Study uncovers a specialized gut-brain pathway for glucose sensing

"How does the brain distinguish glucose from the many nutrients absorbed in the gut?" In a groundbreaking study, a research team at KAIST has uncovered a gut-brain circuit that enables the brain to selectively recognize glucose—beyond simply registering total caloric intake. This discovery opens a new avenue for developing targeted strategies to control appetite and treat metabolic disorders such as obesity and diabetes.

On July 9, KAIST (President Kwang Hyung Lee) announced that the research was led by Professor Greg S.B. Suh of the Department of Biological Sciences in collaboration with Professor Young-Gyun Park (BarNeuro), Professor Seung-Hee Lee (Department of Biological Sciences), and researchers at Albert Einstein College of Medicine in New York.

The team demonstrated that, in a state of hunger, animals are capable of detecting and preferentially selecting D-glucose in the gut via a specialized gut-brain circuit.

While it has long been known that the gut transmits caloric information to the brain to regulate appetite—primarily through suppressing hunger-related neurons in the hypothalamus—this study is the first to reveal a nutrient-specific neural pathway that allows the brain to detect glucose itself, not just general caloric content.

Using a combination of optogenetics, neural imaging, and nutrient infusions, the researchers found that a subset of CRF neurons in the paraventricular nucleus (PVN) of the hypothalamus respond selectively—and rapidly—to D-glucose introduced directly into the small intestine. These neurons did not respond, or responded inversely, to other nutrients like L-glucose, amino acids, or fats.

Further mapping of the pathway showed that D-glucose signals are conveyed from the small intestine to the dorsolateral parabrachial nucleus (PBNdl) in the brainstem via the spinal cord, and then relayed to CRF neurons in the PVN. This is in contrast to signals from amino acids and fats, which travel to the brain via the vagus nerve.

Inhibiting the activity of CRF neurons in fasting mice eliminated their natural preference for glucose, confirming the necessity of this circuit for glucose-specific nutrient selection.

The study builds on Professor Suh's earlier work at NYU, where his team identified DH44 neurons in fruit flies that detect sugar in the gut. Inspired by the possibility that mammals might possess similar glucose-sensing neurons, the KAIST team launched this investigation.

Dr. Jineun Kim (KAIST Ph.D., now at Caltech) played a leading role in the study, demonstrating that fasting mice preferred glucose over other nutrients delivered directly into the stomach and that CRF neurons responded in real time. Wongyo Jung (KAIST B.S., now a Ph.D. student at Caltech) contributed modeling and behavioral analyses, while Dr. Shinhye Kim uncovered the role of specific spinal neurons in transmitting nutrient signals from the gut to the brain.

Drs. Kim and Kim noted,
"This study began with a simple but fundamental question: How does the brain distinguish glucose from other nutrients absorbed in the gut? We've shown that spinal-based gut-brain circuits play a central role in maintaining energy balance and metabolic homeostasis."

Professor Suh added,
"By identifying a specialized gut-brain pathway for glucose sensing, this research opens up new therapeutic possibilities for metabolic diseases. Moving forward, we aim to investigate how similar circuits detect other essential nutrients, such as amino acids and fats, and how these systems interact."

Ph.D. student Jineun Kim, Dr. Shinhye Kim, and student Wongyo Jung (co-first authors) contributed to this study, which was published online in the international journal Neuron on June 20, 2025.