USF Health Identifies Brain Circuit Regulating Metabolism in Response to Cold

USF Health researchers identified a previously unknown brain circuit in the hypothalamus that regulates metabolism and appetite in response to cold exposure, with potential implications for treating obesity and diabetes.

USF Health researchers have uncovered a previously unstudied brain region, the dorsal posterior periventricular hypothalamic nucleus (dPVp), that acts as a control center for the body’s metabolic responses to cold temperatures. The discovery, published in Neuron, reveals how this region coordinates eating, heat production, and energy use when temperatures drop, offering new insights into metabolic regulation.

A Hidden Circuit for Cold-Induced Metabolism

The study, led by Dr. Yong Xu and Dr. Hailan Liu at USF Health’s Center for Molecular Psychiatry, focused on the dPVp, a region of the hypothalamus that had received little scientific attention. Researchers found that the dPVp becomes highly active when body temperatures fall, triggering a cascade of metabolic and behavioral changes. We identified a very understudied brain region and then found the first function for that brain region, Xu said.

Experiments on non-human models showed that activating dPVp neurons increased appetite while boosting energy expenditure, helping prevent weight gain and improving glucose regulation. This dual effect suggests the region plays a critical role in balancing fuel intake and energy use during cold exposure. Instead of simply lowering food intake, this pathway may help the body use energy more efficiently, Xu explained.

Two researchers in lab coats examine a sample tray and computer data at a laboratory workstation — Photo: usf.edu

A Cold Sensor Protein as a Therapeutic Target

The research also identified a protein called KCNK2 (also known as TREK-1) within dPVp neurons that acts as a biological “cold sensor.” This protein detects temperature changes and coordinates the body’s response. If successful treatments were developed targeting the cold sensor, we wouldn’t have to expose people to cold temperatures to achieve those benefits; one could maintain metabolic health without dieting, Xu said.

Dr. Liu, the study’s first author, emphasized the potential for drug development. One of the future directions is to use that as a drug target to try to develop highly selective inhibitors for KCNK2 as a future medicine, she said. The findings suggest that therapies targeting this pathway could offer an alternative to traditional weight-loss strategies by enhancing energy efficiency rather than suppressing appetite.

Implications for Obesity and Metabolic Disorders

The discovery could reshape approaches to treating obesity, type 2 diabetes, and other metabolic conditions. Current treatments often focus on reducing calorie intake, but the dPVp pathway offers a new mechanism: improving the body’s ability to burn and use energy. The basic function of the dPVp is to sense temperature fluctuations and then coordinate a comprehensive set of behaviors or metabolic changes to deal with cold exposure, Xu said.

While the research is still in early stages, the team noted that further studies are needed to determine whether the pathway can be safely targeted in humans. The findings highlight the dPVp’s potential as a novel therapeutic target, with the possibility of mimicking the metabolic benefits of cold exposure without requiring actual temperature changes.

What’s Next for the Research

If successful treatments were developed targeting the cold sensor, we wouldn’t have to expose people to cold temperatures to achieve those benefits, Xu reiterated.

The study, conducted in non-human models, shows that further research is needed to validate these results in human subjects. For now, the discovery represents a significant step forward in understanding how the brain regulates metabolism and opens new avenues for developing innovative therapies.

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