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 tell 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 Jill Schneider described their research on hamsters, which were chosen because of their clockwork four-day estrous cycles. The experiments were remarkably consistent. These animals will go into heat whether they are fat or lean, and they will continue to cycle, as long as they can eat as much food as they want. If both fatty-acid
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 will shut down their reproductive cycles. In hamsters, insulin infusion “totally blocks” estrous cycles, unless the animals are allowed to increase their normal food intake substantially 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 will act as if it’s starving. In such a situation, Wade and Schneider said, “there will 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) will benefit more from a diet that lowers insulin but still 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 successfully 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 will perceive the consequences as caloric deprivation and compensate accordingly. Energy expenditure will be reduced, and weight loss will be temporary at best. On the other hand, any drug that works locally on the fat cells to release fatty acids into the circulation will inhibit hunger because it will be increasing the flow of fuel to the cells. 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 will 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 will weigh, on average, six to ten pounds less than nonsmokers. When they quit, they will 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 will, but according to studies only in the first two or three weeks. After a month, former smokers will 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 Rockefeller 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 cells to increase their insulin resistance, while also decreasing the lipoprotein-lipase activity on these cells, 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 cells that are normally 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. All 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 cells and then directing them to the muscle cells, 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 cells 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 virtually all 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 will 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 colleague Dan Porte observed in 1976. “This relationship has also been shown to occur in every commonly used model of altered body weight, including…genetically 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 mellitus, 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
