Food Safety and Health Research Center, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, Guangdong, China; Department of Toxicological and Biochemical Test, Guangzhou Center for Disease Control and Prevention, Guangzhou, Guangdong, China.
Food Safety and Health Research Center, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, Guangdong, China.
J Nutr Biochem. 2024 Oct;132:109696. doi: 10.1016/j.jnutbio.2024.109696. Epub 2024 Aug 1.
Nobiletin has been reported to protect against obesity-related metabolic disorders by enhancing the circadian rhythm; however its effects on lipid metabolism in adipose tissue are unclear. In this study, mice were fed with high-fat diet (HFD) for four weeks firstly and gavaged with 50 or 200 mg/kg bodyweight/day nobiletin at Zeitgeber time (ZT) 4 for another four weeks while still receiving HFD. At the end of the 8-week experimental period, the mice were sacrificed at ZT4 or ZT8 on the same day. Mature 3T3-L1 adipocytes were treated with nobiletin in the presence or absence of siBmal1, siRora, siRorc, SR8278 or SR9009. Nobiletin reduced the weight of white adipose tissue (WAT) and the size of adipocytes in WAT. At ZT4, nobiletin decreased the TG, TC and LDL-c levels and increased serum FFA level and glucose tolerance. Nobiletin triggered the lipolysis of mesenteric and epididymal WAT at both ZT4 and ZT16. Nobiletin increased the level of RORγ at ZT16, that of BMAL1 and PPARγ at ZT4, and that of ATGL at both ZT4 and ZT16. Nobiletin increased lipolysis and ATGL levels in 3T3-L1 adipocytes in Bmal1- or Rora/c- dependent manner. Dual luciferase assay indicated that nobiletin enhanced the transcriptional activation of RORα/γ on Atgl promoter and decreased the repression of RORα/γ on PPARγ-binding PPRE. Promoter deletion analysis indicated that nobiletin inhibited the suppression of PPARγ-mediated Atgl transcription by RORα/γ. Taken together, nobiletin elevated lipolysis in WAT by increasing ATGL levels through activating the transcriptional activity of RORα/γ and decreasing the repression of RORα/γ on PPARγ-binding PPRE.
川陈皮素已被报道通过增强昼夜节律来预防肥胖相关的代谢紊乱；然而，其对脂肪组织中脂质代谢的影响尚不清楚。在这项研究中，首先用高脂肪饮食（HFD）喂养小鼠 4 周，然后在 Zeitgeber 时间（ZT）4 时用 50 或 200mg/kg 体重/天的川陈皮素灌胃 4 周，同时仍接受 HFD。在 8 周的实验期结束时，在同一天的 ZT4 或 ZT8 处死小鼠。成熟的 3T3-L1 脂肪细胞在存在或不存在 siBmal1、siRora、siRorc、SR8278 或 SR9009 的情况下用川陈皮素处理。川陈皮素减少白色脂肪组织（WAT）的重量和 WAT 中脂肪细胞的大小。在 ZT4 时，川陈皮素降低了 TG、TC 和 LDL-c 水平，增加了血清 FFA 水平和葡萄糖耐量。川陈皮素在 ZT4 和 ZT16 时触发肠系膜和附睾 WAT 的脂肪分解。川陈皮素在 ZT16 时增加了 RORγ 的水平，在 ZT4 时增加了 BMAL1 和 PPARγ 的水平，在 ZT4 和 ZT16 时增加了 ATGL 的水平。川陈皮素以 Bmal1-或 Rora/c-依赖的方式增加了 3T3-L1 脂肪细胞中的脂肪分解和 ATGL 水平。双荧光素酶测定表明，川陈皮素增强了 Atgl 启动子上 RORα/γ 的转录激活，并降低了 RORα/γ 对 PPARγ 结合 PPRE 的抑制作用。启动子缺失分析表明，川陈皮素抑制了 RORα/γ 对 PPARγ 介导的 Atgl 转录的抑制作用。总之，川陈皮素通过激活 RORα/γ 的转录活性和降低 RORα/γ 对 PPARγ 结合 PPRE 的抑制作用，增加 ATGL 水平，从而提高 WAT 中的脂肪分解。
