In terms of controlling diabetes and obesity, it’s easy to think of fat as the enemy. But there’s a type of fat that burns calories, producing heat and lowering blood glucose levels. Now, a new study has uncovered a molecule that helps regulate the energy-burning activity of these thermogenic fat cells. Understanding the chemical reactions inside these fat cells could provide new leads for treating conditions like diabetes and obesity.
The thermogenic fat cells generate heat and are particularly important for babies, helping them stay warm. Adults have them too, and so do mice, which is helpful for studying them in the lab. Inside the thermogenic fat cells, tiny structures called mitochondria run the heat-producing reactions. Researchers know that an enzyme called UCP1 acts like a gate in the membrane of the mitochondria, allowing protons to flow inside when activated. The flow of protons rushing through the UCP1 enzyme is how the thermogenic fat cells primarily generate heat.
In a study published in Science Advances, graduate students Alek Peterlin and Jordan Johnson, working with senior author Katsu Funai, PhD, an associate professor in the Department of Nutrition & Integrative Physiology at University of Utah Health, showed that a molecule called phosphatidylethanolamine (PE) helps control the flow of ions through the UCP1 channel. First, the researchers showed that when mice are kept in cold temperatures, the amount of PE in their cells increases. When they are kept warm, the PE levels drop. They also showed that mice genetically altered to produce less PE could no longer generate heat, even though they had normal amounts of fully functional UCP1. In other words, PE functions like a thermostat for UCP1.
To get to the bottom of how PE and UCP1 interact, Peterlin had to learn a highly specialized technique called patch-clamping. Only a few labs around the world have the right expertise and specialized equipment to perform this analysis on mitochondria. Fortunately, one of them was at the University of Utah.
“You need a high-tech microscope and electrode setup,” Peterlin says. “There’s a lot of electronics and a lot of skill involved.” Peterlin worked closely with Enrique Balderas, PhD, a research scientist in the lab of Dipayan Chaudhuri, MD, PhD, at the Nora Eccles Harrison Cardiovascular Research and Training Institute. The two spent a long time perfecting the protocol until they were able to collect consistent data.
Briefly, the technique works like this. Mitochondria have a double membrane, and UCP1 is contained in the inner membrane, so Peterlin first had to extract the mitochondria from the cells and remove the outer membrane. Then, he fused a pipette with an electrode to the inner membrane. “The tip of the pipette fuses to the inner mitochondrial membrane in such a way that it has penetrated to the inner portion, called the matrix,” he explains. “When electrical current is applied, it measures how many protons are entering the matrix.” This provides a valuable direct measurement of UCP1 activity.
Understanding the role of PE in regulating UCP1 activity could help someday develop tests or even health interventions for people with obesity or diabetes. “If we were able to take a biopsy of [someone’s] brown adipose tissue and look at the lipid composition of the mitochondrial membranes, we’d have some indication of how active UCP1 might be,” Peterlin says. “It's interesting because it's something that can be changed, not necessarily with genetic interventions, just with changes in lifestyle.”