“Defining the Independence of the Liver Circadian Clock” & “BMAL1-Driven Tissue Clocks Respond Independently to Light to Maintain Homeostasis”

摘要

Introduction Metabolism and the circadian rhythms constitute an inseparable couple. Our 24-h internal clock dictates our sleep-wake patterns, which in turn determines what we eat and when, with a direct impact on our metabolic cycles. These rhythms are nominally self-sustained but can be adjusted to the environment by stimuli, such as light or food, called Zeitgebers (the German word for “time-givers”) (Aschoff, 1965 ). Like the principal conductor leading a symphonic orchestra, a tiny pack of suprachiasmatic nucleus (SCN) neurons in the brain residing directly above the optic chiasm work as a master coordinator of the rest of the circadian clocks of the body. Changes in light are transmitted directly from the retina to the SCN, which actively synchronize the geophysical and environmental cycle with its own clock before entraining other organs (Schibler and Sassone-Corsi, 2002 ). Although the molecular mechanisms regulating the brain central clock have been studied extensively, the degree of contribution of individual organs to “timekeeping” is still unclear. The transcription factor BMAL1 (ARNTL) has been shown to be essential for rhythmic gene expression in the mammalian circadian timing system (Haque et al., 2019 ). BMAL1 forms a heterodimer with CLOCK, another core circadian transcription factor, to drive the expression of the Period and Cryptochrome genes, by direct binding to E-box regulatory elements (Takahashi, 2017 ). In a classical transcriptional feedback loop, PER and CRY transcription factors form a complex that translocates to the nucleus to inhibit BMAL1-CLOCK mediated gene expression (Eckel-Mahan and Sassone-Corsi, 2013 ), ensuring proper functioning of the 24-h molecular oscillator. Bmal knockout mice, in addition to loss of circadian rhythms, show characteristics of premature aging and a number of phenotypes including defective glucose homeostasis, calcification of joints and corneal degeneration (Kondratov et al., 2006 ). In back-to-back publications in Cell (Koronowski et al., 2019 ; Welz et al., 2019 ), the authors go one step further in transgenic engineering and generate a mouse model that reconstitutes Bmal1 expression in one particular organ, such as the epidermis (Bmal1-RE mouse) or the liver (Liver-RE mouse), with Bmal1 being completely absent in any other parts of the mouse body ( Figure 1 ). This provides them with a valuable tool to dissect the unique contribution of peripheral tissues and organs to the master circadian mechanism, as well as to assess their degree of autonomy. Figure 1 Schematic representation of the main findings from the dual publication (Koronowski et al., 2019 ; Welz et al., 2019 ) commented. The mouse model reconstituting Bmal1 expression exclusively in the epidermis (Bmal1-RE mouse) or the liver (Liver-RE mouse) was generated from a conventional full-body Bmal1 knockout mouse (Bmal1-KO). In mammals, the brain central clock works as a master circadian coordinator of the rest of circadian clocks in the body. The autonomous responses in Bmal1 reconstituted organs (epidermis or liver) ensured basic homeostasis of the organs (e.g., epidermal turnover, glycogen metabolism) and were only dependent on inputs of light and darkness. WT, wild type. Liver Circadian Clock Sets Its Own Pace One of the main discoveries in these studies takes place at the hepatic level (Koronowski et al., 2019 ). In the liver, many rate-limiting enzymes of key metabolic outputs (including detoxification, carbohydrate, lipid, and amino acid metabolism) are under direct circadian control. In contrast to the master clock, for which light is the dominant Zeitgeber, the liver clock can be efficiently entrained by feeding-fasting rhythms to the point of being fully uncoupled from SCN rhythms (Damiola et al., 2000 ; Stokkan et al., 2001 ; Reinke and Asher, 2016 ). Transcriptomics and metabolomics experiments were conducted in the liver-RE mice mouse model, which exclusively expresses Bmal1 in the liver and compared to wild type animals. These studies revealed a series of metabolic pathways and metabolites that are able to oscillate autonomously from all other clocks, and constitute around 20% of the hepatic rhythms, including essential processes such as glycogen turnover and the NAD ~(+) salvage pathway. Importantly, this autonomous response of the liver clock was independent from food, being only disrupted by a prolonged exposure to complete darkness. Postulating a Bifid Model for Synchronization of Peripheral Clocks Some of these findings can be extrapolated to other peripheral tissues, including non-metabolically active organs, as demonstrated in the companion publication on the epidermis (Welz et al., 2019 ). The skin is the largest organ in the body and a huge sensory light receptor. Bmal1 deficient mouse models have shown premature aging: hair graying, loss of subcutaneous fat layer and delayed tissue healing (Kondratov et al., 2006 ). Thus, elucidating circadian oscillations in the epid