Diet-Induced Circadian Enhancer Remodeling Synchronizes Opposing Hepatic Lipid Metabolic Processes

Cell. 2018 Aug 9;174(4):831-842.e12. doi: 10.1016/j.cell.2018.06.031. Epub 2018 Jul 26.


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 PPARα, which was also required for FAO. Provision of a pharmacological activator of PPARα abrogated the requirement of SREBP for FAO (but not FA synthesis), suggesting that SREBP indirectly controls FAO via production of endogenous PPARα ligands. The high-amplitude rhythm of PPARα imparted time-of-day-dependent responsiveness to lipid-lowering drugs. Thus, acquisition of rhythmicity for non-core clock components PPARα and SREBP1 remodels metabolic gene transcription in response to overnutrition and enables a chronopharmacological approach to metabolic disorders.

Keywords: PPAR; SREBP; chronotherapy; circadian rhythms; diet-induced obesity; enhancers; fatty acid oxidation; fatty liver; lipogenesis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Circadian Rhythm*
  • Diet / adverse effects*
  • Gene Expression Regulation
  • Lipid Metabolism
  • Lipogenesis
  • Liver / drug effects
  • Liver / metabolism*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Obesity / etiology
  • Obesity / metabolism*
  • Obesity / pathology
  • PPAR alpha / genetics
  • PPAR alpha / metabolism*
  • Sterol Regulatory Element Binding Protein 1 / genetics
  • Sterol Regulatory Element Binding Protein 1 / metabolism*


  • PPAR alpha
  • Srebf1 protein, mouse
  • Sterol Regulatory Element Binding Protein 1