Targeting the peroxisomal FASN-ACOX2 axis to modulate energy homeostasis: therapeutic potential and challenges

Abstract

Peroxisomes are increasingly recognized as active contributors to cellular thermogenesis beyond their classical oxidative role. The Nature study by Liu et al. identifies a peroxisomal FASN-ACOX2 axis in adipocytes that mediates UCP1-independent heat production through cyclic synthesis and oxidation of monomethyl branched-chain fatty acids (mmBCFAs). In adipocytes, cold exposure induces the cytoplasmic enrichment of fatty acid synthase (FASN) adjacent to peroxisomes, where it provides substrates for acyl-CoA oxidase 2 (ACOX2)-dependent oxidation. The FASN spatial relocation may couple lipogenesis with energy dissipation, raising the possibility that enzyme subcellular distribution represents a way of fine-tuned metabolic regulation. Adipocyte ACOX2 acts as the peroxisomal executor of this UCP1-independent thermogenesis cycle and a potential metabolic target linking lipid flux to systemic energy expenditure. However, the metabolic role of the FASN-ACOX2 axis outside adipose tissue, and the upstream signals that coordinate FASN redistribution with ACOX2 induction, remain to be defined. Elucidating these mechanisms could ultimately inform novel therapeutic strategies aimed at modulating peroxisomal thermogenesis to treat obesity-associated metabolic disorders.

Keywords

Peroxisomes / FASN-ACOX2 axis / UCP1-independent thermogenesis / Adipocyte / Obesity

Ethical statements

Not applicable.

Author contributions

The authors confirm contributions to the paper as follows: study conception, manuscript revision and supervision: Yan T, Gonzalez FJ; draft manuscript preparation, figure creation: Xu X, Fang Y; critical revision and expert input:Zhang Y. All authors reviewed the results and approved the final version of the manuscript. Note: figures were created with BioRender.com.

Data availability

Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.

Acknowledgements

This study was supported by the National Natural Science Foundation of China (Grant Nos 82404732 and 82574484 to Tingting Yan) and the Natural Science Foundation of Jiangsu Province (Grant No. BK20241592 to Tingting Yan). This research was supported (in part) by the Intramural Research Program of the National Institutes of Health (NIH), National Cancer Institute, CCR, CIL.

Conflict of interest

The authors declare no conflict of interest. We confirm that we have not received any financial support or sponsorship from any organization that could be perceived as influencing the results or interpretations presented in this work. The contributions of the NIH author(s) were made as part of their official duties as NIH federal employees, are in compliance with agency policy requirements, and are considered Works of the United States Government. However, the findings and conclusions presented in this paper are those of the author(s) and do not necessarily reflect the views of the NIH or the U.S. Department of Health and Human Services.

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