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A Hunger ‘Set Point’
Dishes of jelly beans and peanuts sit in the office reception room of Friedman’s lab at Rockefeller University in New York. I try not to take a yellow jelly bean, my favorite, making myself grab a handful of peanuts instead. Tall and lanky with a graying beard and glasses, wearing gray-green corduroys and a flannel shirt, Friedman takes a couple of red jelly beans, which his assistant buys by the bagful. As we talk, my eyes keep wandering to the jelly beans. Later, I can’t help myself: I grab a few as we leave for lunch. I ask Friedman if the candy and peanut bowls are a test. He says no, though this is the core of his quest: determining how a person decides to eat or not to eat at a given moment in time. “Eating is binary,” he says. “We either do it, or we don’t. But where in the brain is this decision made, and what is the input that makes the decision?”

Several areas of the brain feed into this decision – behavioral and decision-making centers in the cerebral cortex, for instance, and the regions that process sensory input. But all of these, says Friedman, are trumped by the mechanism that drives organisms to eat. It is centered in the hypothalamus at the base of the brain, where two types of neurons appear to be the chief regulators of appetite. They tell us when we’re hungry and when we’re not. The so-called NPY neuron stimulates hunger, and the POMC inhibits it, each neuron turned up or down by chemicals that wash over them. “A dominant factor in controlling weight is this basic neural circuit,” says Friedman. The chief chemical is leptin, a hormone produced by fat cells in the belly. As people put on the pounds, fat cells increase the levels of leptin, which tells the POMC neuron to suppress appetite. In times of privation–or dieting–body fat is reduced, which decreases the levels of leptin. Less leptin mean the POMC turns down and the NPY neuron predominates, which ramps up hunger in people. Other chemicals–fats, sugars, and neural transmitters–also influence the actions of these neurons, but leptin seems to be the key.

Friedman is famous for his 1994 discovery of the gene that codes for leptin. For a brief moment in the mid-1990s, leptin seemed to be a potential wonder cure for obesity, when Friedman and others showed that a mutation affecting the leptin gene caused morbid obesity in mice and humans. But leptin injections work for only a small percentage of the obese. It turns out that the majority do produce leptin, though their bodies actually resist the effects of the hormone by blocking its ability to turn up the hunger-suppressing action of the POMC neuron. So their appetites remain large, and they keep eating–and gaining weight–until they reach the point at which the resistance stops. Where that point lies, Friedman believes, is determined by genetic makeup.

Why leptin resistance occurs in some people is poorly understood, Friedman says. It may be a relic of the thrifty-gene response, ramping up appetite in those whose ancestors lacked adequate food. The Rockefeller team measured leptin levels in the Kosraean population; Friedman is using that data to help correlate leptin resistance with genes that might be responsible for it. According to Friedman, each of us has a “set point” of hunger and satiation, which we inherited from our individual forebears. We are born with this setting, and we are driven to keep eating until we reach it.

Friedman’s “blame the genes” hypothesis flies in the face of arguments mounted by nutritionists and the diet industry, and of the popular belief that eating habits – grabbing a handful of jelly beans, for instance – can be controlled through willpower. “We have some control over eating from our reasoning centers of our brain,” says Friedman, “but this seldom overrides our basic instinct to eat when we’re hungry.” Friedman advocates an entirely new way of thinking about fat, saying it’s pointless to tell most obese people that they can lose dramatic amounts of weight by force of will. “Obesity is a disease,” he insists, comparing current attitudes to those once associated with ulcers and cancer. “Because it’s largely genetic, and the drive to eat largely beyond our control, we should be sympathetic, not judgmental.”

When I ask him whether more Big Macs are at least partly to blame, Friedman says, “Diets are important for heart disease and overall health, but there is no evidence that types of food affect obesity.” Some people are just programmed to eat more, he says, and high-calorie fast foods simply allow them to do so quickly–and therefore cause a faster weight gain.

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