Columbia scientists have found specialized neurons in the brains of mice that order the animals to stop eating.
Though many feeding circuits in the brain are known to play a role in monitoring food intake, known neurons in those circuits do not make the final decision to cease eating a meal.
The newly identified neurons, a new element of these circuits, are located in the brainstem, the oldest part of the vertebrate brain. Their discovery could lead to new treatments for obesity.
"These neurons are unlike any other neuron involved in regulating satiation," says Alexander Nectow, a physician-scientist at Columbia University Vagelos College of Physicians and Surgeons, who led the research with Srikanta Chowdhury, an associate research scientist in the Nectow lab.
"Other neurons in the brain are usually restricted to sensing food put into our mouth, or how food fills the gut, or the nutrition obtained from food. The neurons we found are special in that they seem to integrate all these different pieces of information and more."
New single-cell technique reveals neurons
The decision to stop eating is a familiar phenomenon. "It happens every time we sit down to eat a meal: At a certain point while we're eating, we start to feel full, and then we get fuller, and then we get to a point where we think, okay, that's enough," Nectow says.
How does the brain know when the body has had enough-and how does it act on that information to stop eating?
Other researchers had previously tracked the decision-making cells to the brainstem, but the leads ended there.
Nectow and Chowdhury deployed a new single-cell technique that makes it possible to peer into a region of the brain and discern different types of cells that until now have been difficult to distinguish from one another.
"This technique-spatially resolved molecular profiling-allows you to see cells where they are in the brainstem and what their molecular composition looks like," Nectow says.
During their profiling of a brainstem region known for processing complex signals, the researchers spotted previously unrecognized cells that had similar characteristics to other neurons involved in regulating appetite. "We said, 'Oh, this is interesting. What do these neurons do?'"
Neurons track each bite
To see how the neurons influenced eating, the researchers engineered the neurons so they could be turned on and off, by the researcher, with light.
When the neurons were activated by the light, the mice ate much smaller meals. The intensity of the activation determined how quickly animals stopped eating. "Interestingly, these neurons don't just signal an immediate stop; they help the mice to slow down their eating gradually," Chowdhury says.
Nectow and Chowdhury also looked at how other eating circuits and hormones affected the neurons. The researchers found that the neurons were silenced by a hormone that increases appetite and activated by a GLP-1 agonist, a class of drugs now popular for treating obesity and diabetes. These experiments found that these inputs helped the neurons track each bite the mice took."Essentially these neurons can smell food, see food, feel food in the mouth and in the gut, and interpret all the gut hormones that are released in response to eating. Ultimately, they leverage all of this information to decide when enough is enough."
"Essentially these neurons can smell food, see food, feel food in the mouth and in the gut, and interpret all the gut hormones that are released in response to eating," Nectow says. "And ultimately, they leverage all of this information to decide when enough is enough."
Though the specialized neurons were found in mice, Nectow says their location in the brainstem, a part of the brain that is essentially the same in all vertebrates, suggests that it is highly likely that humans have the same neurons.
"We think it's a major new entry point to understanding what it means to be full, how that comes about, and how that is leveraged to end a meal," Nectow adds. "And we hope that it could be used for obesity therapies down the road."
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Additional information
Alexander Nectow, MD, PhD, is a postdoctoral clinical fellow in the Department of Medicine at Columbia University Vagelos College of Physicians and Surgeons.
All authors (from Columbia unless noted): Srikanta Chowdhury, Nachiket G. Kamatkar, Wendy Xueyi Wang (Broad Institute, Massachusetts Institute of Technology, and Harvard University), Christa A. Akerele, Jiahao Huang (Broad Institute and MIT), Junlin Wu, Amajindi Nwankpa, Charlotte M. Kane, Varun M. Bhave, Hao Huang (Princeton University), Xiao Wang (Broad Institute and MIT), and Alexander R. Nectow.
The research was supported by a Russell Berrie Foundation Fellowship, the American Diabetes Association, Damon Runyon Cancer Research Foundation's Damon Runyon-National Mah Jongg League, Inc. Fellowship, the Searle Scholars Program, Thomas D. and Virginia W. Cabot and Edward Scolnick Professorships, Ono Pharma Breakthrough Science Initiative Award, a Merkin Institute Fellowship, an NIH New Innovator Award, New York Nutrition and Obesity Research Center, and the Berrie Program in the Neurobiology of Body Weight Regulation.
Xiao Wang is a co-founder of Stellaromics, Inc.
