Good Calories, Bad Calories

Le Magnen learned that when rats are allowed to eat whenever they want, the size of the meal determines how long rats will go before they get hungry again. As a new supply of ingested calories is exhausted by the rat’s energy expenditure, the animal is motivated to eat again. “All increase or decrease in the two sides of this balance (calories eaten in meals versus metabolic expenditures) will lead to an immediate shortening or lengthening of the meal-to-meal interval,” Le Magnen explained. And this is “the major and direct agent of the regulation of food intake.”

The second observation was one that is obviously true for humans as well: Rats eat to excess during their waking hours, which means their intake exceeds their expenditure of energy, and so they are hyperphagic while awake, storing fat during this period. While they’re sleeping, the rats are in negative energy balance—hypophagic—and they live off the fat accumulated during the waking hours. Weight peaks as the rats are going to sleep and it ebbs as they awake. In humans, this cycle would explain, among other things, why hunger doesn’t (or at least shouldn’t) wake us from the depths of a night’s sleep so we can raid the refrigerator.

While rats are sleeping, they progressively mobilize more and more fatty acids from their adipose tissue and use these fatty acids for fuel. “The restitution of these stored fats and their utilization to cover an important part of the current metabolism reduces the concomitant requirement for an external supply of calories by food intake,” Le Magnen wrote. When he used insulin to suppress this mobilization of free fatty acids, the rats ate immediately. Fatty acids released from the adipose tissue, Le Magnen concluded, simply replace or “spare” the available glucose and, by doing so, delay the onset of hunger and the impetus to feed. The liberal availability of these fatty acids in the blood promotes satiety and inhibits hunger.

Another way to phrase this is that anything that induces fatty acids to escape from the fat tissue and then be burned as fuel will promote satiety by providing fuel to the tissues. Anything that induces lipogenesis, or fat synthesis and storage, will promote hunger by removing the available fuel from the circulation. And so hypophagia and hyperphagia, satiety and hunger, Le Magnen wrote, are “indirect and passive consequences” of “the neuroendocrine pattern of fat mobilization or synthesis.”

By the mid-1970s, Le Magnen had demonstrated that insulin is the driver of this diurnal cycle of hunger, satiety, and energy balance. At the beginning of waking hours, the insulin response to glucose—the “insulin secretory responsiveness,” Le Magnen called it—is enhanced, and it’s suppressed during sleep. This pattern is “primarily responsible” for the fat accumulation during the waking hours and the fat mobilization during the sleeping hours. “The hyperinsulin secretion in response to food” during the period when the animals are awake and eating, and the “opposite train” when they are asleep, he explained, produces “a successive fall and elevation” of the level of fatty acids in the blood on a twenty-four-hour cycle—twelve hours during which the fatty acids are depressed and glucose is the primary fuel, and then twelve hours in which they’re elevated and fat is the primary fuel. Both hunger, or the urge to eat, and satiety, or the inhibition of eating, are compensatory responses to these insulin-driven cycles of fat storage followed by fat mobilization. Insulin secretion is released in the morning upon waking and drives us to eat, Le Magnen concluded, and it ebbs after the last meal of the day to allow for prolonged sleep without hunger.

This hypothesis of eating behavior did away with set points and lipostats and relied instead on the physiological notion of hunger as a response to the availability of internal fuels and to the hormonal mechanisms of fuel partitioning. Hunger and satiety are manifestations of metabolic needs and physiological conditions at the cellular level, and so they’re driven by the body, no matter how much we like to think it’s our brains that are in control.

Several variations on this hypothesis were published from the mid-1970s onward by Le Magnen and others. The most comprehensive account was published in 1976 by Edward Stricker at the University of Pittsburgh, and Mark Friedman, then at the University of Massachusetts and now at the Monell Chemical Senses Center in Philadelphia. Their article, “The Physiological Psychology of Hunger: A Physiological Perspective,” should be required reading for anyone seriously interested in eating behavior and weight regulation.