Peroxisomes Show Promise as Backup heat Generators, Possibly Aiding Metabolism

St. Louis, MO – Researchers at Washington University in St. Louis have identified peroxisomes as a potential alternative pathway for heat production in brown fat, offering a possible compensatory mechanism if mitochondria – the cell’s primary heat-producing organelles – become impaired. The findings, published September 17, 2025, in Nature, suggest a novel approach to combating obesity and improving metabolic health.

The study, led by Dr. Imran J. Lodhi and colleagues, centers on acyl-CoA oxidase 2 (ACOX2), a key protein within peroxisomes. Experiments with mice revealed that ACOX2 plays a critical role in consuming fuel and generating heat. Mice lacking ACOX2 in their brown fat exhibited reduced cold tolerance, displaying lower body temperatures when exposed to cold environments compared to control mice. These mice also demonstrated impaired insulin sensitivity and a greater susceptibility to obesity when fed a high-fat diet.

Conversely, mice genetically engineered to produce elevated levels of ACOX2 in brown fat showed increased heat production, improved cold tolerance, and enhanced insulin sensitivity, alongside better weight control on the same high-fat diet. Researchers utilized a newly developed fluorescent heat sensor and infrared thermal imaging to confirm these findings, demonstrating that ACOX2 metabolism of specific fatty acids directly correlates with increased heat within brown fat cells, and that ACOX2-deficient mice generated less heat.

The fatty acids utilized by ACOX2 are naturally produced by the human body, but are also present in dairy products, human breast milk, and are synthesized by certain gut microbes.This discovery opens the door to potential dietary interventions – including foods, probiotics, or “nutraceuticals” – designed to boost this heat-production pathway. Dr. Lodhi also noted that his team is exploring drug compounds that could directly activate ACOX2.

“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.” He emphasized that while a correlation exists, further research is needed to establish 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.”

The research was supported by grants from the National Institutes of Health (NIH), including R01DK133344, R01DK115867, R01DK132239, GM103422, T32DK007120, S10 OD032315, DK020579 and DK056341, as well as funding from the FP7 funded European Infrafrontier-I3 project.Lodhi and co-author Xiaowei liu have filed a provisional patent application related to targeting ACOX2 activation as a treatment for obesity and related metabolic diseases.

Source: Liu, X., et al. (2025) Peroxisomal metabolism of branched fatty acids regulates energy homeostasis. Nature. doi.org/10.1038/s41586-025-09517-7