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

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 si Bmal1 , siRora, Rora , siRorc, Rorc , 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 ROR gamma gamma at ZT16, that of BMAL1 and PPAR gamma gamma 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 ROR alpha/gamma alpha / gamma on Atgl promoter and decreased the repression of ROR alpha/gamma alpha / gamma on PPAR gamma-binding gamma-binding PPRE. . Promoter deletion analysis indicated that nobiletin inhibited the suppression of PPAR gamma-mediated gamma-mediated Atgl transcription by ROR alpha/gamma. alpha / gamma . Taken together, nobiletin elevated lipolysis in WAT by increasing ATGL levels through activating the transcriptional activity of ROR alpha/gamma alpha / gamma and decreasing the repression of ROR alpha/gamma alpha / gamma on PPAR gamma-binding gamma-binding PPRE. . (c) 2024 Published by Elsevier Inc.