Appetite Control With New Brain Receptor

Connie K. Ho for

Losing weight and eating healthier have gone hand-in-hand for some time. Researchers from Columbia University Medical Center (CUMC) recently discovered how to help people in their goals for weight loss; a brain receptor that was found to have abilities to help regulate appetite.

The study, published in the online edition of Cell, could help create new drugs focused on combating obesity.

“We’ve identified a receptor that is intimately involved in regulating food intake,” noted study leader Dr. Domenico Accili, professor of Medicine at CUMC, in a prepared statement. “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.”

The aim of the project was new obesity therapies and, as such, scientist studied the hypothalamus, which is a small brain structure that can control appetite. Other studies have suggested that neurons express a neuropeptide that acts as a regulatory mechanism or brain modulator called AgRP. Scientists don´t know yet what influences AgRP.

In the project, CUMC researchers tracked the reactions of insulin and leptin to better understand appetite control. They found that insulin and leptin could maintain energy balance. These two hormones also inhibited AgRP.

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

The researchers tested their hypothesis by producing a group of mice whose AgRP didn´t have Fox01, a protein that´s necessary for insulin and leptin signaling. Removing Fox01 impacted the appetite of the mice.

“Mice that lack Fox01 ate less and were leaner than normal mice,” explained lead author Dr. Hongxia Ren, an associate research scientist in Medicine, in the statement. “In addition, the Fox01-deficient mice had better glucose balance and leptin and insulin sensitivity – all signs of a healthier metabolism.”

Researchers also wanted to see how they could inhibit the action of Fox01. They ended up using gene-expression profiling and found a gene that is expressed by normal AgRP but not expressed in mice that lack in Fox01 neurons. The gene, discovered to be G-protein coupled receptor 17, provided a cell-surface receptor called Gpr17. The researchers then injected a Gpr17 activator into normal mice to see if the receptor was able to manage appetite control; the appetite in the mice actually increased. On the other hand, when the mice were given a Gpr17 inhibitor, the appetite decreased.

There are a few reasons why researchers support Gpr17 for anti-obesity medications. For one, Gpr17 is found in humans. As well, it is connected to the G-protein-coupled receptor family and, as such, is highly durable. Lastly, the receptor has many AgRP neurons and not other neurons, which could limit drug side effects.

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