The findings were published Sept. 17 in Nature.

Brown fat is unique because it turns energy (calories) from food into heat. Unlike white fat, which stores energy, or muscle, which uses it 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've identified could provide opportunities to target the energy expenditure side of the weight loss equation, potentially making it easier for the body to burn more energy by helping brown fat produce more heat," said senior author Irfan Lodhi, PhD, a professor of medicine in the Division of Endocrinology, Metabolism & Lipid Research at WashU Medicine. "Boosting this kind of metabolic process could support weight loss or weight control in a way that is perhaps easier to maintain over time than traditional dieting and exercise. It's a process that basically wastes energy -- increasing resting energy expenditure -- but that's a good thing if you're trying to lose weight."

A back-up heater in brown fat

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

The new research identifies peroxisomes, small structures within cells that process fats, as an alternative heat source in brown fat. When exposed to cold, these peroxisomes multiply. This effect was even stronger in mice whose mitochondria lacked uncoupling protein 1, suggesting that peroxisomes can step in 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 that lacked ACOX2 in their brown fat were less able to tolerate cold, showed lower body temperatures after exposure to cold, and had poorer insulin sensitivity. When fed high-fat diets, they also gained more weight than typical mice.

In contrast, mice genetically engineered to make 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 metabolized certain fatty acids, brown fat cells got hotter. They also used an infrared thermal imaging camera to show that mice lacking ACOX2 produced less heat in their brown fat.

While human bodies can manufacture these fatty acids, the molecules also are found in dairy products and human breast milk and are made by certain gut microbes. Lodhi said this raises the possibility that a dietary intervention based on these fatty acids -- such as a food, probiotic or "nutraceutical" intervention -- could boost this heat-production pathway and the beneficial effects it appears to have. He and his colleagues also are investigating possible drug compounds that could activate ACOX2 directly.

"While our studies are in mice, there is evidence to suggest this pathway is relevant in people," Lodhi said. "Prior studies have found that individuals with higher levels of these fatty acids tend to have lower body mass indices. But since correlation is not causation, our long-term goal is to test whether dietary or other therapeutic interventions that increase levels of these fatty acids or that increase activity of ACOX2 could be helpful in dialing up this heat production pathway in peroxisomes and helping people 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 by the FP7 funded European Infrafrontier-I3 project. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

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