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Diet-induced circadian enhancer remodeling synchronizes opposing hepatic lipid metabolic processes

ABSTRACT: Overnutrition disrupts circadian rhythms leading to dysregulated metabolism by mechanisms that are not well understood. Here we show that diet-induced obesity (DIO) causes massive remodeling of circadian enhancer activity and gene transcription in mouse liver. Remarkably, DIO triggers synchronous, high amplitude circadian rhythms of both fatty acid (FA) synthesis and oxidation. This gain of circadian rhythmicity in lipid metabolic pathways that oppose each other emphasizes the importance of balance and flux in normal hepatic lipid metabolism. DIO-promoted rhythmicity of Sterol Regulatory Element-Binding Protein (SREBP) activation, which was required not only for the induction of FA synthesis but also, surprisingly, for FA oxidation (FAO). DIO also brought about a high amplitude circadian rhythm of peroxisome proliferated receptor a (PPARa), which was required for FAO. Provision of a pharmacological ligand for PPARa abrogated the requirement of SREBP for FA oxidation (but not FA synthesis), suggesting that SREBP indirectly controls FA oxidation via production of an endogenous PPARa ligand. Moreover, the high amplitude circadian rhythm of PPARa imparts time-of-day-dependent responsiveness to lipid-lowering drugs. Thus, acquisition of rhythmicity for the non-core clock components PPARa and SREBP1 remodels metabolic gene transcription in response to a challenging nutritive environment and enables a chronopharmacological approach to metabolic disorders.

ORGANISM(S): Mus musculus

PROVIDER: GSE108878 | GEO | 2018/07/26

REPOSITORIES: GEO

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