Lower body temperature found to directly influence glucose metabolism in mice

Some mammals are capable of hibernating during periods of low food availability in an effort to conserve energy and survive. While it is easy to understand why species have evolved this survival mechanism, exactly how these animals regulate their metabolism and body temperature remains a mystery.

Researchers have known for decades that the lower body temperatures observed during hibernation go hand in hand with lower metabolism. The metabolism of glucose, a sugar commonly used to generate the energy used by cells, produces heat, and maintaining lower body temperatures conserves energy when food is scarce. What researchers haven't established, however, is whether metabolism determines body temperature or if body temperature changes the organism's metabolism-until now.

The conventional view in the hibernation field suggested that body temperature was controlled by the heat generated by metabolism. The direct relationship between the two couldn't be determined, however, because there was no method to safely lower mammalian body temperature independently of any changes to the animal's metabolism. To address this issue, a group of researchers from the Exploratory Research Center on Life and Living Systems (ExCELLS) and the National Institute for Physiological Sciences (NIPS) at the National Institutes Natural Sciences (NINS) employed a recently developed mouse model of hibernation, known as Q-neuron-induced hypothermia and hypometabolism (QIH). This model enabled the team to safely induce hypothermia in mice and isolate the effect of body temperature on metabolism.

"Understanding how body temperature actively regulates metabolism could have profound implications not only for understanding the physiology of hibernating animals but also for developing non-pharmacological approaches to treat metabolic disorders like diabetes and obesity in humans," said Ryosuke Enoki, associate professor in the ExCELLS and NIPS,and senior author of the research paper.

Remarkably, the team found that mice in the QIH state exhibited elevated fasting glucose and insulin levels in their blood, two hallmarks of insulin resistance. Insulin resistance occurs when cells do not respond appropriately to insulin and are unable to transport glucose into the cells for energy. The condition can eventually lead to type 2 diabetes.

To reverse the hypothermia, the research team simply warmed mice to normal body temperature by increasing ambient temperature. Both the insulin and glucose levels in the hypothermic mice normalized after rewarming.

The key message is simple but powerful: lowering body temperature alone, without drugs or genetic manipulation, can reversibly induce a diabetes-like state in healthy animals. Just by rewarming, normal metabolism is rapidly restored. This demonstrates that body temperature is not a passive output, but an active regulator of systemic glucose metabolism."

Ming-Liang Lee, assistant professor and first author of the research study

Closer analysis of specific organs revealed that glucose metabolism in brown adipose tissue, a heat-generating organ; skeletal muscle; heart and brain were significantly lowered in hypothermic mice, which paralleled decreases in animal movement and energy consumption. Importantly, the reversal of the high glucose and insulin levels in rewarmed mice suggests that that temperature is directly affecting glucose metabolism rather than activation of Qrfp neurons.

While the team's discovery is revealing and challenges the long-standing view that temperature is simply a consequence of metabolic activity, the researchers acknowledge that understanding exactly how temperature affects metabolism will be a significant challenge.

"Our next step is to uncover the molecular and cellular mechanisms that link body temperature with glucose regulation across different tissues. Ultimately, we aim to apply this knowledge to develop "therapeutic hypometabolism" strategies capable of temporarily reducing body metabolic stress in diabetic patients or easing systemic inflammation. Long term, we hope this research will open a path toward new, temperature-based interventions for metabolic disease," said Ming-Liang Lee.