New discovery in the neurochemical pathways of appetite sheds light on future treatment of overeating
It’s 11 a.m., almost lunchtime. Your grumbling stomach sends the signal: I’m hungry! There’s more than just a growling gut instigating those hunger pangs, though. Behind the sensation of hunger lies a complex system of biochemical processes running throughout your intestines, fat and brain. Though scientists have generally understood the neurochemical pathways of appetite for several years, a new study from researchers at UC Santa Cruz, the Vanderbilt University and King’s College, London, reveals that the previous explanation was missing a crucial step. The discovery of a previously overlooked protein involved in the process could lead to better medicine for those who struggle with under-eating and overeating.
The project, supported by grants from the National Institutes of Health, explored how our cells communicate with each other to cause the sensation of hunger. “What makes this remarkable really is a technical thing,” says co-author of the study and UCSC biochemist Glenn Millhauser. “But it’s a real game changer in terms of understanding cellular signaling.”
The old explanation isn’t far off the mark: Whether you feel hungry or stuffed begins with two hormones: ghrelin and leptin. When you start eating, fat cells release leptin, and, through a series of biochemical interactions, you start to feel less hungry. But when your body needs nutrients, ghrelin steps in. Intestinal cells secrete ghrelin into your bloodstream, and in response the body releases a special molecule called Agouti-related protein, which scientists refer to as AgRP (pronounced ag-rip).
“AgRP drives feeding behavior,” says Millhauser. “It makes you want to eat. When you get hungry, your AgRP neurons are firing away.”
AgRP stimulates hunger by binding to melanocortin 4 (or MC4) receptors, which are like stationary couriers that relay messages from outside the neuron. Faulty MC4 receptors can prevent the cessation of hunger, causing a person to eat much more than their body actually needs. Many people who struggle with severe obesity for genetic reasons have mutated MC4 receptors.
Here’s where the old explanation had it wrong: Scientists suspected that hunger comes shortly after AgRP tells the MC4 receptor to send its signal. But when researchers at the University of Vanderbilt tested that system, they found something surprising.
They blocked the MC4 receptor signal, which should have brought the process (and the onset of hunger) to a screeching halt. But it didn’t. The neurons still fired. So they started blocking other parts inside the cell. By turning one thing off at a time, they eventually found an overlooked player in the game: a special protein, Kir7.1, that communicates with the MC4 receptor. When the researchers blocked the once-unnoticed protein, that finally quieted the neuron, and hunger pathway.
“From a human health perspective, this is huge in that it gives us a new insight into such a critical metabolic pathway,” says Rafael Palomino, another co-author of the study and graduate student in Millhauser’s lab. Palomino, who holds a fellowship from the National Institutes of Health, suggested that the discovery could allow future scientists to create more precise and specialized medicine to treat eating disorders. “As with any drug, you want to avoid off-target molecules that can lead to side effects,” Palomino says. “Moving away from an on-off switch model to something that can be fine tuned to a specific response requires learning as much as we can about this pathway.”
That medicine could come through altering AgRP’s structure. By tweaking the protein’s shape, Millhauser can create versions of AgRP that either enhance or dull hunger. “When we inject modified versions of AgRP into rats,” says Millhauser, “we can produce feeding behavior that goes way beyond or way less than normal.”
Hunger-enhancing versions of AgRP could help people who suffer from cachexia, a wasting syndrome that afflicts patients with cancer, AIDS, multiple sclerosis and other diseases. Cachexia drives the body to consume its own healthy tissues, Millhauser explained, and can be hard to treat. “Once cachexia kicks in, for reasons that are not well understood, it’s very difficult to reverse,” says Millhauser. “One of the few molecules that can do it is AgRP.”
Hunger-dulling versions of AgRP could help people who struggle with overeating as well. “The obesity epidemic has profound health consequences,” says Millhauser, who explained that his lab had produced a type of Trojan horse version of AgRP that still binds to the MC4 receptor, but steals the place of regular AgRP and produces a much shorter hunger response instead. “If we could develop drugs that interfere with this system, that interfere with AgRP’s action, then that could be great way to develop therapeutics to help people stay at a healthier weight.”
I COULD EAT A HORSE New study leads to a greater understanding of the cellular signaling responsible for the hunger sensation.