A hidden “backup heater” helps burn fat and boost metabolism

The results were published on September 17 nature.

Brown fat is unique because it converts energy (calories) from food into heat. Unlike white fat, which stores energy, or muscles use immediately, brown fat helps keep the body warm in cold environments. Exposure to cold can increase the amount of brown fat, and scientists have long suggested that activating it could support weight loss by increasing calorie burning.

“The pathway we identified could provide opportunities to target the energy expenditure side of the weight loss equation, which may make it easier for the body to burn more energy by helping brown fat produce more heat,” said lead author Irvan Lodhi, MD, professor of medicine in the Division of Endocrinology, Metabolism and Lipid Research at Washoe Medicine. “Boosting this type of metabolism can support weight loss or weight control in a way that is perhaps easier to maintain over time than with traditional diet and exercise. It’s a process that essentially wastes energy — which increases resting energy expenditure — but that’s a good thing if you’re trying to lose weight.”

Backup heater in brown fat

Until now, scientists have understood brown fat’s heat production mainly through mitochondria, the energy centers in cells. Mitochondria found in brown fat can switch from making fuel to generating heat through a molecule called uncoupling protein 1. However, studies have shown that mice lacking this protein are still able to burn energy and produce heat, suggesting another system at work.

New research identifies peroxisomes, small structures inside cells that process fat, as an alternative source of heat in brown fat. When exposed to cold, these peroxisomes multiply. This effect was stronger in mice whose mitochondria lacked uncoupling protein 1, suggesting that peroxisomes can intervene when mitochondria lose their ability to produce heat.

Lodhi and his team discovered that peroxisomes burn fuel and release heat through a process involving a protein called acyl-CoA oxidase 2 (ACOX2). Mice lacking ACOX2 in brown fat were less tolerant of cold, showed lower body temperatures after cold exposure, and had lower insulin sensitivity. When they were fed high-fat diets, they also gained more weight than conventional mice.

In contrast, mice genetically engineered to produce unusually high amounts of ACOX2 in brown fat showed increased heat production, better cold tolerance, and improved insulin sensitivity and weight control when fed the same high-fat diet.

Using a fluorescent heat sensor they developed, the researchers found that when ACOX2 metabolizes certain fatty acids, brown fat cells become hotter. They also used an infrared thermal imaging camera to show that mice lacking ACOX2 produced less heat in brown fat.

While human bodies can synthesize these fatty acids, the molecules are also found in dairy products and human breast milk and are made by some gut microbes. This raises the possibility that a nutritional intervention based on these fatty acids — such as food, probiotics, or a “dietary” intervention — could enhance the heat production pathway and the beneficial effects it appears to have, Lodhi said. He and his colleagues are also investigating potential drug compounds that can directly activate ACOX2.

“Although our studies were conducted in mice, there is evidence to suggest that this pathway is relevant in humans,” Lodhi said. “Previous studies have found that individuals with higher levels of these fatty acids tend to have lower BMIs. But since association is not causal, our long-term goal is to test whether nutritional or other therapeutic interventions that increase levels of these fatty acids or that increase ACOX2 activity could be useful in connecting to the heat production pathway in peroxisomes and helping people to lose weight and improve their metabolic health.”

This work was supported by the National Institutes of Health (NIH), Grant Numbers R01DK133344, R01DK115867, R01DK132239, GM103422, T32DK007120, S10 OD032315, DK020579 and DK056341; And through the European Infrafrontier-I3 project funded by FP7. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Lodhi and Liu are named in a provisional patent application filed by the University of Washington regarding targeting ACOX2 activation as a treatment for obesity and related metabolic diseases.