Good Calories, Bad Calories (79 page)

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

The evidence suggests that nicotine induces weight loss by working on fat cel s to increase their insulin resistance, while also decreasing the lipoprotein-lipase activity on these cel s, both of which serve to inhibit the accumulation of fat and promote its mobilization over storage, as we discussed earlier (see Chapter 22). Nicotine also seems to promote the mobilization of fatty acids directly by stimulating receptors on the membranes of the fat cel s that are normal y triggered by hormones such as adrenaline. The drug also increases lipoprotein-lipase activity on muscles, and this may explain the steep rise in metabolic rate that occurs immediately after smoking. Al of this fits with the observations that smokers use fatty acids for a greater proportion of their daily fuel than nonsmokers, and heavy smokers burn more fatty acids than light smokers. In short, nicotine appears to induce weight loss and fat loss not by suppressing appetite but by freeing up fatty acids from the fat cel s and then directing them to the muscle cel s, where they’re taken up and oxidized, providing the body with some excess energy in the process. When smokers quit, they gain weight because their fat cel s respond to the absence of nicotine by significantly increasing lipoprotein-lipase activity. (There’s also evidence that the weight-reduction drug fenfluramine—the “fen” half of the popular weight-loss drug phen/fen, which was banned by the FDA in 1997—works in a similar manner, by decreasing lipoprotein-lipase activity in the fat tissue.)

This alternative hypothesis of obesity and its physiological perspective on hunger forces us to rethink virtual y al our cherished notions about how weight changes and why. By this hypothesis, any long-term variations in weight, appetite, and energy expenditure—even our inclination to exercise or go for a walk—are likely to be induced at a fundamental level by changes in the regulation of fat metabolism and the partitioning and availability of metabolic fuels in the body. These in turn are driven, first and foremost, by changes in insulin secretion and how our fat and muscle tissue respond to that insulin. In this sense, insulin becomes what researchers who study hibernation and other seasonal weight variations in animals refer to as the adjustable regulator.

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

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

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

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

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