Expression profiling by high throughput sequencing
Summary
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.
Overall design
Circadian time course of liver mRNA profile of WT, Bmal1-liverKO, Rev-erbα/β-liverdoubleKO, Cry1Cry2 double KO after 12 weeks of high fat diet feeding ad libitum or time-restricted feeding.
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