For a long time, scientists haven’t fully understood how the human body regulates its heating mechanisms. However, in a recent study published in Nature Metabolism, researchers have found new information on how the body uses insulin to stimulate the production of body heat.
The research was led by Johathan Bogan, MD, associate professor of medicine (endocrinology) and of cell biology. Bogan and his colleagues discovered that, in mice at least, insulin activates genes that control body temperature so that the body produces heat, which stimulates the removal of glucose from the bloodstream.
The production of body heat is an important way that humans can burn energy. “Previously, how the body regulates heat after meals has not been well understood,” explains 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.”
The workings of this process are a little bit complicated. Insulin acts on fat and muscle cells to chop TUG proteins into two pieces. The front half carries glucose transporters to the cell surface, which enables glucose absorption. Meanwhile, the back half of the TUG protein (known as the TUG C-terminal cleavage product) enters the cell nucleus and turns on genes that generate body heat.
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The researchers concluded that insulin-stimulated TUG cleavage increases glucose uptake at an individual’s metabolic rate. They believe alterations in this process, potentially created by variants in genes, might affect diabetes in humans.
In the future, researchers hope to better understand TUG action and the proteins it works with, as genetic variation occurring in 20 to 25 percent of people may play an important role in the development of diabetes.
“How insulin acts in fat and muscle is a fascinating problem in cell biology, as well as being important for diabetes,” says Bogan. “In my lab, I wanted to approach it at that level, because there is the possibility of having fundamental new insights.”
Bogan used a genetic approach to identify the TUG protein, which was first reported in the journal Nature in 2003. His team’s most recent paper built on work he did with colleague Gerald Shulman, MD, PhD, which studied mice with 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,” says 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.”
In people with obesity, this mechanism is impaired, resulting in insulin resistance. Bogan believes energy expenditure may also be affected, meaning insulin resistance may contribute to obesity by offsetting the balance between calories consumed and expended, creating a vicious cycle that’s difficult to free oneself from.
However, Bogan’s team believes they may have a new way to treat metabolic disease based on their findings. The Blavatnik Fund for Innovation at Yale awarded Bogan a grant to help him develop a method to target this particular pathway. We can’t wait to see what he and his team come up with!Whizzco