| First Author | Guan D | Year | 2018 |
| Journal | Cell | Volume | 174 |
| Issue | 4 | Pages | 831-842.e12 |
| PubMed ID | 30057115 | Mgi Jnum | J:272719 |
| Mgi Id | MGI:6284950 | Doi | 10.1016/j.cell.2018.06.031 |
| Citation | Guan D, et al. (2018) Diet-Induced Circadian Enhancer Remodeling Synchronizes Opposing Hepatic Lipid Metabolic Processes. Cell 174(4):831-842.e12 |
| abstractText | Overnutrition disrupts circadian metabolic rhythms by mechanisms that are not well understood. Here, we show that diet-induced obesity (DIO) causes massive remodeling of circadian enhancer activity in mouse liver, triggering synchronous high-amplitude circadian rhythms of both fatty acid (FA) synthesis and oxidation. SREBP expression was rhythmically induced by DIO, leading to circadian FA synthesis and, surprisingly, FA oxidation (FAO). DIO similarly caused a high-amplitude circadian rhythm of PPARalpha, which was also required for FAO. Provision of a pharmacological activator of PPARalpha abrogated the requirement of SREBP for FAO (but not FA synthesis), suggesting that SREBP indirectly controls FAO via production of endogenous PPARalpha ligands. The high-amplitude rhythm of PPARalpha imparted time-of-day-dependent responsiveness to lipid-lowering drugs. Thus, acquisition of rhythmicity for non-core clock components PPARalpha and SREBP1 remodels metabolic gene transcription in response to overnutrition and enables a chronopharmacological approach to metabolic disorders. |
