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Leaping after leptin

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The hypothalamus helps govern eating behavior in rodents and people.

Courtesy of
The Whole Brain Atlas.


Lean rats get a bigger kick from an electrical jolt to the lateral hypothalamus.

How I lost 84 lbs. In 7 days!
Fat rat brain
slice of cheesecake Hungry? You want deep-fried cheese curds or a cheeseburger? Cheesecake or a chocolate éclair? If these are tough decisions for you, consider the lowly rat. Too dumb to read a menu, with a brain smaller than a slice of dill pickle, how's it supposed to make thorny choices about entrees?

And don't forget that rats have other things to think about, like skulking around and avoiding housecats?

Now, Canadian researchers have opened a window into how rats make dining decisions. In the process, they have shed some light on human obesity.

The research concerns the effects of leptin, a hormone made by fat cells. Since its discovery in 1994, leptin caused a major ruckus when researchers used it to cause a near-miraculous slimming in genetically obese rats.

Leptin seems to send a simple message from fat cells to the brain: "Enough, awready! I'm stuffed. Waiter, gimme a Perrier lite, double, on the rocks!"

To find out what gives leptin such power, Peter Shizgal, a psychologist and neurobiologist at Concordia University in Montreal, Canada, studies the chemical in rats. He says food intake in normal mice, rats and monkeys is reduced by leptin, and that the hormone also cuts the "tremendously high" food intake of genetically obese mice while increasing their activity. Shizgal, who directs the center for studies in behavioral neurobiology at Concordia, says that unlike mice, the effect does not appear in genetically obese rats. Lacking a receptor for leptin, they do not benefit from getting more of it.

Broad of beam
If leptin is so great, a brief glance at the broadening American beam indicates that leptin's signal doesn't always get through. Indeed, many obese people have plenty of leptin, indicating that something else is failing in the leptin communications system.

What exactly is leptin's role? How does it affect the brain and behavior? With obesity a multi-billion dollar problem, and with leptin being seen as a potential magic bullet, these are $64,000 questions.

Shizgal's latest experiment was designed to answer a simple question: How do you bridge between this molecule [leptin] and the desire to eat, the attractiveness of food? To fork over the answers, he and colleagues Stephanie Fulton and Barbara Woodside implanted electrodes in the lateral hypothalamus (yes, the name will be on the test!) in the brains of male rats (see "Modulation of Brain..." in the bibliography).

diagram of the brain and hypothalamus The hypothalamus helps control behavior related to food, and Kenneth Carr of New York University had already found that it was, as might be expected, sensitive to the long-term energy balance in the animal -- its degree of obesity.

Translated, lean rats get a bigger kick from an electrical jolt to the lateral hypothalamus than well-fed ones. Research by the Concordia group was premised on the idea that the desire to get that jolt could stand, in the rat's "mind," for the desire to eat. Being hungry makes you want to stimulate the hypothalamus with food -- or electricity.

The rats were allowed to press a lever to get that jolt to the hypothalamus, under three varying conditions:

  1. Strength of the electrical signal. With a weak signal, the rat did not bother to press the lever very much. "If it's very weak, the animal will not work for those wages," Shizgal says.

  2. Body fat. Extremely lean rats (which had lost 25 percent of body weight before the experiment) were vigorous lever pressers, even with a weak electrical signal. "In all subjects under all conditions, we could find a level of stimulation for which the rats would work 'full time,'" Shizgal notes. "What changed was the strength required to convince the rats to work this hard." In the lateral hypothalamus, a stronger stimulation was needed to elicit full-time work in lean rats.

  3. Leptin. Injections of leptin changed the effects of leanness and signal strength. In a sense, leptin increased the wage the rats demanded in order to work. "When treated with leptin," Shizgal says, "we had to 'pay' them with stronger stimulation."

Shizgal says leptin may play a key role in a system that helps make rodent dining decisions. Put in human terms, the system would answer this type of question: "How sweet does that strawberry have to be for you to go into the field and harvest it?" If you're hungry, Shizgal notes, "it doesn't have to be very sweet. If you've just had Christmas dinner, it's got to be awfully good."

Rodent-human connection
Shizgal says people may act like rats with electrodes in their brains: When your fat stores are wanting, you're far more willing to invest the time and possibly money to get fed -- you'll keep stuffing bills in the vending machines. When you're plump, other needs take precedence, and you may decide to, say, clean the garage or pay your taxes instead of chowing down.

Curiously, leptin may play another role in regulating food. When the electrodes were moved by, say, the thickness of a rat's whisker, the results changed dramatically. Instead of reducing the desire to get a brain-jolt -- to eat -- leptin increased it. In other words, extra leptin made these rats "willing to work for lower wages," Shizgal explains.

Shizgal speculates that leptin may play a kind of balancing role that helps the animal adapt to the demands of survival. "From the point of view of an animal making a living in the natural world, it needs minerals, fluid, food, nesting material," he says. "You'd think it would have to go about measuring the value of each," and then use a simple calculation to decide how to spend its time. Such a method would allow a rat to make crucial decisions with a thinking machine that wouldn't be insulted by the phrase, "That ain't worth a rat's brain!"

What can leptin do for me?

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