The mammalian circadian system consists of a central clock in the brain that synchronizes clocks in peripheral tissues. While the hierarchy between the central and peripheral clocks is established, little is known regarding the specificity and functional organization of peripheral clocks. Here, we employ altered feeding paradigms in conjunction with liver-clock mutant mice to map disparities and interactions between peripheral rhythms. We find that peripheral clocks largely differ in their responses to feeding-time. Disruption of the liver-clock, despite its prominent role in nutrient processing, does not affect rhythmicity of clocks in other peripheral tissues. Yet, unexpectedly, liver-clock disruption strongly modulates peripheral tissues’ transcriptional rhythmicity, primarily upon daytime feeding. Concomitantly, liver-clock mutant mice exhibit impaired glucose and lipid homeostasis, which are aggravated by daytime feeding. Overall, our findings suggest that, upon nutrient challenge, the liver-clock buffers the effect of feeding-related signals on rhythmicity of peripheral tissues, irrespective of their clocks.

In mammals, daily changes in body temperature (Tb) depend on the integrity of the suprachiasmatic nucleus (SCN). Fasting influences the Tb in the resting period and the presence of the SCN is essential for this process. However, the origin of this circadian/metabolic influence is unknown. We hypothesized that, not only the SCN but also the arcuate nucleus (ARC), are involved in the Tb setting through afferents to the thermoregulatory median preoptic nucleus (MnPO). Therefore, we investigated by neuronal tracing and microdialysis experiments the possible targeting of the MnPO by the SCN and the ARC in male Wistar rats. We observed that vasopressin release from the SCN decreases the temperature just before light onset, whereas ␣-melanocyte stimulating hormone release, especially at the end of the dark period, maintains high temperature. Both peptides have opposite effects on the brown adipose tissue activity through thermoregulatory nuclei such as the dorsomedial nucleus of the hypothalamus and the dorsal raphe nucleus. The present study indicates that the coordination between circadian and metabolic signaling within the hypothalamus is essential for an adequate temperature control.

The circadian system, headed by the suprachiasmatic nucleus, synchronizes behaviour and metabolism according to the external light-dark cycle through neuroendocrine and autonomic signals. Metabolic diseases, such as steatosis, obesity and glucose intolerance, have been associated with conditions of circadian misalignment wherein the feeding schedule has been moved to the resting phase. Here we describe the physiological processes involved in liver lipid accumulation and show how they follow a circadian pattern importantly regulated by both the autonomic nervous system and the feeding-fasting cycle. We propose that an unbalanced activity of the sympathetic-parasympathetic branches between organs induced by circadian misalignment provides the conditions for the development and progression of non-alcoholic fatty liver disease.

Circadian disruption is associated with metabolic disturbances such as hepatic steatosis (HS), obesity and type 2 diabetes. We hypothesized that HS, resulting from constant light (LL) exposure is due to an inconsistency between signals related to food intake and endocrine-driven suprachiasmatic nucleus (SCN) outputs. Indeed, exposing rats to LL induced locomotor, food intake and hormone arrhythmicity together with the development of HS. We investigated whether providing temporal signals such as 12-h food availability or driving a corticosterone plus melatonin rhythm could restore rhythmicity and prevent the metabolic disturbances under LL conditions in male rats. Discrete metabolic improvements under these separate treatments stimulated us to investigate whether the combination of hormone treatment together with mealtime restriction (12-h food during four weeks) could prevent the metabolic alterations. LL exposed arrhythmic rats, received daily administration of corticosterone (2.5 µg/kg) and melatonin (2.5 mg/kg) in synchrony or out of synchrony with their 12-h meal. HS and other metabolic alterations were importantly ameliorated in LL-exposed rats receiving hormonal treatment in synchrony with 12-h restricted mealtime, while treatment out of phase with meal time did not. Interestingly, liver bile acids, a major indication for HS, were only normalized when animals received hormones in synchrony with food indicating that disrupted bile acid metabolism might be an important mechanism for the HS induction under LL conditions. We conclude that food-elicited signals, as well as hormonal signals, are necessary for liver synchronization and that HS arises when there is conflict between food intake and the normal pattern of melatonin and corticosterone.