Good Calories, Bad Calories

more common in women than in men. In men, the activity of LPL is higher in the fat tissue of the abdominal region than in the fat tissue below the waist, which would explain why the typical male obesity takes the form of the beer belly. Women have more adipose-tissue LPL activity in the hips and buttocks than in the abdominal region, although after menopause the LPL activity in their abdominal region catches up to that of men.

These various fat deposits are also regulated over time by the changing flux of sex hormones, so LPL can be considered the point at which insulin and sex hormones interact to determine how and when we fatten. The male sex hormone testosterone, for instance, suppresses LPL activity in the abdominal fat, but has little or no effect on the LPL in the fat of the hips and buttocks. Increasing fat accumulation in the abdomen as men age may therefore be a product of both increasing insulin and decreasing testosterone. The female sex hormone progesterone increases the activity of LPL, particularly in the hips and buttocks, but estrogen, another female sex hormone, decreases LPL activity.^*120 It’s the decrease in estrogen secretion during menopause—and so the increase in LPL activity—that may explain why women frequently gain weight as they pass through menopause. The effect of decreasing estrogen secretion on LPL activity would also explain why women typically fatten after the removal of the uterus in a hysterectomy. The change in hormonal regulation of LPL also explains how and why fat deposition changes during pregnancy and, after birth, with nursing.

In 1981, M. R. C. Greenwood, who was a student of Jules Hirsch and was then at Vassar College, proposed what she called the “gatekeeper hypothesis” of obesity, based on the hormonal regulation of LPL. “Conditions which favor increases in adipose tissue LPL,” Greenwood wrote, “result in increased fat accumulation and, when food intake is constant, lead to alterations in body composition.” Greenwood proposed the hypothesis based on her studies of the obese strain of rats known as Zucker rats, in which LPL activity in the fat tissue is elevated in the womb—apparently the effect of fetal hyperinsulinemia, though it then persists well into adulthood. As a result, Zucker rats grow monstrously obese. But they will actually lay down more fat, Greenwood reported, if they’re kept to a strict diet than they will if they’re allowed to eat freely to satisfy their hunger. The less they’re allowed to eat, however, the smaller their muscles will be; their brains and kidneys will also be “significantly reduced” in size. “In order to develop this obese body composition in the face of calorie restriction,” Greenwood wrote, “several developing organ systems in the obese rats were compromised.”

Since Greenwood proposed this LPL gatekeeper hypothesis, researchers have reported that obese humans have increased LPL activity in their fat tissue. They’ve also reported that LPL activity in fat tissue increases with weight loss on a calorie-restricted diet and it decreases in muscle tissue; both reactions will work to maintain fat in the fat tissue, regardless of any negative energy balance that may be induced by the semi-starvation diet. During exercise, LPL activity increases in muscle tissue, enhancing the absorption of fatty acids into the muscles to be burned as fuel. But when the workout is over, LPL activity in the fat tissue increases. The sensitivity of fat cells to insulin will also be “sufficiently altered,” as the University of Colorado physiologist Robert Eckel has described it, so as to restock the fat tissue with whatever fat it might have surrendered.

The open question, as Eckel wrote, is whether the particular hormonal environment that leads us to regain weight once we’ve lost it—elevated LPL activity on the fat cells and decreased LPL activity in the skeletal muscle—is the same as the one that leads us to grow fat to begin with. If insulin drives obesity, then this is an obvious hypothesis. There is no evidence to refute it, so it must be taken seriously. It has to be noted, too, that carbohydrate-rich meals increase LPL activity in the fat tissue, which would be expected, because they increase insulin secretion as well. Fat-rich meals do not. And so, as Eckel, a recent president of the American Heart Association, has put it, “habitual dietary carbohydrate intake may have a stronger effect on subcutaneous fat storage than does dietary fat intake.”

Since none of this research is particularly controversial, it’s hard to imagine why obesity researchers would not take seriously the hypothesis that carbohydrates have a unique ability to fatten humans—or, as Thomas Hawkes Tanner put it in The Practice of Medicine almost 140 years ago, that “farinaceous and vegetable foods are fattening, and saccharine matters are especially so.” Researchers who study carbohydrate metabolism have found this science compelling. In 1991, the Belgian physiologist Henri-Gery Hers, an authority on what are known as glycogen-storage diseases, one of which is named after him, put it this way: “Eating carbohydrates will stimulate insulin secretion and cause obesity. That looks obvious to me….” But this simple chain of cause and effect has nonetheless been rejected out of hand by authority figures in the field of human obesity, who believe that the cause of the condition is manifestly obvious and beyond dispute, that the law of energy conservation dictates that obesity has to be caused by eating too much or moving too little.

George Cahill, a former professor at the Harvard Medical School, is a pedagogical example. Cahill had done some of the earliest research on the regulation of fat-cell metabolism by insulin in the late 1950s, and had coedited the 1965 Handbook of Physiology on adipose-tissue metabolism. In 1971, when Cahill gave the Banting Memorial Lecture at the annual meeting of the American Diabetes Association, he described insulin as “the overall fuel control in mammals.” “The concentration of circulating insulin,” he explained, “serves to coordinate fuel storage and fuel mobilization into and out of the various depots with the needs of the organism, and with the availability or lack of availability of fuel in the environment.” When I interviewed Cahill in 2005, he told me it was true that “carbohydrate is driving insulin is driving fat.” But Cahill did not consider this chain of cause and effect to be a sufficient reason to speculate that carbohydrates drive obesity. Nor did he consider it a possibility that avoiding carbohydrates might reverse the process. Rather, he believed unconditionally that positive caloric balance was the critical factor. When it came to weight regulation, Cahill repeatedly told me, “a calorie is a calorie is a calorie.” He acknowledged that the obese ate no more, on average, than the lean, and this is why he believed that the obese must be fundamentally lazy and this was the proximate cause of their obesity.^*121 There was no reason to test competing hypotheses, Cahill said, because any competing hypothesis would contradict the laws of physics as he understood them.

When clinical investigators tried to unravel the connection between diet, insulin, and obesity in human subjects, as the University of Washington endocrinologist David Kipnis did in the early 1970s, the results were invariably analyzed in light of this same preconception. Kipnis had fed ten “grossly obese” women a series of three-and four- week diets that were either high or low in calories, and high or low in carbohydrates. The fat-rich diets lowered insulin levels, Kipnis reported in The New England Journal of Medicine in 1971, and the carbohydrate-rich diets raised them, regardless of how many calories were being consumed. Even when these women were semi-starved on fifteen hundred calories a day, a high-carbohydrate content (72 percent carbohydrates and only 1 percent fat) still increased their insulin levels, even compared with the hyperinsulinemia of these obese women on their normal diets.

One interpretation of these results is that we could remove the carbohydrates from the diet and replace them with fat, and weight would be lost, perhaps without hunger, because insulin levels would drop, even if the total calories consumed did not. Kipnis’s results, as the University of Heidelberg clinicians Gotthard Schettler and Guenter Schlierf wrote in 1974, underlined the “necessity of restricting carbohydrates in obesity in order to restore insulin levels to normal, thus hopefully decreasing appetite and fat deposition….”

Kipnis, however, refused to believe that carbohydrates might cause obesity, or that avoiding carbohydrates might ameliorate the problem. When I interviewed him over thirty years later, he described the findings of his research as “very obvious.” “You manipulate the amount of carbohydrates you give a human,” he said, “you can manipulate his or her basal insulin level.” He also said that “insulin causes deposition of fat in fat cells.” But when it came to the cause of human obesity or weight gain, Kipnis rejected the relevance of these physiological phenomena. “Most people are obese because they eat more than they need to sustain the energy requirements that they have,” he said. “They eat too damn much.”