Ye Chenji, Duan Jinjie, Zhang Xuejiao, Yao Liu, Song Yayue, Wang Guangyan, Li Qi, Wang Biqing, Ai Ding, Wang Chunjiong, Zhu Yi
Tianjin Key Laboratory of Metabolic Diseases, Department of Physiology and Pathophysiology, Collaborative Innovation Center of Tianjin for Medical Epigenetics, Tianjin Medical University, Tianjin, 300070, China.
Tianjin Key Laboratory of Medical Epigenetics, Tianjin Medical University, Tianjin, 300070, China.
Sci China Life Sci. 2021 Mar;64(3):404-418. doi: 10.1007/s11427-020-1779-2. Epub 2020 Aug 11.
Targeting the white-to-brown fat conversion is important for developing potential strategies to counteract metabolic diseases; yet the mechanisms are not fully understood. Yes-associated-protein (YAP), a transcription co-activator, was demonstrated to regulate adipose tissue functions; however, its effects on browning of subcutaneous white adipose tissue (sWAT) are unclear. We demonstrated that YAP was highly expressed in cold-induced beige fat. Mechanistically, YAP was found as a target gene of miR-429, which downregulated YAP expression and In addition, miR-429 level was decreased in cold-induced beige fat. Additionally, pharmacological inhibition of the interaction between YAP and transcriptional enhanced associate domains by verteporfin dampened the browning of sWAT. Although adipose tissue-specific YAP overexpression increased energy expenditure with increased basal uncoupling protein 1 expression, it had no additional effects on the browning of sWAT in young mice. However, we found age-related impairment of sWAT browning along with decreased YAP expression. Under these circumstances, YAP overexpression significantly improved the impaired WAT browning in middle-aged mice. In conclusion, YAP as a regulator of sWAT browning, was upregulated by lowering miR-429 level in cold-induced beige fat. Targeting the miR-429-YAP pathway could be exploited for therapeutic strategies for age-related impairment of sWAT browning.
靶向白色脂肪向棕色脂肪的转化对于制定对抗代谢性疾病的潜在策略至关重要；然而其机制尚未完全明确。Yes相关蛋白（YAP）作为一种转录共激活因子，已被证明可调节脂肪组织功能；然而，其对皮下白色脂肪组织（sWAT）褐变的影响尚不清楚。我们证明YAP在冷诱导的米色脂肪中高表达。从机制上讲，YAP被发现是miR - 429的靶基因，miR - 429下调YAP表达，此外，在冷诱导的米色脂肪中miR - 429水平降低。此外，维替泊芬对YAP与转录增强关联域之间相互作用的药理学抑制减弱了sWAT的褐变。虽然脂肪组织特异性YAP过表达通过增加基础解偶联蛋白1的表达增加了能量消耗，但对年轻小鼠sWAT的褐变没有额外影响。然而，我们发现sWAT褐变存在与年龄相关的损伤以及YAP表达降低。在这种情况下，YAP过表达显著改善了中年小鼠受损的白色脂肪组织褐变。总之，YAP作为sWAT褐变的调节因子，在冷诱导的米色脂肪中通过降低miR - 429水平而上调。靶向miR - 429 - YAP途径可用于治疗与年龄相关的sWAT褐变损伤的策略。
