TitleDiet-Induced Circadian Enhancer Remodeling Synchronizes Opposing Hepatic Lipid Metabolic Processes.
Publication TypeJournal Article
Year of Publication2018
AuthorsGuan, D, Xiong, Y, Borck, PC, Jang, C, Doulias, P-T, Papazyan, R, Fang, B, Jiang, C, Zhang, Y, Briggs, ER, Hu, W, Steger, D, Ischiropoulos, H, Rabinowitz, JD, Lazar, MA
Date Published2018 08 09
KeywordsAnimals, Circadian Rhythm, Diet, Gene Expression Regulation, Lipid Metabolism, Lipogenesis, Liver, Male, Mice, Mice, Inbred C57BL, Obesity, PPAR alpha, Sterol Regulatory Element Binding Protein 1

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.

Alternate JournalCell
PubMed ID30057115
PubMed Central IDPMC6086765
Grant ListR01 DK045586 / DK / NIDDK NIH HHS / United States
F32 DK116519 / DK / NIDDK NIH HHS / United States
R01 HL054926 / HL / NHLBI NIH HHS / United States
P30 ES013508 / ES / NIEHS NIH HHS / United States
R01 DK098542 / DK / NIDDK NIH HHS / United States
P30 DK019525 / DK / NIDDK NIH HHS / United States