Fat hormone leptin has opposite effect on two distinctive groups of nerve cells
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Boston, MA, August 25, 1999--From the belly to the brain, a new study 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.
The paper by Carol Elias, PhD and her colleagues in endocrinology and neurology at Beth Israel Deaconess Medical Center and Harvard Medical School is published August 27 in the monthly journal Neuron. "We're starting to understand the brain pathways underlying body weight regulation," says senior author Joel Elmquist, DVM, PhD, a neuroendocrinology researcher at BI-Deaconess and assistant professor of neurology and medicine at Harvard Medical School. "This study directly links neurons that respond to the fat hormone leptin and critical populations of nerve cells that regulate feeding behavior."
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.
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.
In the past several years, the researchers in Elmquist's lab have combined genetic techniques with neuroanatomic methods to tease out the details of the neural pathways linking leptin to eating behavior.
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.
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.
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.
Elias is now an assistant professor of anatomy at the University of Sao Paulo, Brazil. Elmquist is also Director of the Laboratory of Anatomic and Molecular Neuroendocrinology at BI-Deaconess. Flier is also a professor of medicine at Harvard Medical School. Other co-authors include Harvard medical student Carl Aschkenasi; research assistant Charlotte Lee; research assistant Joseph Kelly; Rexford Ahima PhD MD, now assistant professor at University of Pennsylvania Medical School; Christian Bjorbaek PhD, instructor in medicine at Harvard Medical School; and Clifford Saper MD, PhD, James Jackson Putnam Professor of Neurology and Neuroscience at Harvard Medical School and chair of the neurology department at Beth Israel Deaconess. The research was funded by the National Institutes of Health (NIDDK), the American Heart Association, and Eli Lilly.
Editors, please note: an illustration is available at http://www.hms.harvard.edu/news/releases/leptin.html
Beth Israel Deaconess Medical Center is a major clinical, research, and teaching affiliate of Harvard Medical School and a founding member of CareGroup Healthcare System.
Journal
Neuron