| First Author | Liu X | Year | 2025 |
| Journal | Nature | Volume | 646 |
| Issue | 8087 | Pages | 1223-1231 |
| PubMed ID | 40963015 | Mgi Jnum | J:374063 |
| Mgi Id | MGI:8255700 | Doi | 10.1038/s41586-025-09517-7 |
| Citation | Liu X, et al. (2025) Peroxisomal metabolism of branched fatty acids regulates energy homeostasis. Nature |
| abstractText | Brown and beige adipocytes express uncoupling protein 1 (UCP1), a mitochondrial protein that dissociates respiration from ATP synthesis and promotes heat production and energy expenditure. However, UCP1(-/-) mice are not obese(1-5), consistent with the existence of alternative mechanisms of thermogenesis(6-8). Here we describe a UCP1-independent mechanism of thermogenesis involving ATP-consuming metabolism of monomethyl branched-chain fatty acids (mmBCFA) in peroxisomes. These fatty acids are synthesized by fatty acid synthase using precursors derived from catabolism of branched-chain amino acids(9) and our results indicate that beta-oxidation of mmBCFAs is mediated by the peroxisomal protein acyl-CoA oxidase 2 (ACOX2). Notably, cold exposure upregulated proteins involved in both biosynthesis and beta-oxidation of mmBCFA in thermogenic fat. Acute thermogenic stimuli promoted translocation of fatty acid synthase to peroxisomes. Brown-adipose-tissue-specific fatty acid synthase knockout decreased cold tolerance. Adipose-specific ACOX2 knockout also impaired cold tolerance and promoted diet-induced obesity and insulin resistance. Conversely, ACOX2 overexpression in adipose tissue enhanced thermogenesis independently of UCP1 and improved metabolic homeostasis. Using a peroxisome-localized temperature sensor named Pexo-TEMP, we found that ACOX2-mediated fatty acid beta-oxidation raised intracellular temperature in brown adipocytes. These results identify a previously unrecognized role for peroxisomes in adipose tissue thermogenesis characterized by an mmBCFA synthesis and catabolism cycle. |
