Researchers discover new brain target for appetite control

With obesity in the United States steadily on the rise, many are looking for a genetic culprit responsible for the increase, as well as for a way to help shed copious amounts of weight.  Now, a recent discovery in the brain may lead to answers about obesity as well as the development of new drugs to more effectively control appetite.

Researchers from the Columbia University Medical Center (CUMC) have revealed a brain receptor that plays a key role in the regulation of appetite.  When inhibited in mice, the cell-surface receptor – called Gpr17 – caused their appetite to decrease.  Conversely, when the mice were injected with a Gpr17 activator, their appetites increased.

“We call it an orphan receptor,” Dr. Domenico Accili, professor of medicine and the study’s leader, told  “We know it’s a receptor, but we don’t know the substance that activates this receptor. However, we know from past studies that there are certain drugs that can activate or inhibit this receptor.  Because a similar receptor exists in people, it can be used by people for similar purposes, so we hope to do a clinical study to see if this holds true.”

Scientists searching for new targets to battle obesity have often focused on the hypothalamus, a small structure in the brain responsible for regulating appetite.  Previous studies have suggested that the structure’s mechanism for regulation is found in neurons that activate a neuropeptide called AgRP.

With this past research in mind, Accili and his colleagues focused on the actions of both insulin and leptin, hormones that inhibit AgRP.

“We had been interested for a long time in studying insulin resistance, which is a common problem with overweight individuals and also with individuals who develop Type 2 diabetes,” Accili said.

The researchers created a strain of mice whose AgRP neurons lacked a protein responsible for signaling both insulin and leptin.  Sure enough, the mice did not eat as much and were much leaner. The researchers then used gene-expression in the protein-deficient mice to see if they could find a good target for appetite suppression.

“We interrogated these neurons important for food intake for the expression of proteins that might be responsible for regulating how mice eat,” Accili said.  “So we isolated all the genes that are transcribed in the neurons, and out of this list, we focused on those that we thought could be most druggable” – leading them to the gene Gpr17 and its cell-surface receptor also called Gpr16, both of which are also found in humans.

Accili said it’s possible that appetite-suppressant drugs that inhibit Gpr17 could be on the market soon – because they already exist in other forms.

“One drug is Singulair, used by people with asthma,” Accili said.  “Another medication that’s used that inhibits Gpr17 is Brilinta, a blood thinner.  So the drugs already exist.  The problem is the drugs that are used do not cross into the brain, so they’re unlikely to have an effect in their present chemical form.”

As for adverse side effects that come with inhibiting Gpr17, Accili said they have not found any.  Instead, any effects that come with Gpr17 have all been positive.

“Those that we know of would be beneficial for people who are overweight and have diabetes,” Accili said of the effects. “[Gpr17 inhibition] decreases aggregation of platelets in the blood - what blood thinners do that are given to people with cardiovascular disease.  Another side effect we can predict is protection against stroke, so it’s a beneficial aspect for overweight people.”

Not only does Gpr17’s discovery lead to possible effective appetite-suppression drugs, but it also may play an even larger role in the burgeoning obesity epidemic.  As BMIs have increased, many researchers have started to suspect a gene mutation or other involuntary factor contributing to increasing waistlines.  Accili hopes that their discovery  will add to that body of research.

“One of the things we’re hoping to learn over the next few weeks is to ask whether the same gene that we identified has also been implicated in any of the genetic studies of obesity,” Accili said. “We’re optimistic that when geneticists do gene hunts for obesity, one of the first things they’ll do is to look into their databases to see if our gene is lighting up.  Maybe it will suggest that there are mutations activating Gpr17.  Our data does not deny a genetic role in obesity.”

With nothing but encouraging data and evidence propelling them forward, Accili thinks the results of their study could have a real life impact very soon.

The timeline of this could be a few years to a few months,” Accili said.  “This is a clear path forward to the clinic.  We just have to modify the existing drugs.”