New Brown Fat Pathway Could Make Weight Loss Easier To Maintain

Scientists discover alternative cellular process for producing heat that may enhance metabolic health.

Researchers at Washington University School of Medicine in St. Louis have uncovered a previously unknown mechanism by which brown fat — the type of fat that burns energy — can drive the body’s metabolism. In mouse studies, they found that brown fat can use cellular fuel to generate heat in a way that enhances metabolic health. These results point to new strategies for targeting brown fat in the treatment of conditions such as obesity and insulin resistance.

The findings were recently published in the journal Nature.

Brown fat is distinct from white fat, which serves as a long-term energy reserve, and from muscle, which provides immediate energy for activity. Instead, brown fat specializes in converting food-derived calories into heat. This heat production is vital for maintaining body temperature in cold environments, and exposure to cold can increase brown fat levels. Because of its ability to burn calories, scientists have suggested that stimulating brown fat could play a role in weight-loss therapies.

“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

The traditional view of how brown fat generates heat centers on mitochondria, often described as the cell’s power plants. In this tissue, mitochondria can switch from producing cellular energy to generating heat through the action of a protein known as uncoupling protein 1. However, researchers have long observed that even mice lacking this protein in their brown fat are still capable of burning energy and producing heat, suggesting that cells have alternative ways of generating warmth.

The latest study points to peroxisomes as key contributors to this backup system. Peroxisomes are tiny structures within cells that specialize in breaking down fatty acids. The researchers found that exposure to cold increases the number of peroxisomes in brown fat. This rise was even greater in mice missing uncoupling protein 1, indicating that peroxisomes may help take over heat production when mitochondrial pathways are compromised.

The role of ACOX2

Lodhi and his colleagues discovered that peroxisomes consume fuel and produce heat in a metabolic process that centers on a key protein in these cell parts called acyl-CoA oxidase 2 (ACOX2). Mice missing ACOX2 in brown fat lost some ability to tolerate cold, showing lower body temperatures after exposure to cold compared with typical mice. In addition, compared with typical mice, their tissues did not make good use of the blood sugar-regulating hormone insulin, and they were more prone to obesity when fed high-fat diets.

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.

Implications for humans

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.”

Reference: “Peroxisomal metabolism of branched fatty acids regulates energy homeostasis” by Xuejing Liu, Anyuan He, Dongliang Lu, Donghua Hu, Min Tan, Abenezer Abere, Parniyan Goodarzi, Bilal Ahmad, Brian Kleiboeker, Brian N. Finck, Mohamed Zayed, Katsuhiko Funai, Jonathan R. Brestoff, Ali Javaheri, Patricia Weisensee, Bettina Mittendorfer, Fong-Fu Hsu, Paul P. Van Veldhoven, Babak Razani, Clay F. Semenkovich and Irfan J. Lodhi, 17 September 2025, Nature.
DOI: 10.1038/s41586-025-09517-7

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.

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