For many years, how the human body regulates body heat has not been well understood. In new research published in Nature Metabolism, researchers found that insulin stimulates the production of body heat. Led by Jonathan Bogan, MD, associate professor of medicine (endocrinology) and of cell biology, the unexpected discovery builds on two decades of research into insulin action.
Obesity can result from a slight imbalance between the number of calories eaten and the calories burned. Exercise burns calories, but the production of body heat is another important way the body burns calories. “Previously, how the body regulates heat after meals has not been well understood,” explained Bogan. “In my lab, we've been studying how insulin regulates glucose uptake. To our surprise, we found that the production of body heat is activated directly by insulin, and that this is coupled to insulin’s effect to stimulate glucose uptake.”
In the new work, the researchers discovered that insulin activates genes that control body temperature. To stimulate the removal of glucose from the bloodstream, insulin acts on fat and muscle cells to chop TUG proteins in two. The front half then carries glucose transporters to the cell surface, enabling glucose absorption. The new results show that the back half–the TUG C-terminal cleavage product–travels into the cell nucleus and turns on genes that generate body heat.
The research, done in mouse models, concluded that insulin-stimulated TUG cleavage matches one’s metabolic rate with glucose uptake, and that alterations in this process might affect diabetes in humans. The investigators found that the TUG product acts together with a protein that is the main target of glitazone diabetes drugs. Genetic variations in this protein affect the risk of diabetes, but how this occurs has not been understood. The new findings indicate that these variations affect TUG action. Since this genetic variation influences as much as 20-25% of diabetes in the population, understanding this pathway could have a major impact on public health.
Bogan received his undergraduate degree from Yale. After earning his medical degree from Harvard and completing his residency and fellowship at Massachusetts General Hospital, he worked at the Whitehead Institute for Biomedical Research before returning to Yale in 2002 and starting his lab. “How insulin acts in fat and muscle is a fascinating problem in cell biology, as well as being important for diabetes,” he noted. “In my lab, I wanted to approach it at that level, because there is the possibility of having fundamental new insights.”
His lab identified the TUG protein using a genetic approach, which was reported in Nature in 2003. His team’s recent paper built on work with his colleague Gerald Shulman, MD, PhD, to study mice with ongoing, unregulated cleavage of the TUG protein.
“Sure enough, we saw increased glucose uptake. But there were a couple of things that we didn't expect,” said Bogan. “It turns out that TUG regulates not only glucose transporters, but also other proteins that are present in the same membranes and that may contribute to blood pressure and cholesterol metabolism. And now we’ve discovered an effect of the TUG cleavage product to control metabolic rate.”
This mechanism is impaired in obesity, resulting in insulin resistance, in large part through mechanisms defined in the Shulman lab. Bogan now believes that energy expenditure may also be affected, suggesting that insulin resistance may contribute to an imbalance between calories consumed and expended, setting up a vicious cycle and promoting further obesity. The work also suggests a possible new approach to treat metabolic disease. In 2020, the Blavatnik Fund for Innovation at Yale awarded Bogan a grant to develop a therapeutic to target this pathway.
Other members of the research team include Estifanos N. Habtemichael, PhD; Don T. Li, PhD; João Paulo Camporez, PhD; Xavier O. Westergaard; Chloe I. Sales; Xinran Liu, MD, PhD; Francesc López-Giráldez, PhD; Stephen G. DeVries, MD; Hanbing Li, PhD; Diana M. Ruiz; Kenny Y. Wang; Bhavesh S. Sayal; Sofia González Zapata; Pamela Dann; Stacey N. Brown, PhD; Sandro Hirabara, PhD; Daniel F. Vatner, MD, PhD; Leigh Goedeke, PhD; William Philbrick, PhD; and Shulman.
Yale’s Section of Endocrinology & Metabolism works to improve the health of individuals with endocrine and metabolic diseases by advancing scientific knowledge; applying new information to patient care; and training the next generation of physicians and scientists to become leaders in the field. To learn more about their work, visit Endocrinology & Metabolism.
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