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Abstract
Increased susceptibility of circadian clock mutant mice to metabolic diseases has
led to the idea that a molecular clock is necessary for metabolic homeostasis. However,
these mice often lack a normal feeding-fasting cycle. We tested whether time-restricted
feeding (TRF) could prevent obesity and metabolic syndrome in whole-body Cry1;Cry2
and in liver-specific Bmal1 and Rev-erbα/β knockout mice. When provided access to
food ad libitum, these mice rapidly gained weight and showed genotype-specific metabolic
defects. However, when fed the same diet under TRF (food access restricted to 10 hr
during the dark phase) they were protected from excessive weight gain and metabolic
diseases. Transcriptome and metabolome analyses showed that TRF reduced the accumulation
of hepatic lipids and enhanced cellular defenses against metabolic stress. These results
suggest that the circadian clock maintains metabolic homeostasis by sustaining daily
rhythms in feeding and fasting and by maintaining balance between nutrient and cellular
stress responses.