Recently, pharmacological activation of thermogenesis in brown fat and induction of white fat browning (beiging) have been considered as promising strategies in the development of anti-obesity drugs. During the screening of natural compounds that may stimulate thermogenesis, urolithin A (UroA), which is metabolized from pomegranate ellagitannins by gut microflora, was identified as a potent anti-obesity candidate. In the present study, we elucidated the role of UroA to induce the brown-like phenotype in 3T3-L1 white adipocytes. UroA treatments of up to 50 µM were non-toxic to cells. UroA at 15 µM significantly increased the protein expression levels of brown-fatspecific markers such as UCP1, PRDM16, PGC-1α, C/EBPβ, and PPARα. In addition, it remarkably increased the expression of beige-specific genes, including Cd137, Cidea, Cited1, Tbx1, and Tmen26, in 3T3-L1 white adipocytes and significantly elevated expressions of the brown-fatspecific genes (Ppargc1, Prdm16, and Ucp1) in white adipocytes. Furthermore, UroA treatment of 3T3-L1 white adipocytes cells reduced the expression of key adipogenic transcription factors, whereas enhanced lipolysis and the fat oxidation process. Mechanistic study revealed that UroA treatment induces browning in white adipocytes via activation of β3-AR- and p38 MAPK-dependent signaling pathways. Taken together, UroA has the potential to treat obesity by its capacity to recruit beige fat cells in white adipocyte tissue, thereby contributing to an increase in thermogenesis.

近来，在抗肥胖药的开发中，已经考虑了在棕色脂肪中生热的药理活化和诱导白色脂肪褐变（米色）是有希望的策略。在筛选可能刺激产热的天然化合物的过程中，尿石榴素A（UroA）是一种有效的抗肥胖候选药，它通过肠道菌群从石榴皮鞣质中代谢而来。在本研究中，我们阐明了UroA在3T3-L1白色脂肪细胞中诱导褐色样表型的作用。高达50 µM的UroA处理对细胞无毒。15 µM的UroA显着提高了棕色脂肪特异性标志物（如UCP1，PRDM16，PGC-1α，C /EBPβ和PPARα）的蛋白质表达水平。此外，它显着增加了米色特异性基因的表达，包括Cd137，Cidea，Cited1，Tbx1和Tmen26在3T3-L1白色脂肪细胞中，棕色脂肪特异性基因（Ppargc1，Prdm16和Ucp1）在白色脂肪细胞中的表达明显升高。此外，UroA处理3T3-L1白色脂肪细胞可减少关键的脂肪形成转录因子的表达，而增强脂解作用和脂肪氧化过程。机理研究表明，UroA处理可通过激活β3-AR-和p38 MAPK依赖性信号传导途径诱导白色脂肪细胞褐变。综上所述，UroA具有通过在白色脂肪细胞组织中募集米色脂肪细胞的能力来治疗肥胖症的潜力，从而有助于增加生热作用。