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Leptin, Brain, Appetite and Weight

A new study (1999) by Boston researchers shows how the fat hormone leptin works in the brain to trigger the nerve cells that control eating. The study adds important details about how leptin, which is released into the blood stream from fat, may control the cognitive aspects of feeding behavior.

Leptin’s Appetite Suppressant Messages to Hypothalamus

In the medial hypothalamus, leptin activates “anorectic” nerve cells, which release appetite-suppressing neuropeptides (POMC and CART). At the same time, leptin inhibits another group of leptin-sensitive nerve cells, called “orexigenic,” which release appetite-regulatory neuropeptides (NPY and AGRP). The two groups of leptin-sensitive cells send appetite-suppressing signals to key nerve cells in the lateral hypothalamus thought to control several behaviors including feeding (ORX and MCH).

Hypothalamus Controls Appetite

Since the 1940s, scientists have known that the hypothalamus played a key role in regulating food intake and body weight. In these classic experiments with rats, lesions in one part of the hypothalamus created massively obese rats. Lesions in another part of the hypothalamus blocked the urge to eat and even caused death by starvation. However, the lack of understanding of the genes for controlling body weight regulation inhibited significant further progress. Nearly five years ago, Jeffrey Friedman MD, PhD, a professor at Rockefeller University, New York, and his research group rejuvenated the field. They discovered that the hormone leptin is made by fat cells and is a crucial signal to the brain to control eating. Suddenly there was hope for finding new ways to control eating disorders, obesity, and related disorders, such as diabetes. Research support and the number of scientists in the field increased dramatically.

Leptin Related to Body Fat

In the body, leptin comes from fat cells in direct proportion to the amount of stored energy. Thicker thighs, flabbier arms and a bigger belly mean more leptin is circulating in the blood stream. Studies in both people and animals have shown that lack of leptin triggers a voracious appetite. When leptin levels return to normal, the urge to eat goes away. Until recently, the responsible pathways in the brain were unclear.

Last year, postdoctoral fellow Elias and her colleagues identified the pathway between the two parts of the hypothalamus that apparently linked leptin to eating. The new study tells how that pathway may work.

Links Between Hypothalamus and Leptin

Using two genetic markers of leptin action and nerve cell activity, the researchers have shown that two distinctive groups of cells in one part of the hypothalamus respond in opposite ways to leptin. Specifically, they’ve shown these leptin-sensitive cells have hardwired connections to key cells in another region of the hypothalamus that control the urge to eat.

In the medial hypothalamus, leptin activates “anorectic” nerve cells, which release appetite-suppressing neuropeptides. At the same time, leptin inhibits another group of leptin-sensitive nerve cells, called “orexigenic,” which literally means to eat. Leptin prevents orexigenic cells from releasing a potent appetite-stimulating neuropeptide.

The net effect is that the leptin-sensitive cells send appetite-suppressing signals to key nerve cells in the lateral hypothalamus thought to control several behaviors including feeding, including a group that release the MCH neuropeptide. Last year, co-author Jeffrey Flier MD, chief of the division of endocrinology at BI-Deaconess, Eleftheria Maratos-Flier MD, a researcher at Joslin Diabetes Center and their colleagues showed that knock-out mice lacking the MCH gene ate significantly less than littermates and were lean — just like the rats with lesions of the lateral hypothalamus in cruder experiments 50 years ago.

More Leptin Research Needed

This study does not have immediate disease-related or therapy-related implications. However, the researchers hope to use the new genetic markers for leptin developed for this study of normal rats to investigate what goes wrong in animal models for obese people. It’s a mystery and another story about why overweight or obese people can retain hearty appetites in the midst of so much leptin flowing through their veins.

Source: Neuron (August 1999)

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