Researchers ID Brain Receptor Controlling Appetite

Researchers at Columbia University Medical Center (CUMC) have identified a brain receptor that may play a central role in regulating appetite, according to a new study published in the journal Cell. The findings may lead to drug therapies for preventing or treating obesity.

“We’ve identified a receptor that is intimately involved in regulating food intake," said study leader Domenico Accili, MD, professor of Medicine at CUMC. “What is especially encouraging is that this receptor is belongs to a class of receptors that turn out to be good targets for drug development, making it a highly ‘druggable’ target. In fact, several existing medications already seem to interact with this receptor. So, it’s possible that we could have new drugs for obesity sooner rather than later."

In their search for new targets for obesity therapies, scientists have focused on the hypothalamus, a tiny brain structure that regulates appetite. Numerous studies suggest that the regulatory mechanism is concentrated in neurons that express a neuropeptide, or brain modulator, called AgRP. But the specific factors that influence AgRP expression are not known. CUMC researchers found new clues to appetite control by tracing the actions of insulin and leptin—two hormones involved in maintaining the body’s energy balance, and inhibiting AgRP.

“Surprisingly, blocking either the insulin or leptin signaling pathway has little effect on appetite," they said. “We hypothesized that both pathways have to be blocked simultaneously in order to influence feeding behavior."

To test their theory, the researchers created a strain of mice whose AgRP neurons lack a protein— Fox01—that is integral to both insulin and leptin signaling. They found mice that lack Fox01 ate less and were leaner than normal mice. The Fox01-deficient mice also had better glucose balance and leptin and insulin sensitivity—all signs of a healthier metabolism..

Since Fox01 is a poor drug target, the researchers searched for other ways to inhibit the action of this protein. Using gene-expression profiling, they found a gene that is highly expressed in mice with normal AgRP neurons but is effectively silenced in mice with Fox01-deficient neurons. That gene is Gpr17 (for G-protein coupled receptor 17), which produces a cell-surface receptor called Gpr17.

To confirm that the receptor is involved in appetite control, the researchers injected a Gpr17 activator into normal mice, and their appetite increased. Conversely, when the mice were given a Gpr17 inhibitor, their appetite decreased. Similar injections had no effect on Fox01-deficient mice.

There are several reasons why Gpr17, which is also found in humans, would be a good target for anti-obesity medications. The researchers said since Grp17 is part of the so-called G-protein-coupled receptor family, it is highly druggable. About one-third of all existing drugs work through G-protein-coupled receptors. In addition, the receptor is abundant in AgRP neurons but not in other neurons, which should limit unwanted drug side effects.