Abstract
Circadian rhythms are the product of the interaction of molecular clocks and environmental signals, such as light-dark cycles and eating-fasting cycles. Several studies have demonstrated that the circadian rhythm of peripheral clocks, and behavioural and metabolic mediators are re-synchronized in rodents fed under metabolic challenges, such as hyper- or hypocaloric diets and subjected to time-restricted feeding protocols. Despite the metabolic challenge, these approaches improve the metabolic status, raising the enquiry whether removing progressively the hypocaloric challenge in a time-restricted feeding protocol leads to metabolic benefits by the synchronizing effect. To address this issue, we compared the effects of two time-restricted feeding protocols, one involved hypocaloric intake during the entire protocol (HCT) and the other implied a progressive intake accomplishing a normocaloric intake at the end of the protocol (NCT) on several behavioural, metabolic, and molecular rhythmic parameters. We observed that the food anticipatory activity (FAA) was driven and maintained in both HCT and NCT. Resynchronization of hepatic molecular clock, free fatty acids (FFAs), and FGF21 was elicited closely by HCT and NCT. We further observed that the fasting cycles involved in both protocols promoted ketone body production, preferentially beta-hydroxybutyrate in HCT, whereas acetoacetate was favoured in NCT before access to food. These findings demonstrate that time-restricted feeding does not require a sustained calorie restriction for promoting and maintaining the synchronization of the metabolic and behavioural circadian clock, and suggest that metabolic modulators, such as FFAs and FGF21, could contribute to FAA expression.
Highlights
Circadian rhythms are the product of the interaction of molecular clocks and environmental signals, such as light-dark cycles and eating-fasting cycles
The HCT group showed a pattern that started with a significant reduction of the calorie intake comparing to ad libitum (AL) condition and reached a plateau at the end of the protocol (45% calorie restriction); this involves hypocaloric intake as previously reported[16]
Time-restricted food access or time-restricted feeding (TRF) with a sustained hypocaloric intake (HCT) consists in limiting the daily period of food intake to a short window of time (2 h of food access), which involves daily fasting-refeeding cycles, features that promote adaptations in metabolic and health indices by the synchronising effect of TRF. It is unclear whether these physiological responses are mediated by the metabolic challenge of the continuous calorie restriction during the protocol
Summary
Circadian rhythms are the product of the interaction of molecular clocks and environmental signals, such as light-dark cycles and eating-fasting cycles. Daytime restricted feeding (2 h of food access) in rats is a hypocaloric condition (HCT) that elicits the expression of FAA as the behavioural output of the FEO22 Based on this information, the present study aimed at elucidating whether a protocol of daytime restricted feeding that progressively accomplishes a normocaloric intake (NCT), using a standard lab rodent diet, was able to induce metabolic signals associated to FAA. We observed that restricting the timing of food intake during 21 days promoted a sustained expression of the FAA, and, at the end of the protocols, it induced the synchronization of hepatic clock genes, and the elevation of circulating free fatty acids (FFAs), regardless of calorie intake during the protocols Parameters such as endocrine responses, adipose tissue amount and morphology, hepatic pro-oxidant reactions, redox regulation, and oxidised or reduced forms of ketone bodies, varied according to the ingested calorie intake. These data allow us to further understand the molecular and energetic elements that underlie circadian synchronization by restricted feeding schedules and the associated FEO expression
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