiments became one of a half-dozen critical turning points in obesity research, a point at which the individuals involved in this research chose to accept an interpretation of the evidence that fit their preconceptions rather than the evidence itself and, by so doing, further biased the perception of everything that came afterward.

The hypothalamus sits directly above the pituitary gland, at the base of the brain. It is hard-wired by the nervous system to the endocrine organs, which al ows it to regulate the secretion of hormones and thus al physiological functions that themselves are regulated hormonal y. Tumors in the hypothalamus have been linked to morbid obesity since 1840, when a German physician discovered such a tumor in a fifty-seven-year-old woman who had become obese in a single year. The manifestation of these tumors can be both grotesque and striking. Stylianos Nicolaidis of the Col ege de France recounted the story of being driven to study obesity as a young physician in 1961, when a forty-eight-year-old woman was referred to his hospital for tests after gaining thirty pounds in a single month. He never got a chance to do the tests, however, because she literal y choked to death over the hospital dinner.

"She was eating so fast that she swal owed down the wrong pathway and suffocated," Nicolaidis said. "When I performed the autopsy, I cut the brain in sections and found two very, very tiny metastatic tumors in the hypothalamus."

Because of the proximity of the hypothalamus to the pituitary gland-the two together are known as the hypothalamic-pituitary axis-a question that haunted this research in its early years was which of these two regions played the dominant role in weight regulation. Researchers had managed to induce extreme corpulence in rats, mice, monkeys, chickens, dogs, and cats by puncturing their brains in this pituitary-hypothalamic region. The controversy was definitively resolved in 1939 by Stephen Ranson, who was then director of the Inst.i.tute of Neurology at Northwestern University and perhaps the leading authority on the neuroanatomy of the brain, and his graduate student Albert Hetherington. The two demonstrated that it was, indeed, the hypothalamus, not the pituitary, that regulated adiposity in the rats; lesions in a region cal ed the ventromedial hypothalamus (VMH) would induce corpulence even in those animals that had their pituitary glands removed.

John Brobeck, a Yale researcher who had done his Ph.D. work with Ranson, was the first to propose a mechanistic explanation for the phenomenon.

Brobeck had replicated Hetherington's experiments in his Yale laboratory and then read Newburgh's articles arguing a perverted appet.i.te as the cause of obesity. Now Brobeck perceived his research as providing experimental confirmation in laboratory animals of Newburgh's hypothesis. The hypothalamic lesions, Brobeck argued, served to damage what amounted to a center of hunger regulation in the hypothalamus. The lesions made the rats hungry, and so the rats over ate and grew obese. He would later write about his astonishment at how voraciously these surgical y lesioned rats ate. Because obesity in most of his rats (but not al ) appeared only after the rats began eating ravenously, Brobeck reasoned incorrectly that "the laws of thermodynamics suggest that...food intake determines weight gain." Brobeck coined the term hyperphagia to describe the extraordinary hunger manifested by these animals, and hyperphagia would become the accepted technical term for a perverted appet.i.te that leads to obesity.

The alternative hypothesis, that the obesity in these animals was a disorder of fat metabolism, came from Ranson and Hetherington. Whereas Brobeck interpreted his argument in the context of Newburgh's beliefs, Ranson interpreted his from the context of thirty years of brain research. Some of the lesioned animals ate voraciously, Ranson noted, which might have been due to hunger alone, but others ate normal y and stil grew obese. (Several of Brobeck's rats also grew obese while eating no more than lean rats did, but Brobeck dismissed their relevance to his overeating hypothesis on the basis that some other effect "related to the feeding habits" of these animals might be responsible.*107 ) Ranson also noted "the tremendously decreased activity of these obese rats."

Ranson argued that Brobeck's hyperphagia hypothesis missed the bigger picture. "Insistence upon the primary importance" of either overeating or inactivity "would in al probability represent oversimplification of the problem, and this for at least two reasons," Ranson wrote.

In the first place, the two factors are complementary in their effect upon body weight. Both would tend to increase it. A very sedentary life, combined with a high caloric intake would seem to be an ideal combination for building up a thick panniculus adiposus [layer of fat]. Secondly, these two factors may be only symptomatic, and not fundamental. It is not difficult to imagine, for example, a condition of hidden cel ular semistarvation caused by a lack of easily utilizable energy-producing material, which would soon tend to force the body either to increase its general food intake or to cut down its energy expenditure, or both.

Damage to the ventromedial hypothalamus caused a defect that directed nutrients away from the tissues and organs where they were needed for fuel and into the fat tissue, Ranson argued. It made the animals more lipophilic. This reduced the supply of fuel to the other cel s of the body and so caused "hidden cel ular semistarvation," or what Astwood later cal ed "internal starvation." That in turn led to the voracious hunger-hyperphagia-that Brobeck had considered the primary defect. As long as nutrients continued to be channeled into fat and away from the cel s of other tissues and organs, the animals would remain hungry. If they couldn't satisfy this hunger by eating more-when their food supply was restricted, for instance-they would respond by expending less energy.

Brobeck's scenario-that the primary role of the ventromedial hypothalamus is to regulate food intake-would survive into the modern era of obesity research, but Ranson's insights were far more profound. Only Ranson could explain al the observations, and he did so based on an ongoing revolution in the understanding of the brain, and particularly the role of the hypothalamus. This was Ranson's expertise. The hypothalamus is the "concertmaster" of homeostasis, as Time wrote in 1940, reporting on a two-day conference dedicated to discussing the "orchestral effects" of the hypothalamus and paying tribute to Ranson, who had done much of the research.

Just before Ranson and Hetherington took to inducing corpulence in rats, Ranson had studied the hypothalamic regulation of fluid balance. This influenced his interpretation of the later research. Our bodies conserve fluids and water, just as they do fuel. Even our saliva and gastric juices are reabsorbed and reused. Just as damage to the ventromedial hypothalamus can induce obesity, damage elsewhere in the hypothalamus can induce diabetes insipidus. The symptoms of this rare condition are excessive urination and a tremendous and constant thirst. These symptoms appear in uncontrol ed diabetes mel itus as wel , but in diabetes insipidus, insulin secretion is not impaired, so blood sugar and fat metabolism remain regulated and no sugar appears in the urine.

The similarities between diabetes mel itus and diabetes insipidus had led Ranson and other physiologists to conclude that the homeostatic regulation of fluid balance was akin to that of blood sugar. That both diabetes insipidus and obesity could be caused by hypothalamic lesions informed Ranson's interpretation of the underlying disorders. In the case of diabetes insipidus, the lesions inhibit the ability of the kidneys to conserve water by suppressing the secretion of an anti-diuretic hormone that normal y works in the healthy animal to inhibit urination. This failure in the homeostatic regulation of fluids causes the kidney to excrete too much water, and that leads to a compensatory thirst to replace the fluid that's lost.

The same cause and effect are evident in Type 1 diabetes mel itus. The inability of diabetics to utilize the food they eat, and particularly the carbohydrates, results in a state of starvation and extreme hunger. Diabetics also urinate more, because the body gets rid of the sugar that acc.u.mulates in the bloodstream by al owing it to overflow into the urine, and this is why diabetics wil be abnormal y thirsty as wel .

Lesions to the ventromedial hypothalamus can induce tremendous hunger and cause obesity, but now Ranson considered it naive to a.s.sume that the hunger caused the obesity. Rather, the hunger was another consequence of a breakdown in homeostasis-the loss of calories into the fat tissue. This is why the animals get fat even when they aren't al owed to satisfy their appet.i.te. And this is why these lesioned animals are always hungry, at least until they put on enough fat so that the excess counteracts the damage caused by the hypothalamic lesion. Sedentary behavior is another way their bodies compensate for the loss of calories to the fat tissue. As Ranson perceived it, both hunger and physical inactivity are manifestations of the internal starvation of the tissues. These are the ways that the homeostatic regulation of energy balance compensate for the loss of nutrients into the fat tissue.

It's hard to avoid the suggestion that one major factor in how this research played out was the preconceptions of the investigators and their urge to make a unique contribution to the science. Ranson had suggested that al the more obvious manifestations of hypothalamic lesions were the consequences of a primary defect in the homeostatic control of energy balance that made the animals acc.u.mulate excessive fat in the adipose tissue. Brobeck and the other investigators who took to studying hypothalamic obesity would conclude that whatever phenomenon they happened to find most rema