Researchers at Washington University School of Medicine in St. Louis have uncovered a groundbreaking cellular mechanism in brown adipose tissue that may revolutionize approaches to obesity and metabolic disease treatment. By delving into the metabolic pathways within brown fat, they identified an alternative heat-generating system centered on peroxisomes, small organelles typically overlooked in energy metabolism research. This novel insight opens new avenues for harnessing the energy-burning capabilities of brown fat to combat insulin resistance and obesity, offering hope for innovative therapies beyond conventional diet and exercise.
Brown fat, distinct from white fat, plays a vital role in thermogenesis—the production of heat by burning calories. Historically, mitochondria in brown fat cells have been credited with this heat generation, chiefly through a protein known as uncoupling protein 1 (UCP1). UCP1 facilitates the dissipation of the proton gradient generated during cellular respiration, releasing energy as heat instead of storing it as ATP. This process supports temperature regulation, especially in cold environments, and has been proposed as a target for weight loss since activating brown fat increases energy expenditure.
Surprisingly, earlier studies revealed that brown fat in mice lacking UCP1 still managed to generate heat and consume calories, indicating the presence of yet unidentified “back-up” heat-producing systems. In a recent study published in Nature, the research team led by Dr. Irfan Lodhi unearthed that peroxisomes, organelles involved in lipid metabolism, serve as this critical alternative source of thermogenesis. They demonstrated that peroxisomes in brown fat cells ramp up both in number and metabolic activity when exposed to cold, especially compensating when UCP1-dependent mitochondrial heat production is impaired.
Central to this alternative thermogenic pathway is a peroxisomal enzyme called acyl-CoA oxidase 2 (ACOX2). This enzyme orchestrates the breakdown of branched-chain fatty acids within peroxisomes, a metabolic process that consumes energy and results in heat production. Through genetic manipulation, researchers found that mice deficient in ACOX2 within their brown fat exhibited impaired cold tolerance, reduced heat output, and showed metabolic disturbances such as insulin resistance and a propensity for obesity when subjected to high-fat diets.
Conversely, mice engineered to overexpress ACOX2 in their brown fat displayed a remarkable metabolic advantage. These animals maintained higher body temperatures during cold exposure, demonstrated improved glucose homeostasis, and resisted weight gain even when consuming calorie-dense diets. These findings underscore the functional significance of ACOX2-driven peroxisomal metabolism as a metabolic amplifier capable of enhancing energy expenditure and protecting against diet-induced metabolic dysfunction.
To visualize and quantify these effects at the cellular level, the researchers employed innovative tools including a fluorescent heat sensor that illuminated increased cellular temperatures upon ACOX2-mediated metabolism of specific fatty acid substrates. Complementary infrared thermal imaging corroborated diminished heat generation in mice lacking ACOX2, painting a compelling picture of peroxisomal thermo-metabolic activity’s role in whole-body energy balance.
Intriguingly, the branched fatty acids metabolized by ACOX2 are not exclusive to endogenous synthesis. They are also sourced from dietary components such as dairy products and human breast milk, as well as produced by certain gut microbiota. This raises the tantalizing prospect of nutritional or probiotic interventions tailored to augment this peroxisomal heat-generating pathway. Such strategies could pave the way for non-invasive, accessible therapies aimed at enhancing metabolic rates and mitigating obesity and insulin resistance.
While the current investigations are conducted in murine models, there is mounting evidence supporting the translational relevance of this pathway in humans. Previous epidemiological studies noted a correlation between elevated plasma levels of these branched fatty acids and lower body mass indices among individuals, although causality remains to be definitively established. The research team is actively pursuing clinical studies to test whether dietary supplementation or pharmacological activation of ACOX2 can amplify this metabolic circuitry in people.
The study not only broadens the fundamental understanding of brown fat biology but also challenges the orthodox view that mitochondrial UCP1 activity is the sole driver of thermogenesis in adipose tissue. It highlights peroxisomes as dynamic, energetically significant organelles that contribute critically to systemic energy homeostasis. This dual thermogenic mechanism offers redundancy during cold stress and possibly other metabolic challenges, underscoring the evolutionary importance of maintaining body temperature and metabolic flexibility.
From a therapeutic standpoint, activating ACOX2 presents a promising target for drug development. The authors have filed a provisional patent through Washington University to explore pharmacological means of enhancing ACOX2 activity and thus stimulating peroxisomal heat production. If successful, this approach could complement or even outperform traditional weight-loss methods by harnessing the body’s intrinsic energy-burning capacity with potentially fewer side effects or compliance issues than current treatments.
Ultimately, these findings illuminate a sophisticated metabolic interplay within brown fat that orchestrates the breakdown of specialized fatty acids to generate heat and regulate glucose metabolism. The peroxisomal metabolism pathway adds a vital dimension to the regulation of energy expenditure, making it a compelling focus for future research aimed at tackling the global epidemic of obesity and metabolic disorders. As Dr. Lodhi emphasizes, modulating this pathway may facilitate sustainable weight control and metabolic health, transforming paradigms in obesity management.
This comprehensive investigation marks a significant stride toward leveraging the body’s natural thermogenic machinery to combat metabolic disease. It invites scientists, clinicians, and nutritionists alike to rethink current strategies, consider novel metabolic targets, and embrace an integrated approach incorporating cellular metabolism, dietary factors, and microbial contributions to holistic metabolic wellness.
Subject of Research: Brown adipose tissue thermogenesis and metabolic regulation via peroxisomal metabolism
Article Title: Peroxisomal metabolism of branched fatty acids regulates energy homeostasis
News Publication Date: 17-Sep-2025
Web References: http://dx.doi.org/10.1038/s41586-025-09517-7
References: Liu X, He A, Lu D, Hu D, Tan M, Abere A, Goodarzi P, Ahmad B, Kleiboeker B, Finck BN, Zayed M, Funai K, Brestoff JR, Javaheri A, Weisensee P, Mittendorfer B, Hsu F, Van Veldhoven PP, Razani B, Semenkovich CF, Lodhi IJ. Peroxisomal metabolism of branched fatty acids regulates energy homeostasis. Nature. Sept. 17, 2025. DOI: 10.1038/s41586-025-09517-7.
Image Credits: Weisensee Lab
Keywords: Brown adipose tissue, metabolism, peroxisomes, acyl-CoA oxidase 2, thermogenesis, branched fatty acids, obesity, insulin resistance, energy expenditure
