ADAMTSs belong to the superfamily of secreted metalloendopeptidases, some of which are reported to be closely associated with obesity. However, the role of ADAMTS15 is not well characterized in adipocytes. This study investigates the effect of Adamts15 deficiency on lipid metabolism in 3T3-L1 and HIB1B adipocytes, with a focus on the role of browning of white adipocytes. Quantitative real-time PCR, immunoblot analysis, immunofluorescence, and staining methods were applied to evaluate the effects of ADAMTS15 on other target proteins and genes involved in lipid metabolism, after silencing Adamts15 by applying the siRNA technique. Our results demonstrate that ADAMTS15 is expressed in both white and brown adipocytes, and the deficiency of Adamts15 promotes browning of white adipocytes by enhancing the expression of brown adipocyte-specific genes and proteins. In addition, silencing of Adamts15 activates brown adipocytes and also upregulates lipid metabolic activity in both white and brown adipocytes, by increasing mitochondrial biogenesis as well as the levels of lipolytic and fat oxidative marker proteins, and reducing adipogenic factors. Moreover, mechanistic studies revealed that depletion of Adamts15 induces browning via activation of the β3AR-PKA-CREB signaling pathway. Taken together, our data unveiled a previously unknown mechanism of ADAMTS15 in the regulation of lipids, and the significance of this protein as a pharmacotherapeutic target to treat obesity-related metabolic disorders.

ADAMTS属于分泌型金属内肽酶的超家族，据报道其中一些与肥胖症密切相关。但是，ADAMTS15的作用在脂肪细胞中并未得到很好的表征。这项研究调查了Adamts15缺乏对3T3-L1和HIB1B脂肪细胞脂质代谢的影响，重点是白色脂肪细胞褐变的作用。在通过使用siRNA技术沉默Adamts15之后，应用定量实时PCR，免疫印迹分析，免疫荧光和染色方法来评估ADAMTS15对参与脂质代谢的其他靶蛋白和基因的影响。我们的结果表明，ADAMTS15在白色和棕色脂肪细胞中均有表达，并且Adamts15缺乏通过增强棕色脂肪细胞特异性基因和蛋白质的表达，促进白色脂肪细胞的褐变。此外，通过增加线粒体的生物发生以及脂解和脂肪氧化标记蛋白的水平，并减少成脂因子，Adamts15的沉默可激活褐色脂肪细胞，并同时上调白色和褐色脂肪细胞中的脂质代谢活性。此外，机理研究表明，Adamts15的耗竭可通过激活β3AR-PKA-CREB信号通路诱导褐变。综上所述，我们的数据揭示了ADAMTS15在调节脂质方面的未知机制，以及该蛋白质作为治疗肥胖相关代谢性疾病的药物治疗靶点的重要性。