The Cure for Obesity : FOX01, Gpr17 and Your Hypothalamus???

Researchers at Columbia University Medical Center (CUMC) have identified a brain receptor (FOX01) that appears to play a central role in regulating appetite.

“We’ve identified a receptor that is intimately involved in regulating food intake,” said study leader Domenico Accili, MD. “What is especially encouraging is that this receptor 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.”

What is FOX01…How did they find it… and what does it do???

Previous research on the hypothalamus region of the brain suggest that the hypothalamus regulates appetite via a neuropeptide (brain regulator) called AgRP.

Unfortunately, up to this point, we don’t have a firm grip on the factors that influence AgRP expression.

In this study, the researchers “found new clues to appetite control by tracing the actions of insulin and leptin. Both hormones are involved in maintaining the body’s energy balance, and both are known to inhibit AgRP. “Surprisingly, blocking either the insulin or leptin signaling pathway has little effect on appetite,” says Dr. Accili. “We hypothesized that both pathways have to be blocked simultaneously in order to influence feeding behavior.”

To test this hypothesis, they engineered a strain of lab mice whose AgRP neurons lack the FOX01 protein. They focused on FOX01 because it is integral to insulin & leptin secretion and therefore should have a strong effect on appetite.

What happened when they got rid of the FOX01?

“The mice that lack Fox01 ate less and were leaner than normal mice,” said lead author Hongxia Ren, PhD. “In addition, the Fox01-deficient mice had better glucose balance and leptin and insulin sensitivity — all signs of a healthier metabolism.”

Alright, now we’re on to something…what’s next?

Unfortunately…. Fox01 is a poor drug target…. so the researchers searched for other ways to inhibit it.

Using gene-expression profiling, they discovered that the gene Gpr17 is highly expressed in mice with normal AgRP neurons but is effectively silenced in mice with Fox01-deficient neurons.

To confirm that the Gpr17 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.

What does all this science stuff mean to ME and my Jelly-Belly???

According to Dr. Accili, since Grp17 is part of the so-called G-protein-coupled receptor family, it greatly increases the odds of actually creating and effective anti-obesity drug.

  • About a third of all existing drugs work through G-protein-coupled receptors.
  • And the receptor is abundant in AgRP neurons but not in other neurons, which should limit unwanted drug side effects.
Of course, we’re probably still years and years away from a drug being on the market…if at all.