In the U.S. drama "Game of Thrones," the Stark family, which rules the North, repeated the phrase "winter is coming" as they prepared for hardships and adversity that could strike at any time. As if a Stark family of the brain, neurons that first detect cold signals rising from the skin and lead the body's defensive response have been found.
A research team led by Kim Seong-yeon, a professor in the Department of Chemistry and the Institute of Molecular Biology and Genetics at Seoul National University, said in an article published on Aug. 13 in the international journal Nature Metabolism that it found in animal experiments brain neurons that receive cold information sensed by the skin and trigger the body's defensive response. The team named this group of neurons in the parabrachial nucleus (PB) of the hindbrain "PBCold neurons."
The hindbrain is the lower part of the brain and connects to the spinal cord. It is responsible for sustaining life and maintaining the body's balance. The researchers said that as the temperature drops, activity of cold neurons in the mice's hindbrain increases. In particular, when cold neurons were activated, the mice ate more due to increased appetite but did not gain weight. The finding suggests clues to an anti-obesity drug that allows eating freely without gaining weight.
◇ Shivering to generate heat, boosting appetite to replenish calories
Temperature changes are first sensed by the skin. TRP proteins, which are channels through which electrically charged ions pass in the skin, do that job. TRPM8 senses cold, and TRPV1 senses heat. Even without a temperature drop, menthol makes peppermint feel cool because menthol activates TRPM8. Likewise, when capsaicin in chili peppers activates TRPV1, it feels hot.
The researchers found that cold neurons not only transmit cold signals from the skin to other brain regions but also induce bodily responses to the cold. When cold neurons were activated, mice sought warmer places even when it was not cold, and more heat was produced in brown fat. Appetite increased as if to compensate for the increased energy expenditure. This induced bodily responses to overcome the cold.
Conversely, when cold neurons were suppressed, all responses to cold weakened. Even when the temperature dropped, the mice did not actively seek warmer places, and multiple thermoregulatory responses to warm the body failed to function properly. Survival time at low temperatures also dropped sharply. The researchers explained that these results mean PBCold neurons serve as a conductor that integratively orchestrates diverse thermoregulatory responses.
The study was assessed as providing an integrated explanation of how cold sensations are processed in the brain and lead to protective bodily responses. Expectations also emerged that it could lay the groundwork for treating thermoregulation disorders, obesity, and metabolic diseases.
◇ Possibility of an anti-obesity drug that prevents weight gain even when eating freely
Cold neurons were involved not only in bodily responses that warm the body but also in emotional aspects such as comfort. When an air conditioner is turned on in sweltering heat, dopamine is released in the brain's reward circuitry, inducing positive emotions. When PBCold neurons were blocked, these responses dropped markedly. This shows that even without actually lowering the ambient temperature, adjusting cold neurons can alter bodily responses to heat.
Mice exhibit thermoregulatory behavior by stretching out when hot. When the researchers stimulated the mice's cold neurons, this behavior disappeared. Even without temperature changes, the brain received a cold signal and did not feel hot. In situations where body temperature rises excessively, such as heat-related illness, suppressing cold neuron activity to reduce heat production and conservation could conversely lead to a new treatment strategy.
In particular, a new obesity treatment could allow people to eat freely while maintaining body weight. When the researchers stimulated cold neurons for four weeks, the amount the mice ate increased by 50% but their weight did not increase. That is because energy expenditure rose to maintain body temperature. If this can be selectively controlled, it could become a target for a new obesity treatment, the team said.
The study was conducted with support from the National Research Foundation of Korea (NRF) Basic Research Laboratory program. Professor Kim is the corresponding author of the paper. Jeong Si-eun, a postdoctoral fellow at the University of California, San Francisco (UCSF), and Anna Kondaurova, a graduate researcher in Professor Kim's lab, were listed as co-first authors.
References
Nature Metabolism (2026), DOI: https://doi.org/10.1038/s42255-026-01565-1