Obesity affects a staggering 40 percent of adults and 20 percent of children in the United States. While some new popular therapies are helping to tackle the epidemic of obesity, there is still so much that researchers do not understand about the brain-body connection that regulates appetite. Now, researchers have discovered a previously unknown population of neurons in the hypothalamus that regulate food intake and could be a promising new target for obesity drugs.

In a study published in the Dec. 5 issue of Nature, a team of researchers from the Laboratory of Molecular Genetics at Rockefeller University in New York, the Institute for Genome Science (IGS) at the University of Maryland School of Medicine (UMSOM) in Baltimore, as well as New York and Stanford universities discovered a new population of neurons that is responsive to the hormone leptin. Leptin responsive neurons are important in obesity since leptin is sent to the brain from the body’s fat stores to suppress hunger.

Brian Herb, PhD

“We’ve long known that the hypothalamus — located deep in the brain — plays a role in hunger, hormone levels, stress responses, and body temperature,” said Brian Herb, PhD, a scientist at IGS and a research associate of the Department of Pharmacology, Physiology, and Drug Development at UMSOM. His research published in 2023 in Science Advances was the first time that scientists used single-cell technology to map the cells in the developing hypothalamus in humans, from precursor stem cells to mature neurons.

“Since our earlier research showed that unique regulatory programs in genes give rise to specialized neuronal populations — it makes sense that this new research discovered a previously unknown set of neurons that regulate energy and food intake,” Herb added.

Through several experiments with mice, the researchers found that this previously unknown neuronal population that expresses both receptors for leptin and the BNC2 gene not only helps suppress hunger, but also responds to food-related sensory cues, such as food palatability and nutritional status. For example, the researchers used CRISPR-Cas 9 to knock out the leptin receptor (LEPR) in these BNC2 neurons. Those mice ate more and gained more weight than control mice. In addition, researchers added fluorescence to the BNC2 neurons and noticed when they fed mice after fasting, the BCN2 neurons activated, whereas previously known neuronal populations in the hypothalamus did not react.

“BNC2 neurons in the hypothalamus, which are activated by the hunger hormone leptin, provide the potential for a completely new class of obesity drugs," said Mark T. Gladwin, MD, who is the John Z. and Akiko K. Bowers Distinguished Professor and dean of UMSOM, and vice president for medical affairs at University of Maryland, Baltimore. "These drugs would be distinct from Ozempic and other GLP-1 agonists, which stimulate insulin secretion. Leptin-targeting drugs could be beneficial for those who can’t tolerate GLP-agonists due to gastrointestinal side effects like nausea and stomach upset.”