The scientists focused on the hypothalamus, a small area of the brain that controls body temperature, thirst, sleep, fatigue, circadian cycles, and hunger. Previous studies had indicated that the regulatory mechanism is concentrated in neurons that express AgRP - a brain modulator, or neuropeptide. However, exactly what factors influence AgRP expression are poorly understood.
Study leader Domenico Accili, MD, professor of Medicine, said:
"We've identified a receptor that is intimately involved in regulating food intake. 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."
The scientists traced what insulin and leptin did and found clues regarding appetite control. Leptin and insulin are hormones, they play a key part in maintaining energy balance in the body. Leptin and insulin are also known to inhibit AgRP.
Dr. Accili said "Surprisingly, blocking either the insulin or leptin signaling pathway has little effect on appetite. We hypothesized that both pathways have to be blocked simultaneously in order to influence feeding behavior."
They wanted to test their hypothesis. So, they created a strain of mice with AgRP that lacked a protein that forms part of the signaling of leptin and insulin. The protein - Fox01 - had a considerable effect on the mice's appetite.
Lead author Hongxia Ren, PhD, said:
"Mice that lack Fox01 ate less and were leaner than normal mice. In addition, the Fox01-deficient mice had better glucose balance and leptin and insulin sensitivity - all signs of a healthier metabolism."
Fox01 is not a good drug target, so the scientist sought another way of inhibiting the protein's action.
They came across a gene that is highly expressed in animals with normal AgRP neurons, but is silenced in the mice without Fox01 in their neurons. They managed to do this by using gene-expression profiling. The gene is known as Gpr17; it produces a receptor called Gpr17 which lies on the surface of the cell.
They wanted to be sure that the receptor plays a role in controlling appetite, so they injected a Gpr17 activator into unmodified mice - their appetite got bigger. On the other hand, however, when the mice were given a Gpr17 inhibitor, the opposite occurred, their appetite dropped. When they injected the Fox01-deficient mice, there was no effect.
The fat mouse had a Gpr17 activator injected into it, while the slim one received a Gpr17 inhibitor
There are several reasons for targeting Gpr17 in obese humans, Dr. Accili explained - and creating drugs that can do that is feasible. Grp17 is highly druggable because it is part of the G-protein-coupled receptor family. A considerable number of medications work through G-protein-coupled receptors. The receptor is only abundant in AgRP neurons, it is scarce in other neurons. This means the risk of undesirable side effects is low.
Written by Christian Nordqvist