CL316,243 induced thermogenesis in adipose tissue of C57Bl/6J mice

Brown adipose tissue (BAT) thermogenesis confers beneficial effects on metabolic diseases such as obesity and type 2 diabetes. Nevertheless, the mechanism and lipid driving the process that evokes this response have not been investigated yet. Here, utilizing a multi-omics approach of integrative transcriptomic and lipidomic to explore the mechanism of regulating thermogenesis in BAT and providing promising lipid biomarkers and biomarker genes for thermogenic activators as anti-obesity drugs. Lipidomics analysis demonstrated that a high abundance of glycerophospholipids and sphingolipids was more significant in BAT than WAT. Enrichment analysis of upregulated DEGs between WAT and BAT screened suggested the differences were mainly involved in lipid metabolism. Besides, β3-adrenergic agonist stimulation reduced the levels of TAG and DAG, increased the content of PC, PE, CL, and LPC, and expression of genes involved in thermogenesis, fatty acid elongation, and glycerophospholipids metabolism in BAT. In this study, based on interpretating the inherent characterization of BAT as thermogenic tissue through comparison with WAT as fat storage tissue, adrenergic stimulation-induced BAT thermogenesis further identified specific lipid biomarkers (7 TAG species, 10 PC species, 1 LPC species, and 1 CL species), and Elovl3 and Crat gene biomarkers which may provide targets for combating obesity by boosting BAT thermogenesis.棕色脂肪组织（brown adipose tissue，BAT）产热对肥胖、2型糖尿病等代谢性疾病具有有益作用。然而，介导该产热效应的具体分子机制及关键驱动脂质尚未被系统研究。本研究采用整合转录组学与脂质组学的多组学联用策略，探究棕色脂肪组织产热的调控机制，并为作为抗肥胖药物的产热激活剂筛选出极具应用前景的脂质标志物与标志物基因。脂质组学分析显示，棕色脂肪组织中甘油磷脂与鞘磷脂的丰度显著高于白色脂肪组织（white adipose tissue，WAT）。对筛选得到的白色脂肪组织与棕色脂肪组织间的上调差异表达基因（differentially expressed genes，DEGs）进行富集分析，结果表明其主要参与脂质代谢过程。此外，β3肾上腺素能激动剂刺激可降低棕色脂肪组织内甘油三酯（triacylglycerol，TAG）与甘油二酯（diacylglycerol，DAG）的水平，提升磷脂酰胆碱（phosphatidylcholine，PC）、磷脂酰乙醇胺（phosphatidylethanolamine，PE）、心磷脂（cardiolipin，CL）与溶血磷脂酰胆碱（lysophosphatidylcholine，LPC）的含量，并上调产热、脂肪酸延伸及甘油磷脂代谢相关基因的表达。本研究通过将作为产热组织的棕色脂肪组织与作为脂肪储存组织的白色脂肪组织进行对比，阐释了棕色脂肪组织的固有特性，并结合肾上腺素能刺激诱导的棕色脂肪组织产热过程，进一步鉴定得到特异性脂质标志物（7种甘油三酯亚型、10种磷脂酰胆碱亚型、1种溶血磷脂酰胆碱亚型与1种心磷脂亚型）以及Elovl3与Crat基因标志物，上述标志物可为通过激活棕色脂肪组织产热以对抗肥胖提供潜在靶点。