Nobiletin promotes lipolysis of white adipose tissue in a circadian clock-dependent manner

IF 4.8 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
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Abstract

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.

金钗素以昼夜节律依赖的方式促进白色脂肪组织的脂肪分解。
据报道,金没药可通过增强昼夜节律来防止与肥胖有关的代谢紊乱;但它对脂肪组织脂质代谢的影响尚不清楚。在这项研究中,首先用高脂饮食(HFD)喂养小鼠四周,然后在昼夜节律时间(ZT)4给小鼠灌胃50或200毫克/千克体重/天的金没药,持续四周,同时仍接受高脂饮食。在为期 8 周的实验结束时,小鼠在 ZT4 或 ZT8 的同一天被处死。在有或没有 siBmal1、siRora、siRorc、SR8278 或 SR9009 的情况下,用 nobiletin 处理成熟的 3T3-L1 脂肪细胞。nobiletin 可减少白色脂肪组织(WAT)的重量和 WAT 中脂肪细胞的大小。在 ZT4 阶段,金没药可降低 TG、TC 和 LDL-c 水平,提高血清 FFA 水平和葡萄糖耐量。在 ZT4 和 ZT16 阶段,金没药可诱发肠系膜和附睾 WAT 的脂肪分解。在 ZT16 时,金没药能提高 RORγ 的水平;在 ZT4 时,能提高 BMAL1 和 PPARγ 的水平;在 ZT4 和 ZT16 时,能提高 ATGL 的水平。Nobiletin 能以 Bmal1 或 Rora/c 依赖性方式增加 3T3-L1 脂肪细胞的脂肪分解和 ATGL 水平。双重荧光素酶分析表明,龙胆紫可增强 RORα/γ 在 Atgl 启动子上的转录激活,并降低 RORα/γ 在 PPARγ 结合的 PPRE 上的抑制。启动子缺失分析表明,金没药抑制了 RORα/γ 对 PPARγ 介导的 Atgl 转录的抑制。综上所述,金没药通过激活RORα/γ的转录活性,降低RORα/γ对PPARγ结合的PPRE的抑制作用,提高ATGL水平,从而促进脂肪在WAT中的分解。
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来源期刊
Journal of Nutritional Biochemistry
Journal of Nutritional Biochemistry 医学-生化与分子生物学
CiteScore
9.50
自引率
3.60%
发文量
237
审稿时长
68 days
期刊介绍: Devoted to advancements in nutritional sciences, The Journal of Nutritional Biochemistry presents experimental nutrition research as it relates to: biochemistry, molecular biology, toxicology, or physiology. Rigorous reviews by an international editorial board of distinguished scientists ensure publication of the most current and key research being conducted in nutrition at the cellular, animal and human level. In addition to its monthly features of critical reviews and research articles, The Journal of Nutritional Biochemistry also periodically publishes emerging issues, experimental methods, and other types of articles.
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