Vargas-Castillo Ariana, Sun Yizhi, Smythers Amanda L, Grauvogel Louisa, Dumesic Phillip A, Emont Margo P, Tsai Linus T, Rosen Evan D, Zammit Nathan W, Shaffer Sydney M, Ordonez Martha, Chouchani Edward T, Gygi Steven P, Wang Tongtong, Sharma Anand K, Balaz Miroslav, Wolfrum Christian, Spiegelman Bruce M
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Cell Biology, Harvard Medical School, Boston, MA, USA.
Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Cell Metab. 2024 Sep 3;36(9):2146-2155.e5. doi: 10.1016/j.cmet.2024.07.002. Epub 2024 Jul 30.
Although uncoupling protein 1 (UCP1) is established as a major contributor to adipose thermogenesis, recent data have illustrated an important role for alternative pathways, particularly the futile creatine cycle (FCC). How these pathways co-exist in cells and tissues has not been explored. Beige cell adipogenesis occurs in vivo but has been difficult to model in vitro; here, we describe the development of a murine beige cell line that executes a robust respiratory response, including uncoupled respiration and the FCC. The key FCC enzyme, tissue-nonspecific alkaline phosphatase (TNAP), is localized almost exclusively to mitochondria in these cells. Surprisingly, single-cell cloning from this cell line shows that cells with the highest levels of UCP1 express little TNAP, and cells with the highest expression of TNAP express little UCP1. Immunofluorescence analysis of subcutaneous fat from cold-exposed mice confirms that the highest levels of these critical thermogenic components are expressed in distinct fat cell populations.
尽管解偶联蛋白1（UCP1）已被确认为脂肪产热的主要贡献者，但最近的数据表明替代途径具有重要作用，尤其是无效肌酸循环（FCC）。这些途径如何在细胞和组织中共存尚未得到探索。米色细胞脂肪生成在体内发生，但在体外难以模拟；在这里，我们描述了一种小鼠米色细胞系的开发，该细胞系表现出强大的呼吸反应，包括解偶联呼吸和FCC。FCC的关键酶，组织非特异性碱性磷酸酶（TNAP），在这些细胞中几乎只定位于线粒体。令人惊讶的是，从该细胞系进行单细胞克隆表明，UCP1水平最高的细胞几乎不表达TNAP，而TNAP表达最高的细胞几乎不表达UCP1。对冷暴露小鼠皮下脂肪的免疫荧光分析证实，这些关键产热成分的最高水平在不同的脂肪细胞群体中表达。
