MD Conf, May 1961: Margaret Albrink, Yale: Elevated Triglycerides (TG) - not cholesterol - were asso w/ increased risk of heart disease. Low-fat, high-carb diets raised TG. Albrink: Ancel Keys' supporters attacked me, "They were so angry," & the science bullies prevailed.

The occasional occurrence of lactescent or milky serum in patients with certain diseases caused interest and speculation at least as long ago as 1799 when Mariet described turbid sera in some patients with diabetic acidosis (1). The lightscattering fat particles or chylomicrons causing lactescence are present in modest numbers after a fat meal but become scarce in normal postabsorptive sera. In certain pathological states, however, chylomicrons occur in excessive numbers, giving rise to a characteristic milky appearance of the sera. In a previous study, lactescence was reported to be directly proportional to the total triglyceride concentration in serum (2). Turbidity was invariably present when total triglyceride fatty acid concentration exceeded 20 mEq per L. As triglyceride concentration increased further, a progressively greater proportion of cholesterol and phospholipids also occurred in the particulate lipid fraction which could be readily removed by flotation of unaltered serum at moderate speeds in the ultracentrifuge. Serum lipids are now known to exist in a spectrum of lipoproteins of varying density, from very low density particulate chylomicrons composed chiefly of triglycerides, through various classes of low density lipoproteins relatively rich in cholesterol, to high density lipoproteins in which phospholipids are prominent (3). Interest in various classes of low density lipoproteins has been stimulated because of their possible role in the etiology of coronary arterial disease (4). Studies from this laboratory (5-7) have shown serum triglyceride concentration to be intimately associated with this disease. Antonis and Bersohn have also found elevation of serum triglycerides in ischemic heart disease (8). From the known composition of very low density lipoproteins, it might be inferred that their presence in abnormally high concentrations would be associated with increased concentration of total serum triglycerides. The present study was undertaken to learn whether total triglyceride concentration might determine not only the fraction of lipids present in chylomicrons but also the partition of lipids among the various low density lipoproteins. At the same time the lipoprotein composition of the relatively clear subnatant fluid after removal of the chylomicron "cream" layer of lactescent sera could be determined. This clear fraction was previously analyzed in toto (2), but no analysis of lipoproteins was made.

* Supported (in part) by Grant H-3498(C2) from the National Heart Institute, Bethesda, Md., and by a grant from The James Hudson Brown Memorial Fund. This work was done during tenure of an established investigatorship of the American Heart Association.

The Heritage of Corpulence

E. B. ASTWOOD, M.D.

Endocrinology, Volume 71, Issue 2, 1 August 1962, Pages 337–341, https://doi.org/10.1210/endo-71-2-337

OBESITY is a disorder which, like venereal disease, is blamed upon the patient. The finding that treatment doesn’t work is ascribed to lack of fortitude. Corpulence in America is regarded along with narcotic addiction as something wicked, and I shall not be surprised if soon we have a prohibition against it in the name of national security. The condition is referred to in disparaging terms, including the most impolite references to the appetite. Appetite is held to be the cause, but I say it is hunger. I wish to propose that obesity is an inherited disorder and due to a genetically determined defect in an enzyme; in other words, that people who are fat are born fat, and nothing much can be done about it. I would like further to propose that the more serious of the consequences of being fat are not due to the corpulence but to the inherited defects; if this be so and we like food, we might as well eat up and be happy.

Gary Taubes. The Case for Keto: Rethinking Weight Control and the Science and Practice of Low-Carb/High-Fat Eating (Kindle Locations 345-351). Knopf. Kindle Edition. 

A brief lesson in the history of obesity research 

On June 22, 1962, a Tufts University Medical School professor named Edwin Astwood tried and failed to correct how we think about the cause of obesity. We have been living with that failure ever since. Astwood was presenting a counterargument to what had become since the end of the Second World War the dominant thinking among medical authorities and researchers on why we get fat. Astwood called this thinking “the conviction of the primacy of gluttony,” by which he meant the unshakable belief that virtually all cases of obesity, child or adult, mild or extreme, are caused ultimately by the overconsumption of calories; that is, people get fat because they eat too much. Astwood considered this belief system—for that’s what it is—to be almost willfully naïve and perhaps the primary reason so little progress had been made in understanding obesity, let alone preventing and treating it. It is also the reason those who have the misfortune to suffer from obesity are held responsible for their condition. “Obesity is a disorder,” he said in opening his presentation, “which, like venereal disease, is blamed upon the patient,” the direct consequence of their failing. Astwood was an endocrinologist; his medical expertise and the subject of his research were hormones and hormone-related disorders. The venue for his talk was the forty-fourth annual meeting of the Endocrine Society. Astwood was its president that year, and his talk, titled “The Heritage of Corpulence,” was his presidential address. Astwood was also a member of the prestigious National Academy of Sciences. According to his NAS biographical essay, his peers considered him “a brilliant scientist” who had contributed more to our understanding of thyroid hormones and how they work than anyone alive. (He won the Lasker Award, considered one step below the Nobel Prize, for the thyroid work.) Of the young men and women who learned to do their medical research in Astwood’s Boston-area laboratory, thirty-five would go on to become full professors by the time Astwood passed away in 1976. He was “not only driven by an insatiable curiosity,” the NAS biography says of Astwood, “but by a curiosity that sought answers with willful determination.” Although Astwood was known among his friends and colleagues for having little interest in food or eating—he considered meals only “a necessary intervention in the day’s activities solely for the purpose of bodily nutrition”—much of his laboratory work in the latter years of his research career was dedicated to understanding obesity, specifically the influence of hormones on fat accumulation and the use of fat to fuel our metabolism. In the small world of 1960s-era obesity research, Astwood was something of a throwback to the pre–World War II years. While he had a profound understanding of the research literature on obesity and was a serious if not indeed brilliant scientist, he had been a physician also who treated patients in his clinic. In this he was like the physician researchers in Germany and Austria before the war who had dominated thinking on obesity and had also come to their conclusions on the nature of the obese condition by observing it closely in their human patients, taking their histories and coming to understand what they were going through and living with. Doctors would do that with any other disorder—why not do it with such a seemingly intractable disorder as obesity? Many of the most influential of those prewar European authorities had become convinced that obesity must be the result of a hormonal or metabolic dysfunction, not caused by overeating, a concept that they recognized as circular logic. (“To attribute obesity to ‘overeating,’ ” the Harvard nutritionist Jean Mayer had aptly commented eight years before Astwood’s presentation, “is as meaningful as to account for alcoholism by ascribing it to ‘overdrinking.’ ” It’s saying the same thing in two different ways, at best describing the process, not explaining why it’s happening.) Rather, it’s somehow programmed into the very biology of the fat person, a disorder of fat accumulation and fat metabolism, these German and Austrian clinical researchers concluded. They believed, as Astwood came to believe, that obesity is neither a behavioral issue nor an eating disorder, not the result of how much we choose to eat consciously or unconsciously. That German-Austrian research community had evaporated, beginning in 1933 with the rise of the Nazi Party. By the time the war was over, European thinking on obesity, grounded in decades of clinical experience and observation, had evaporated with it. The very lingua franca of medicine shifted from German prewar to English postwar. German-language medical literature was considered of little interest, even unreadable by the new generation of young American physicians and nutritionists, who repopulated the field and found the conventional, simplistic thinking on obesity all too easy to believe. With just a few exceptions, these newly minted experts weren’t burdened with actually having to help obese patients achieve a relatively healthy weight for life. They were guided instead by a theory—technically, a hypothesis—that they believed in unconditionally. They believed the truth was obvious, which is always an impediment to making progress in any scientific endeavor. Their truth was the subject of Astwood’s presentation: a “conviction in the primacy of gluttony,” the notion that obesity is almost invariably caused by eating too much, consuming more calories than we expend, and so is ultimately a behavioral or eating disorder. That conviction implied that the only meaningful difference between lean people and people who struggled with obesity is that the lean can control their food intake and hence their appetites—consume only as many calories as they expend—while people with obesity could not, or at least not once they started to get fat. The idea that the fat tissue of those who become obese might have some physiological drive to accumulate fat that the tissues of lean people don’t, some subtle hormonal disruption, was dismissed by the authorities as nothing more than “lame excuses” (quoting the Mayo Clinic’s leading 1960s-era obesity expert) for fat people not to do what came naturally to lean people—eat in moderation. If anything, the supposedly learned postwar authorities came to consider obesity the result of a psychological defect, not a physiological one. They were not shy in stating that people got fat primarily because of “unresolved emotional conflicts” or because they had “turned toward food to relieve some of the nervous tensions of life.” These authorities counseled those with obesity to embrace a lifetime of walking away from their meals still hungry, of semistarvating themselves, ideally after consulting a psychiatrist first. This is the thinking that Astwood hoped to overturn with his presidential address. He enumerated with elegance and occasional humor the reasons why obesity was surely a genetic disorder, which implied that it almost assuredly had to be a hormonal or endocrinological one. Yes, he acknowledged, this was the implication every time someone afflicted with obesity made a comment along the lines of “everything I eat turns to fat.” It was anything but a lame excuse, according to Astwood; it was a reality. It was true, he said, not just for the kind of extreme obesity that he occasionally saw in patients in his practice, but for “the common or garden varieties … the kind that we see every day.” One thing that seemed to mystify Astwood was that there was nothing subtle about the evidence arguing for a genetic, and so hormonal, influence in obesity and fat accumulation. Obesity ran in families, Astwood said, as the authorities all agreed, but not because fat parents overfed their children. It did so because of a strong genetic component. Identical twins don’t just have the same faces; they have identical body types. If one twin is obese, so almost assuredly will the other one be. Even the distribution of obesity in families suggested genetics were involved. Astwood told his audience about one of his patients who was twenty-four years old, five feet four inches tall, and weighed 457 pounds. This young man had seven siblings, three of whom also suffered from extreme obesity: “His brothers, aged 10, 15, and 21, weighed respectively 275, 380, and 340 pounds.” The four other siblings “were of normal proportions.”

This “looked more like the work of genes,” said Astwood, not the “product of a groaning family board,” an antiquated phrase that refers to a dining table overloaded with food. We know that genes determine stature and hair color, said Astwood, and they determine the size of our feet and a “growing list of metabolic derangements, so why can’t heredity be credited with determining one’s shape?” If we had doubts that this was the case, we only had to look at animals. “Consider the pig,” he said: “His corpulence and gluttony resulted from man’s artificial selection; selective breeding provided us with this hulk with his hoggish ways, and no one will convince me that his gourmandizing is provoked by parental oversolicitude.” A reasonable picture of how those genes might be expressing themselves, Astwood explained, had been worked out since the 1930s. A series of laboratory researchers had generated an enormous amount of information about how our bodies regulate the fat we store and the fat we use for energy. “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. Sex hormones clearly play a role in where fat is stored. Men and women, after all, tend to fatten differently: men above the waist, women below it. Thyroid hormones, adrenaline, and growth hormones all play a role in releasing fat from its depots, as does a hormone known as glucagon, secreted by the pancreas. “The reverse process,” Astwood said, “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.” All this demonstrated “what a complex role the endocrine system plays in the regulation of fat.” An important clue to what might be happening, he added, is the fact that the numerous chronic disorders associated with obesity—“particularly those involving the arteries”—resemble arteries”—resemble those that come with diabetes so closely, it implies “a common defect in the two conditions.” Now imagine, Astwood suggested to his audience, what would happen if just one of these mechanisms went awry, impeding the release of fat from fat cells or promoting its storage. It was all too easy to imagine a slow, gradual accumulation of fat that could lead to extreme obesity if continued over years and decades. As the fat inexorably accumulated, a likely result would be what Astwood described as “internal starvation,” as the body hoarded calories in fat cells that it would otherwise need for fuel, while simultaneously increasing the weight that had to be carried around, day in and day out, requiring the expenditure of more and more energy to move and fuel that bulk. In other words, the same subtle hormonal disruption that could cause fat to accumulate to excess would also make a fat person hungry while it was happening. This would be exacerbated by the advice given to the fat person

 from all sides: Eat less, exercise more. Starve yourself, if necessary. If the proposed treatment for a fat accumulation problem that itself caused internal starvation—that is, hunger—was to starve even more, we can imagine all too easily why it would fail, if not in the short run, certainly eventually. “This theory,” Astwood said, “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 all 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? 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 ‘will power,’ and the constant guilt feelings, and we have reasons enough for the emotional disturbances which preoccupy the psychiatrists.”

In 1963, Sir Stanley Davidson and Dr. Reginald Passmore wrote in the textbook Human Nutrition and Dietetics, the definitive source of nutritional wisdom for a generation of British medical practitioners, that “the intake of foods rich in carbohydrate should be drastically reduced since over-indulgence in such foods is the most common cause of obesity.” They didn’t understand yet why physiologically this was the case—it was just then being worked out in laboratories—but the fact seemed undeniable. That same year Passmore coauthored an article in the British Journal of Nutrition that began with the declaration: “Every woman knows that carbohydrate is fattening: this is a piece of common knowledge, which few nutritionists would dispute.”

Gary Taubes. The Case for Keto: Rethinking Weight Control and the Science and Practice of Low-Carb/High-Fat Eating (Kindle Locations 479-484). Knopf. Kindle Edition. 

We have to live with two realities: that fat cells are exquisitely sensitive to insulin, and that this is a threshold effect. The two together have profound consequences for how different foods will affect not just weight but appetites—our hunger and the foods we crave. Those consequences, in turn, speak directly to the question of whether a drastic, supposedly “unbalanced” diet that removes an entire food category may be necessary. 

As I suggested earlier, think of this fat-cell, insulin-sensitivity threshold as a switch that’s either on or off. When it’s on, above the threshold, your fat cells are storing fat; the rest of your body is fueling itself on carbohydrates. When the switch is off, when insulin is below the threshold, your fat cells are mobilizing fat; you’re burning fat for fuel; you’re getting leaner or at least not getting fatter. 

If you’re insulin resistant, these dynamics still hold true. But now you have more insulin circulating through your body than is ideal, and the amount of insulin will remain high for longer than ideal. This means you’ll spend that much more time above the threshold, with the switch on, storing fat. It’s likely this will be the case even long after you’ve eaten, after blood sugar levels have returned to normal and you might not have carbohydrates (glucose) readily available to burn. Your cells will be primed to burn carbohydrates—that’s what the insulin is telling them to do—but blood sugar will already be in the low range of healthy. And while the insulin is pushing the mitochondria in your cells to burn carbs, it’s actually pushing those same cells, through the same signaling pathway (as it’s technically known), not to burn fat and not to burn protein. Elsewhere, the insulin is causing the fat cells to hold on to fat and the lean cells to hold on to their protein. 

In short, when insulin is above the threshold, when the switch is on, your body is running on carbohydrates. They are your fuel. So it makes sense that you’ll hunger for carbohydrate-rich foods. This is likely why you may not be able to imagine life worth living without your morning bagel, or your sweets, or your pasta. (For me, it was fresh-squeezed orange juice at breakfast.) Ultimately, as we’ll discuss, these carbohydrate-rich foods become your favorites. A likely reason is that your brain has learned to respond to these foods by rewarding you with pleasure when you eat them. 

When insulin is below the threshold, when the switch is in the off position, your body is burning the fat you’ve stored. It will continue to burn fat as long as you remain below the threshold. Now your body has access to plenty of fuel. Twenty pounds of body fat provides fuel for well over two months. Even a lean marathoner like Olympic gold medalist Eliud Kipchoge, who in October 2019 ran the first sub-2-hour marathon ever, at 123 pounds, has enough fat stored to fuel his body on his fat stores alone for a week. Your body is being constantly fed on this supply of stored fat, so it’s satisfied. Your appetite will be blunted. The brain has no reason to think more food is necessary. Your body has no need to ingest more food, hence there’s little or no urge to do so. You experience weight loss—the burning of your stored body fat—without hunger.

Above the insulin threshold, you have to replenish frequently. You have a limited supply of carbohydrates, and insulin works to keep the carbohydrates you’ve stored (a maximum of about two thousand calories of glycogen) locked away as well. As your blood sugar drops, you’ll get hungry. And because carbohydrates are your fuel above the threshold, you’ll hunger for carbohydrate-rich foods. 

These dynamics almost assuredly explain the urge to eat between meals, despite how many days’ or months’ worth of calories we may have stashed away in our fat tissue. It’s why we feel hungry when we should, ideally, be happily living off our own fat. It’s why we don’t feel hungry when insulin is low and we can burn that fat. Another way to think of this is that when you’re restricting carbohydrates and insulin is below the threshold, you’re not starving your body to get fat out of your fat tissue; you’re not at war with your body to lose weight and burn fat, you’re working with it, you’re allowing your body to do what it will now do naturally. 

The relative absence of hunger on these LCHF/ketogenic diets is as consistent an observation as can be found in nutrition science. Remove the carbohydrates and replace the calories with fat, and the stimulus for hunger (and for the obsessive thinking about food that goes with calorie-restricted diets) is lessened significantly. Even those physicians and researchers in the 1960s who were convinced that eating less and semistarvation were the only way to lose weight would often comment in their papers that this didn’t mean it wasn’t easier to do so on an LCHF/ketogenic diet. As one researcher said in the most famous of the papers from this era, “The satiety value of such diets is superior to diets high in carbohydrate and low in fat.” If diets without carbohydrates are more satiating than diets with them, that’s just another way of saying that diets with carbohydrates make us hungrier than diets without. The reason they should is clear. 

My favorite example of a physician researcher designing a diet based on this awareness of insulin’s role in fat accumulation and the implications for our appetites is James Sidbury, Jr. In the mid-1970s, Sidbury was a pediatrician at Duke University and one of the world’s leading authorities on diseases of carbohydrate metabolism—in particular, rare disorders of carbohydrate (glycogen) storage, one of which is named after him. For this reason, it may have been natural for him to think of obesity as a fat-storage disease. Because he was a pediatrician who studied metabolism, the physicians in the Duke medical system would send him their (then) rare cases of children with obesity, hoping he could help them. 

Sidbury knew that carbohydrates stimulate insulin and insulin facilitates fat formation and traps fat in fat tissues. He also knew, as he noted in a 1975 book chapter on this work, that kids with obesity crave carbohydrate-rich foods—“crackers, potato chips, french fries, cookies, soft drinks, and the like.” Restrict the carbohydrates and feed these kids only fat and protein, he reasoned, and their insulin would come down, and their fat metabolism would work as it does in lean kids. These children would burn their stored fat and lose weight without obsessive hunger and without constantly grazing on carbohydrates. He instructed parents to feed their children with obesity only 300 to 700 calories a day, made up of virtually all protein and fat. The kids lost weight as if by magic. “Many parents do not believe their child can be satisfied with so little food,” Sidbury wrote. “Their attitude changes completely,” however, when they see the results and, eventually, the “obvious change in the amount of food which satisfies the children.”

Gary Taubes. The Case for Keto: Rethinking Weight Control and the Science and Practice of Low-Carb/High-Fat Eating (Kindle Locations 1709-1710). Knopf. Kindle Edition.

Another example of this thinking also dates to the 1970s and comes from George Blackburn and Bruce Bistrian at Harvard Medical School. Bistrian and Blackburn developed what they called a “protein-sparing modified fast” to treat patients with obesity: 650 to 800 calories a day of nothing but lean fish, meat, and fowl. It had effectively no carbohydrates, making it a ketogenic diet, albeit a very low-calorie version. Bistrian and Blackburn prescribed the diet to thousands of patients, as Bistrian told me when I interviewed him in January 2003, and half of them lost at least forty pounds. In one 1985 publication reporting on almost seven hundred patients, the average weight loss was nearly fifty pounds in four months. The patients felt little hunger while on the diet. “They loved it,” Bistrian said. “It was an extraordinarily safe way to get large amounts of weight loss.” 

But one point that Bistrian made in our interview was critically important: If he and Blackburn had tried to balance these diets by adding, say, vegetables, whole grains, and legumes, meaning the patients would obviously be eating more calories and more carbohydrates, the diets would have failed. You’d think more calories would mean less hunger, but it would cause more. Bistrian was the first one who pointed out to me the different responses between Ancel Keys’s starvation experiment subjects—eating 1,600 calories a day and, well, starving—and the experiences of the patients he and Blackburn were working with, or Sidbury was treating, who were perfectly content consuming far fewer than 1,000 calories a day. “The proof of the pudding,” he said to me, “was in the eating.” 

Alas, Bistrian and Blackburn’s thinking, and Sidbury’s, was flawed. They were telling their patients—Sidbury’s were kids; Bistrian’s and Blackburn’s were adults—to severely restrict calories because that was what they still thought was necessary. Despite everything they knew about insulin and fat metabolism, they too couldn’t escape the trap of energy balance thinking. Because Bistrian and Blackburn were feeding their patients so few calories, this created a problem that appeared to the two researchers to be insurmountable. It had to do with maintaining the weight loss. 

For a diet to work for a lifetime, it has to be maintained for a lifetime, and for a diet to work—to get us lean, or relatively so—it has to remove or limit the cause of why we get fat. If the cause is too many calories, then a lifetime of calorie restriction at some level is necessary. If the cause is elevated insulin levels and too many carbs, then a diet that maintains insulin at a low threshold for a lifetime—carb-restricted, high in fat—is necessary. There seems no getting around it. Bistrian and Blackburn were perfectly aware of this problem. They knew that if their patients went back to eating the way they did, they’d gain the weight back. If they ate more calories but still worked to keep insulin low, they’d be restricting carbohydrates and replacing them with fat. They’d be eating what Bistrian and Blackburn thought of as an Atkins diet. And unless you believed that eating all that fat was benign—as many physicians finally do today—that was unacceptable. Bistrian said this was a primary reason he and Blackburn left the field. They had two choices, they thought: Tell their formerly fat patients to take appetite-suppressing drugs so they could spend a lifetime battling hunger on a calorie-restricted but balanced diet, or tell them to eat the Atkins/ketogenic way, to satiety of fat and protein. They considered neither to be a safe option. “All that saturated fat,” Bistrian said to me. He and Blackburn turned their attention to other things. We don’t have that luxury.

Gary Taubes. The Case for Keto: Rethinking Weight Control and the Science and Practice of Low-Carb/High-Fat Eating (Kindle Locations 1733-1734). Knopf. Kindle Edition.