Researchers at Yale School of Medicine provide direct evidence that two parts of a neuronal system, one that promotes eating and another that suppresses eating, are critical for the acute regulation of eating and body weight, according to a study published online in the September 11 issue of Nature Neuroscience.

The paper makes it clear that the agouti-related peptide-expressing (AgRP) neurons are mandatory for eating. "Previous studies showed that the brain, particularly the hypothalamus, is responsible for the regulation of eating," said co-senior author Tamas Horvath, chair and associate professor in the Section of Comparative Medicine, and associate professor in neurobiology and the Department of Obstetrics, Gynecology & Reproductive Sciences. "But until now, no experimental evidence was available to prove that AgRP neurons are critical for acute regulation of eating."

Horvath's collaborator Jens Bruening of the University of Cologne in Germany introduced the avian diphtheria toxin receptor into neurons in the feeding support system of transgenic mice. When the animals were adults, two injections of toxin caused the specific cell population to die within 48 hours, impairing the mouse's ability to eat and resulting in acute anorexia. These mice also showed marked reduction in blood glucose, plasma insulin and Leptin concentrations.

"Our results confirm the hypothesis that these two systems are critical for eating and the cessation of eating," said Horvath. "Previous transgenic approaches failed to provide this proof because of compensatory mechanisms that could operate during development. None of those actually knocked out neuronal function. In this case, however, neurons are gone and there is no time to replace their function."

In explaining the significance of the finding, Horvath said, "It is important to ensure that the multibillion dollar academic and pharmaceutical approach against metabolic disorders is leaning in the right direction. The approach in general could also eventually lead to specific destruction of cells in other kinds of diseases."

Other authors on the study included Eva Gropp, Marya Shanabrough, Erzsebet Borak, Allison W. Xu, Ruth Janoschek, Thorsten Buch, Leona Plum, Nina Balthasar, Brigitte Hampel, Ari Waisman, Gregory S. Barsh, and co-senior author Jens Bruning.