华盛顿大学医学院Irfan J. Lodhi课题组取得一项新突破。他们的最新研究探明了支链脂肪酸的过氧化物酶体代谢调节能量稳态。相关论文于2025年9月17日发表在《自然》杂志上。

在这里，课题组研究人员描述了一个不依赖于UCP1的产热机制，涉及过氧化物酶体中单甲基支链脂肪酸（mmBCFA）的ATP消耗代谢。这些脂肪酸是由支链氨基酸分解代谢衍生的脂肪酸合成酶主题前体合成的，结果表明mmBCFAs的β-氧化是由过氧化物酶体蛋白酰基辅酶A氧化酶2 （ACOX2）介导的。值得注意的是，冷暴露上调了热性脂肪中参与mmBCFA生物合成和β氧化的蛋白质。急性热刺激促进脂肪酸合酶向过氧化物酶体的易位。棕色脂肪组织特异性脂肪酸合成酶敲除降低了耐寒性。脂肪特异性ACOX2敲除也会损害耐寒性，促进饮食诱导的肥胖和胰岛素抵抗。相反，脂肪组织中ACOX2的过表达可以独立于UCP1增强产热作用并改善代谢稳态。使用一种名为Pexo-TEMP的过氧化物酶体定位温度传感器，课题组人员发现ACOX2介导的脂肪酸β-氧化提高了棕色脂肪细胞的细胞内温度。这些结果确定了过氧化物酶体在以mmBCFA合成和分解代谢循环为特征的脂肪组织产热中的作用，这是以前未被认识到的。

据了解，棕色和米色脂肪细胞表达解偶联蛋白1 (UCP1)，这是一种线粒体蛋白，可将呼吸与ATP合成分离，促进热量产生和能量消耗。然而,UCP1 ^-/-小鼠不肥胖，这与其他产热机制的存在是一致的。

附：英文原文

Title: Peroxisomal metabolism of branched fatty acids regulates energy homeostasis

Author: Liu, Xuejing, He, Anyuan, Lu, Dongliang, Hu, Donghua, Tan, Min, Abere, Abenezer, Goodarzi, Parniyan, Ahmad, Bilal, Kleiboeker, Brian, Finck, Brian N., Zayed, Mohamed, Funai, Katsuhiko, Brestoff, Jonathan R., Javaheri, Ali, Weisensee, Patricia, Mittendorfer, Bettina, Hsu, Fong-Fu, Van Veldhoven, Paul P., Razani, Babak, Semenkovich, Clay F., Lodhi, Irfan J.

Issue&Volume: 2025-09-17

Abstract: 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 obese1,2,3,4,5, consistent with the existence of alternative mechanisms of thermogenesis6,7,8. 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 acids9 and our results indicate that β-oxidation of mmBCFAs is mediated by the peroxisomal protein acyl-CoA oxidase 2 (ACOX2). Notably, cold exposure upregulated proteins involved in both biosynthesis and β-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 β-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.

DOI: 10.1038/s41586-025-09517-7

Source: https://www.nature.com/articles/s41586-025-09517-7