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

Dongyin Guan, Ying Xiong, Patricia C. Borck, Cholsoon Jang, Paschalis Thomas Doulias, Romeo Papazyan, Bin Fang, Chunjie Jiang, Yuxiang Zhang, Erika R. Briggs, Wenxiang Hu, David Steger, Harry Ischiropoulos, Joshua D. Rabinowitz, Mitchell A. Lazar

Research output: Contribution to journalArticle

42 Scopus citations

Abstract

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. Overnutrition intensifies hepatic circadian rhythms of non-core clock factors SREBP and PPARα such that pharmacological lipid lowering is more effective when PPARα is highest.

Original languageEnglish (US)
Pages (from-to)831-842.e12
JournalCell
Volume174
Issue number4
DOIs
StatePublished - Aug 9 2018

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)

Keywords

  • PPAR
  • SREBP
  • chronotherapy
  • circadian rhythms
  • diet-induced obesity
  • enhancers
  • fatty acid oxidation
  • fatty liver
  • lipogenesis

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