Nuclear Receptors (PPARs, REV-ERBs, RORs) and Clock Gene Rhythms in Goldfish (Carassius auratus) Are Differently Regulated in Hypothalamus and Liver

Abstract

The circadian system is formed by a network of oscillators located in central and peripheral tissues that are tightly linked to generate rhythms in vertebrates to adapt the organism to the cyclic environmental changes. The nuclear receptors PPARs, REV-ERBs and RORs are transcription factors controlled by the circadian system that regulate, among others, a large number of genes that control metabolic processes for which they have been proposed as key genes that link metabolism and temporal homeostasis. To date it is unclear whether these nuclear receptors show circadian expression and which zeitgebers are important for their synchronization in fish. Therefore, the objective of this study was to investigate whether the two main zeitgebers (light-dark cycle and feeding time) could affect the synchronization of central (hypothalamus) and peripheral (liver) core clocks and nuclear receptors in goldfish. To this aim, three experimental groups were established: fish under a 12 h light-12 h darkness and fed at Zeitgeber Time 2; fish with the same photoperiod but randomly fed; and fish under constant darkness and fed at Circadian Time 2. After one month, clock genes and nuclear receptors expression in hypothalamus and liver and circulating glucose were studied. Clock genes displayed daily rhythms in both tissues of goldfish if the light-dark cycle was present, with shifted-acrophases of negative and positive elements, as expected for proper functioning clocks. In darkness-maintained fish hypothalamic clock genes were fully arrhythmic while the hepatic ones were still rhythmic. Among studied nuclear receptors, in the hypothalamus only nr1d1 was rhythmic and only when the light-dark cycle was present. In the liver all nuclear receptors were rhythmic when both zeitgebers were present, but only nr1d1 when one of them was removed. Plasma glucose levels showed significant rhythms in fish maintained under random fed regimen or constant darkness, with the highest levels at 1-h postprandially in all groups. Altogether these results support that hypothalamus is mainly a light-entrained-oscillator, while the liver is a food-entrained-oscillator. Moreover, nuclear receptors are revealed as clear outputs of the circadian system acting as key elements in the timekeeping of temporal homeostasis, particularly in the liver.

Daily Rhythms in the IGF-1 System in the Liver of Goldfish and Their Synchronization to Light/Dark Cycle and Feeding Time

“…The liver of goldfish exhibits daily rhythms in the transcripts of some elements of the IGF-1 system, particularly IGF-1 and some IGFBPs, supporting the hypothesis that the IGF-1 system could be acting as a rhythmic output of this peripheral clock. The daily rhythm in the abundance of igf-1 transcripts found in the liver of goldfish with the acrophase at the end of the dark period matched with daily rhythms of clock genes belonging to the negative limb (e.g., per genes) of the main loop of molecular machinery in the liver clock [ 60 ]. This result points to igf-1 as a clock-controlled gen and reinforces its possible role as a rhythmic output of the liver oscillator.…”

“…Our study demonstrates that a photocycle is required to express the daily rhythm of igf-1 in the liver of goldfish, as this rhythm disappears under 24D conditions, as occurs in tilapia [ 65 ], and supports previous reports that evidence the relevance of photoperiod for the expression of igf-1 daily variations in the liver of teleost [ 35 , 36 , 37 , 39 ]. The fact that clock genes expression ( per1 , clock1 , bmal1 , and rev-erb ) in the liver of goldfish was highly sensitive to the daily photocycle [ 40 , 60 ] demonstrates the key role of the light/dark cycle in the synchronization of this peripheral clock [ 33 , 41 ]. However, the lack of a photocycle does not abolish the daily rhythms of the two rhythmic paralogs of igfbp1 in the liver of goldfish, which maintained significant rhythms with lower amplitudes and shifted the acrophases.…”

“…Light has been traditionally considered the main zeitgeber for the circadian system, but feeding time is a potent synchronizer of peripheral clocks, as the liver, which is considered a food-entrained oscillator [ 33 ]. Little is known about the functional organization of such clocks, but it is demonstrated that the liver drastically alters its molecular clockwork by different exogenous and endogenous inputs [ 33 , 41 , 60 ]. Our data clearly demonstrate the key role of feeding times in the entrainment of igf-1 rhythms in the liver.…”

Circ007071 Inhibits Unsaturated Fatty Acid Synthesis by Interacting with miR-103-5p to Enhance PPARγ Expression in the Dairy Goat Mammary Gland

“…The physiological functions of the PPAR family, a group of ligand-activated nuclear hormone receptors, are closely associated with fatty acid metabolism, glucose metabolism, and cell proliferation and differentiation . The PPAR family consists of three subtypes, namely, PPAR α, PPAR β / δ, and PPAR γ .…”

Circadian hormone secretion of enteroendocrine cells: implication on pregnancy status

“…The circadian system is formed by a network of oscillators found in central and peripheral tissues that are tightly linked to generate rhythms in vertebrates to adapt the organism to cyclic environmental changes. The nuclear receptors PPARs, REV-ERBs, and RORs are transcription factors controlled by the circadian system that regulate, among others, a large number of genes that control metabolic processes for which they have been proposed as key genes that link metabolism and temporal homeostasis ( 19 ).…”