Scripps Research scientists have made a breakthrough that could pave the way for new treatments for weight loss and metabolic health. When exposed to cold temperatures, mammals instinctively expend more energy to maintain a stable body temperature. This surge in energy expenditure prompts increased appetite and food intake, but the specific mechanisms controlling this phenomenon are unknown.
Neuroscientists at The Scripps Research Institute have now identified the brain circuit that causes increased appetite during cold temperatures.
In the new study, recently published in the journal Nature, researchers identified a group of neurons that are the "switch" for this cold-related foraging behavior in mice. The discovery could lead to potential treatments for metabolic health and weight loss.
"This is a fundamental adaptive mechanism in mammals, and future treatments targeting this mechanism may enhance the metabolic benefits of cold or other forms of fat burning," said Dr. Neeraj Lal, the study's senior author and associate professor and the Abed-Vivid Chair in Chemistry and Chemical Biology at Scripps Research. The study's first author is Neeraj Lal, Ph.D., a postdoctoral associate in Ye's lab.
Because exposure to cold environments enhances energy expenditure to stay warm, cold water immersion and other forms of "cold therapy" have been explored as methods for weight loss and improving metabolic health. One drawback of cold therapy is that humans did not evolve their response to cold for the purpose of losing weight (an effect that could have been fatal during pre-modern times of frequent food scarcity). Like diet and exercise, cold can increase appetite, counteracting any weight loss results. In this study, Ye and his team sought to identify the brain circuits that mediate this cold-induced increase in appetite.
One of the first things they observed was that with the onset of cold temperatures (from 73 degrees Fahrenheit to 39 degrees Fahrenheit), mice increased food seeking only after a delay of about six hours, suggesting that this behavioral change was not simply a direct result of the cold sensation.
The researchers used whole-brain clearing and light-sheet microscopy techniques to compare the activity of neurons across the brain in cold and warm conditions. Soon, they discovered a key phenomenon: While most neurons throughout the brain had much lower activity in cold conditions, some neurons in a region called the thalamus were more activated.
Ultimately, the team zeroed in on a specific population of neurons called the midline xiphoid nucleus of the thalamus and showed that, under cold conditions, the activity of these neurons spikes before the mice emerge from cold-induced hibernation to search for food. The increase in activity in the xiphoid nucleus was greater when less food was available at the onset of cold conditions—suggesting that these neurons were responding to the energy deficit caused by the cold rather than the cold itself.
When the researchers artificially activated these neurons, the mice increased food-seeking activity but not other activities. Likewise, when the team inhibited the activity of these neurons, the mice's food-seeking behavior was reduced. These effects only occur under cold conditions, meaning that low temperatures provide a separate signal that must also accompany changes in appetite.
In a final set of experiments, the team found that these xiphoid nucleus neurons project to a brain region called the Akulomb nucleus—an area long known for integrating reward and aversion signals to guide behavior, including eating.
Ye said these results may ultimately have clinical implications because they show it is possible to block the increase in appetite typically caused by cold, making a relatively simple cold-exposure therapy more effective in promoting weight loss.
"One of our main goals now is to figure out how to dissociate increased appetite from increased energy expenditure. We also want to figure out whether this cold-induced increase in appetite is part of a broader mechanism the body uses to compensate for extra energy expenditure, such as after exercise," he said.