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Integration of Feeding Behaviour by the Liver Circadian Clock Reveals Network Dependency of Metabolic Rhythms [ChIP-seq]

ABSTRACT: The mammalian circadian clock, expressed throughout the brain and body, controls daily metabolic homeostasis. Clock function in peripheral tissues is required, but not sufficient, for this task. Due to lack of specialized animal models, it is unclear how tissue clocks interact with extrinsic signals to drive molecular oscillations. Here, we present a model in which the interaction between feeding and the liver clock can be isolated in vivo by reconstituting Bmal1 exclusively in hepatocytes (Liver-RE) in otherwise clock-less mice. We found that the cooperative action of BMAL1 and the transcription factor CEBPB regulates daily liver metabolic transcriptional programs. Functionally, the liver clock and feeding rhythm are sufficient to drive temporal glucose homeostasis. By contrast, liver rhythms tied to redox and lipid metabolism required communication with the skeletal muscle clock, demonstrating peripheral clock cross-talk. Our results highlight how the inner workings of the clock system rely on communicating signals to maintain daily metabolism.

ORGANISM(S): Mus musculus

PROVIDER: GSE169483 | GEO | 2021/06/01

REPOSITORIES: GEO

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Integration of Feeding Behaviour by the Liver Circadian Clock Reveals Network Dependency of Metabolic Rhythms [RNA-seq]

Project description:The mammalian circadian clock, expressed throughout the brain and body, controls daily metabolic homeostasis. Clock function in peripheral tissues is required, but not sufficient, for this task. Due to lack of specialized animal models, it is unclear how tissue clocks interact with extrinsic signals to drive molecular oscillations. Here, we present a model in which the interaction between feeding and the liver clock can be isolated in vivo by reconstituting Bmal1 exclusively in hepatocytes (Liver-RE) in otherwise clock-less mice. We found that the cooperative action of BMAL1 and the transcription factor CEBPB regulates daily liver metabolic transcriptional programs. Functionally, the liver clock and feeding rhythm are sufficient to drive temporal glucose homeostasis. By contrast, liver rhythms tied to redox and lipid metabolism required communication with the skeletal muscle clock, demonstrating peripheral clock cross-talk. Our results highlight how the inner workings of the clock system rely on communicating signals to maintain daily metabolism.

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Project description:Increased susceptibility of circadian clock mutant mice to metabolic diseases has led to the understanding that a molecular circadian clock is necessary for metabolic homeostasis. Circadian clock produces a daily rhythm in activity-rest and an associated rhythm in feeding-fasting. Feeding-fasting driven programs and cell autonomous circadian oscillator act synergistically in the liver to orchestrate daily rhythm in metabolism. However, an imposed feeding-fasting rhythm, as in time-restricted feeding, can drive some rhythm in liver gene expression in clock mutant mice. We tested if TRF alone, in the absence of a circadian clock in the liver or in the whole animal can prevent obesity and metabolic syndrome. Mice lacking the clock component Bmal1 in the liver, Rev-erb alpha/beta in the liver or cry1-/-;cry2-/- (CDKO) mice rapidly gain weight and show genotype specific increased susceptibility to dyslipidemia, hypercholesterolemia and glucose intolerance under ad lib fed condition. However, when the mice were fed the same diet under time-restricted feeding regimen that imposed 10 h feeding during the night, they were protected from weight gain and other metabolic diseases. Transcriptome and metabolome analyses of the liver from there mutant mice showed TRF reduces de novo lipogenesis, increased beta-oxidation independent of a circadian clock. TRF also enhanced cellular defense to metabolic stress. These results suggest a major function of the circadian clock in metabolic homeostasis is to sustain a daily rhythm in feeding and fasting. The feeding-fasting cycle orchestrates a balance between nutrient stress and cellular response to maintain homeostasis.

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Project description:To define regulation of tissue proteomes by Bmal1, daily feeding rhythm, and the interaction, we employed Bmal1-stopFL mice, which do not express the main transcriptional activator of the molecular clock, Bmal1, except in cre recombinase-expressing cells1,2 (Figure 1A). Bmal1-stopFL mice lacking cre (Bmal1 knockout, KO) are analogous to Bmal1-null mice and display severely impaired behavioral and molecular rhythms1-3. Hepatocyte-specific Alfp-cre and skeletal muscle-specific Hsa-cre genes were introduced to generate a single line wherein both hepatocyte and skeletal muscle Bmal1 were reconstituted (Liver+Muscle-RE), i.e., rescued (Smith, Koronowski et al. 2023). This approach had the benefit of analyzing liver and muscle from the same mice but comes with the qualification that the abundance of some proteins may be influenced by Bmal1 function in the other tissue, or by a synergistic effect of Bmal1 in both tissues, rather than through rescue of local Bmal1 function alone. Proteomic anlaysis was performed in liver and skeletal muscle.

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