Abstract
β-catenin, the principal effector of the Wnt pathway, is also one of the cadherin cell adhesion molecules; therefore, it fulfills signaling and structural roles in most of the tissues and organs. It has been reported that β-catenin in the liver regulates metabolic responses such as gluconeogenesis and histological changes in response to obesity-promoting diets. The function and cellular location of β-catenin is finely modulated by coordinated sequences of phosphorylation–dephosphorylation events. In this article, we evaluated the levels and cellular localization of liver β-catenin variants, more specifically β-catenin phosphorylated in serine 33 (this phosphorylation provides recognizing sites for β-TrCP, which results in ubiquitination and posterior proteasomal degradation of β-catenin) and β-catenin phosphorylated in serine 675 (phosphorylation that enhances signaling and transcriptional activity of β-catenin through recruitment of different transcriptional coactivators). β-catenin phosphorylated in serine 33 in the nucleus shows day–night fluctuations in their expression level in the Ad Libitum group. In addition, we used a daytime restricted feeding (DRF) protocol to show that the above effects are sensitive to food access-dependent circadian synchronization. We found through western blot and immunohistochemical analyses that DRF protocol promoted (1) higher total β-catenins levels mainly associated with the plasma membrane, (2) reduced the presence of cytoplasmic β-catenin phosphorylated in serine 33, (3) an increase in nuclear β-catenin phosphorylated in serine 675, (4) differential co-localization of total β-catenins/β-catenin phosphorylated in serine 33 and total β-catenins/β-catenin phosphorylated in serine 675 at different temporal points along day and in fasting and refeeding conditions, and (5) differential liver zonation of β-catenin variants studied along hepatic acinus. In conclusion, the present data comprehensively characterize the effect food synchronization has on the presence, subcellular distribution, and liver zonation of β-catenin variants. These results are relevant to understand the set of metabolic and structural liver adaptations that are associated with the expression of the food entrained oscillator (FEO).
Highlights
Daytime restricted feeding (DRF) is an accepted protocol to study the dynamic relationship between the circadian timing system and metabolic networks [1, 2]
Key experiments show that a variety of 24-h rhythmic responses under the DRF protocol, including the onset and maintenance of food-anticipatory activity (FAA), are elicited even when suprachiasmatic nucleus (SCN) functions are disrupted [references within Ref. [8]], which support the existence of an SCN-independent circadian timing system known as the food entrained oscillator (FEO) [9]
The fasting group (Fa) group exhibited a similar expression of pSer33 β-catenin to DRF at 11:00 hours in all fractions tested, whereas the refeeding group (Rf) group revealed a similar pattern in the total homogenate and in the nuclear fraction, but not in the cytosolic fraction; it showed a 61% reduction in pSer33 β-catenin compared to the DRF group (14:00 hours)
Summary
Daytime restricted feeding (DRF) is an accepted protocol to study the dynamic relationship between the circadian timing system and metabolic networks [1, 2]. DRF (2-h food access per day) involves two underlying aspects of daily physiological adjustments: [1] a circadian synchronization that shifts the phases of clock genes and [2] a hypocaloric food intake. Both aspects influence the adaptive response that allows an optimal metabolic handling of nutrients when food availability is restricted to a particular time of day [4, 5]. [8]], which support the existence of an SCN-independent circadian timing system known as the food entrained oscillator (FEO) [9]. Defining the FEO’s anatomical substrate has been elusive, in part because the existence of several FEOs in different organs and tissues [10] and the emergence of an alternative timing system that complements the SCN’s pacemaker activity [11, 12]
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