Bioinformatics & Biostatistics Core, Joslin Diabetes Center, Harvard Medical School, Boston, MA, USA.
Department of Economics, Ca' Foscari University of Venice, Cannaregio 873, Venice, Italy.
Commun Biol. 2024 Aug 14;7(1):996. doi: 10.1038/s42003-024-06646-z.
Activating brown adipose tissue (BAT) improves systemic metabolism, making it a promising target for metabolic syndrome. BAT is activated by 12,13-dihydroxy-9Z-octadecenoic acid (12,13-diHOME), which we previously identified to be inversely associated with BMI and which directly improves metabolism in multiple tissues. Here we profile plasma lipidomics from 83 people and test which lipids' association with BMI replicates in a concordant direction using our novel tool ScreenDMT, whose power and validity we demonstrate via mathematical proofs and simulations. We find that the linoleic acid diols 12,13-diHOME and 9,10-diHOME are both replicably inversely associated with BMI and mechanistically activate calcium influx in mouse brown and white adipocytes in vitro, which implicates this signaling pathway and 9,10-diHOME as candidate therapeutic targets. ScreenDMT can be applied to test directional mediation, directional replication, and qualitative interactions, such as identifying biomarkers whose association is shared (replication) or opposite (qualitative interaction) across diverse populations.
激活棕色脂肪组织（BAT）可以改善全身代谢，使其成为代谢综合征的一个有前途的治疗靶点。12,13-二羟基-9Z-十八碳烯酸（12,13-二 HOME）可以激活 BAT，我们之前发现它与 BMI 呈负相关，并且可以直接改善多种组织的代谢。在这里，我们对 83 个人的血浆脂质组学进行了分析，并使用我们新的 ScreenDMT 工具测试了哪些脂质与 BMI 的关联在一致的方向上具有可重复性，我们通过数学证明和模拟证明了其功效和有效性。我们发现亚油酸二醇 12,13-二 HOME 和 9,10-二 HOME 都与 BMI 呈负相关，并在体外机制上激活了小鼠棕色和白色脂肪细胞中的钙内流，这表明该信号通路和 9,10-二 HOME 可能是治疗靶点。ScreenDMT 可以用于测试定向中介、定向复制和定性相互作用，例如识别在不同人群中具有共享（复制）或相反（定性相互作用）关联的生物标志物。
Zotero 插件
