Scientists have identified a factor in the brain, called Gpr17, that has a central role in regulation of appetite in mice. It is known that damage to the hypothalamus—a part of the brain that functions to connect the nervous system to the endocrine system—leads to changes in hunger, satiety, and physical activity. Hypothalamic neurons (nerve cells) that produce a protein called AgRP have been directly implicated in promoting feeding behavior: studies have demonstrated that activation of AgRP neurons rapidly increases food intake, while deletion of AgRP neurons causes cessation of feeding and results in starvation.
The hormones insulin and leptin have been previously shown to inhibit the activity of AgRP neurons, but disruption of insulin or leptin signaling specifically within these nerve cells has mild to no effect on feeding behavior, indicating that neither pathway has sole control over how these cells contribute to appetite regulation. In addition, obesity can lead to insulin and leptin resistance. Scientists sought to identify additional pathways in AgRP neuron-dependent food intake that could potentially be targeted by drug therapy to inhibit the activity of AgRP neurons.
A protein called FoxO1 integrates both leptin and insulin signaling, so the researchers generated genetically engineered mice that lack FoxO1 in AgRP neurons and looked to see if removing this protein affected the appetite of the mice. They found that mice lacking FoxO1 in their AgRP neurons are lean, eat less, and show improved glucose control, as well as increased sensitivity to insulin and leptin. Because FoxO1 is a poor drug target, the scientists sought to determine another target with better therapeutic prospects. To do so, they looked for genes whose activity was reduced in FoxO1-deficient AgRP neurons. They identified the gene encoding Gpr17 as a prominent FoxO1 target and found that inhibition of Gpr17, by injecting a chemical into mice, reduced food intake and increased brain sensitivity to hormones and nutrients.
Gpr17 is also found in humans and is part of a family of proteins that is considered “highly druggable”—a number of existing drugs work through this family. In addition, Gpr17 is abundant in AgRP neurons but not in other neurons, potentially minimizing unwanted drug side effects. Additional research will be necessary to demonstrate whether inhibition of Gpr17 leads to the same outcomes in humans, but these findings reveal a new signaling pathway with potential targets to control appetite and obesity.
Ren H, Orozco IJ, Su Y, et al. FoxO1 target Gpr17 activates AgRP neurons to regulate food intake. Cell 149: 1314-1326, 2012.