That simple anatomical model has since been supplanted by a more elaborate biochemical one, in which a web of neurotransmitters, hormones, peptides, and receptors works within and beyond the hypothalamus to help maintain the body's energy balance. Neuroscientist Satya Kalra of the University of Florida at Gainesville calls it the "appetite-regulating orchestra," and it does have a symphonic complexity. The stomach's hunger hormone ghrelin, for example, acts on the hypothalamus to stimulate the release of neuropeptide Y, the most potent appetite enhancer yet discovered. Ghrelin also suppresses the production of proopiomelanocortin (POMC), an appetite inhibitor, in the hypothalamus.
Conversely, the fat-cell satiety factor leptin slows production of neuropeptide Y and promotes POMC production. Cells in the hypothalamus also have receptors for insulin and blood sugar that utilize these same pathways to slow production of NPY and activate POMC release. Some visceral signals reach the brain via nerve cells rather than the bloodstream. A satiety peptide called cholecystokinin (CCK), for instance, released in the small intestine, may work by directly triggering the vagus nerve, which runs from the gut to the brain.
Erring on the Side of Gluttony
The discovery of each of these chemical factors in the past two decades incited lavish hopes of developing weight-loss drugs that mimic or foil their action. Yet no therapy based on the new substances has helped to harness appetite in people. When the appetite-suppressing hormone leptin was discovered by investigators at Rockefeller University in 1994, for example, it was hailed as a potential cure for obesity. Genetically modified lab rats that don't produce leptin spend all their time under the chow hopper and become grossly obese, just like the VMH-compromised rats. Maybe, the reasoning went, obese people were likewise deficient in leptin, and leptin injections would quench their appetites. The California company Amgen certainly banked on it, spending $20 million to license the leptin patent from Rockefeller.
But so far researchers have identified barely a dozen people worldwide who suffer from leptin deficiency. While they are indeed fat, the vast majority of obese people have abnormally high leptin levels—which might be expected, since the hormone is made by fat cells. Leptin therapy doesn't decrease appetite or lead to substantial weight loss in such people, or even in the merely overweight. Obesity researchers now think the brain cells of most fat people may have an insensitivity to leptin not unlike the insulin resistance that typifies Type 2 diabetes. Their bodies may be more finely tuned to detect decreases in leptin levels—reflecting a potentially life-threatening loss of body fat—than increases resulting from leptin injections or being overweight.
In light of the findings, some re-searchers wonder whether leptin's function in the appetite-regulation network has been misinterpreted. Instead of acting primarily as an appetite suppressant that induces satiety when levels are high, leptin's main role may be as a proxy for body fat, sounding the homeostatic alarm when levels start to fall. "It's not clear that leptin's role in the body is to keep us from getting fat," says Princeton psychologist Hoebel. "It's really a way of keeping us from getting too skinny."
Experiments with the appetite stimulant neuropeptide Y also suggest that the stomach-hunger system is rigged to promote appetite more than curb it. Injecting NPY into the brains of rats, for example, causes feeding frenzies, just as you'd expect. But genetically engineered rats with no NPY at all still eat plenty. Why is stomach hunger so intractable?
Obesity experts point out that, from an evolutionary perspective, overeating has until lately been more adaptive for our species than moderation. For most of its history, Homo sapiens lived a hunter-gatherer lifestyle in which supplies of food were scarce and unpredictable. "Under such conditions, the ability to ingest and store as many calories as possible when food is readily available would have obvious survival value," observes neurologist Barry E. Levin of New Jersey Medical School in Newark. Our bodies are metabolically suited to the intermittent availability of food, he explains in a recent report in the Journal of Physiology entitled "Why Some of Us Get Fat and What We Can Do About It." Cheap and easy calories are a relatively recent invention. The appetite-regulation network has evolved over millions of years to err on the side of gluttony.
To aid the cause of gluttony, evolution has also furnished us with a suite of neurochemicals and neural circuits that make eating a deeply pleasurable activity. We want to eat, even—often—in the absence of metabolic need. The brain-hunger system motivates and rewards eating by creating conscious sensations and impulses related to food: I like that, I want that, That was good, I want more. If your mouth waters when you pass the pastry shop after lunch, you can blame brain hunger. If you find yourself exchanging good cash for a nutritionally impaired profiterole, blame brain hunger.
And if that cream puff tastes as good as sex feels, it's no coincidence. Brain hunger emanates from some of the same neural signals and pathways that orchestrate orgasm. They include a part of the limbic system called the striatum, which helps create motivation, and the neurotransmitter dopamine, which guides pleasure seeking and produces feelings of enjoyment. "Now we're not just talking about energy balance," says Gene-Jack Wang, head of medicine at Brookhaven National Laboratory in Upton, New York. "We're talking about human psychology."
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