Circadian Glucose Homeostasis Requires Compensatory Interference Between Brain and Liver Clocks

COMMENTARY

Circadian glucose homeostasis requires compensatory interference between brain and liver clocks

David Gatﬁeld and Ueli Schibler* Department of Molecular Biology and National Center for Competence in Research Frontiers in Genetics, Sciences III, University of Geneva, 30, Quai Ernest Ansermet, CH-1211 Geneva-4, Switzerland

he liver plays an important role they annul the transactivation potential cogenolysis or gluconeogenesis and ex- in adjusting metabolic processes of BMAL1-CLOCK/NPAS2 het- ported into the blood stream via the to daily feeding–fasting cycles. erodimers and thereby shut off tran- GLUT2 transporter. All these processes This role is manifested by the scription of their own genes. This results are under circadian control, but Tcircadian expression of many liver genes in a decrease of PER and CRY proteins GLUT2-mediated export appears to be involved in the metabolism of lipids, below the level required for autore- the rate-limiting step. In wild-type ani- proteins, carbohydrates, and xenobiotics pression and a new daily PER–CRY mals, the food-borne glucose supply (1–4). Moreover, the disruption or mu- accumulation cycle can ensue. The ro- largely meets the requirements during tation of the essential clock genes Bmal1 bustness of this transcription/translation the absorptive phase, and a surge of and Clock results in various metabolic feedback loop is augmented by cycles of GLUT2 expression associated with in- disorders (for review see ref. 5). Al- posttranslational modifications that af- creased liver glucose export keeps blood though these studies clearly demonstrate fect the activity and stability of PER sugar levels adequate during the postab- that BMAL1 and CLOCK are impor- and CRY proteins (10–12). sorptive phase (Fig. 1A). L-Bmal1Ϫ/Ϫ tant regulators of metabolism, they do Owing to their intercellular connec- mice display normal rest–activity and not address the question of whether the tions, SCN neuron clocks maintain feeding rhythms, because their SCN phenotypes have been caused by the loss phase coherence indefinitely in vivo and master clock is fully functional. How- of these genes or the loss of rhythms. for weeks in brain tissue explants (7). In ever, these animals have disabled hepa- However, in this issue of PNAS, Weitz contrast, hepatocyte oscillators or fibro- tocyte oscillators and express GLUT2 at and coworkers (6) present compelling blasts do not talk to each other and constitutively low levels. Although glu- evidence for the physiological impor- rapidly desynchronize in SCN-lesioned coneogenesis and glycogenolysis still run tance of a functional liver clock. Using animals (13) or in tissue culture (9, 14). at adequate rates in these animals, their the Cre-loxP recombination strategy in Hence, peripheral slave oscillators must liver cannot export sufficient amounts of mice, these authors inactivated Bmal1 be phase-entrained daily by the SCN Ϫ Ϫ glucose to keep the blood glucose level either in all cells (Bmal1 / ) or specifi- master clock to run in harmony with Ϫ Ϫ constant during the postabsorptive cally in hepatocytes (L-Bmal1 / ). each other. Feeding–fasting cycles are phase. The result is a temporally re- Animals with a liver-specific Bmal1 dis- the dominant Zeitgebers for cellular ruption suffer from hypoglycemia specif- clocks in liver and many additional pe- stricted hypoglycemia, despite acute ically during the inactivity phase. Yet ripheral organs (1). It therefore appears mechanisms regulating glucose supply mice deficient for BMAL1 in all cells do that under normal conditions the SCN during the fasting phase, such as gluca- gon and glucocorticoid signaling (Fig. not show overt problems with their rest- timekeeper synchronizes subsidiary os- Ϫ/Ϫ ing blood sugar levels. Hence, in cillators in the periphery in an indirect 1B). Bmal1 mice with disrupted L-Bmal1Ϫ/Ϫ mice, the lack of liver fashion. By driving rest–activity rhythms Bmal1 alleles in all cells exhibit some rhythms rather than that of BMAL1 it also imposes feeding–fasting rhythms, phenotypes with regard to acute glucose must have been the cause of impaired which in turn set the phase in most pe- regulation (ref. 15 and this paper). For glucose homeostasis. ripheral cells through molecular signal- example, they readjust normal blood The circadian timing system has a hi- ing pathways yet to be discovered. glucose levels more sluggishly than wild- erarchical structure in that a master The synchronization of peripheral type mice after an i.v. glucose injection pacemaker in the brain’s suprachias- clocks by feeding time makes sense, be- (glucose intolerance) and decrease matic nucleus (SCN) synchronizes slave cause circadian metabolism is probably blood glucose concentrations more dra- oscillators in nearly all body cells (1). a major clock output in many if not matically after an i.v. insulin injection Central and peripheral clocks have a most peripheral cell types. However, the (insulin hypersensitivity). However, de- similar molecular make-up, and both work of Lamia et al. (6) revealed that spite constitutively low hepatic GLUT2 tick in a self-sustained and cell- feeding–fasting cycles also pose a chal- expression, these animals have nearly autonomous fashion (7–9). The mo- lenge to the organism. Glucose plasma normal resting blood glucose concentra- lecular clockwork relies on a negative levels must be kept nearly constant tions. Because Bmal1Ϫ/Ϫ mice are feedback of gene expression (10). Two throughout the day, to provide a con- arrhythmic and ingest food in short tem- cryptochrome (CRY1 and CRY2) and stant source of fuel for brain cells and poral bouts throughout the day, the low two period proteins (PER1 and PER2) erythrocytes. During the absorptive hepatic levels of GLUT2 are supposedly constitute the central part of the molec- phase carbohydrates are plentiful, and sufficient for an adequate hepatic glu- ular oscillators. The genes encoding constant blood sugar levels can readily cose delivery to the organism (Fig. 1C). these proteins are activated by het- be adjusted through the insulin signaling erodimers of the transcription factors pathway. High plasma glucose concen- BMAL1 and CLOCK (or its paralog trations trigger the secretion of insulin Author contributions: D.G. and U.S. wrote the paper. NPAS2). As a consequence, PER and by beta cells, which provokes the uptake The authors declare no conﬂict of interest. CRY proteins accumulate in the cell of excessive glucose by liver and muscle See companion article on page 15172. and form heterotypic complexes, and and its polymerization into glycogen *To whom correspondence should be addressed. E-mail: once these have reached a critical stores. During the postabsorptive phase, [email protected]. threshold concentration (and/or activity) glucose is produced in the liver by gly- © 2008 by The National Academy of Sciences of the USA

www.pnas.org͞cgi͞doi͞10.1073͞pnas.0807861105 PNAS ͉ September 30, 2008 ͉ vol. 105 ͉ no. 39 ͉ 14753–14754 Downloaded by guest on September 30, 2021 A Biological clocks have evolved to gen- erate oscillations in physiology and be- havior so as to anticipate and adapt to daily light–dark and temperature rhythms resulting from the rotation of the earth around its own axis. But for certain physiological parameters, such as blood glucose levels, large fluctuations are undesired. The study by Weitz and colleagues (6) provides compelling evidence for how the liver clock can coun- terbalance the oscillating sugar supply B provoked by SCN-driven feeding–fasting cycles by governing antiphasic rhythms of hepatic glucose delivery. With their work, the authors have therefore es- tablished a convincing case for the importance of peripheral oscillators in modulating circadian physiology. A com- plication in assessing the function of autonomous peripheral clocks is that in one and the same tissue, cyclic gene expression can be driven by both local oscillators and/or rhythmic systemic timing cues (e.g., C hormones, metabolites, body temperature rhythms, and inputs from the peripheral nervous system) (14). However, the de- pendence of oscillating Glut2 transcription on hepatocyte-derived BMAL1 strongly suggests that circadian glucose export is indeed driven by local liver clocks. The further investigation of L-Bmal1Ϫ/Ϫ mice harboring Bmal1-null alleles specifically in hepatocytes is bound to unveil many additional physio- Fig. 1. Hepatocyte oscillators drive the cyclic expression of many enzymes associated with glucose logical phenotypes. Indeed, rhythmically homeostasis, such as glycogen synthase (GYS2), glycogen phosphorylase (PYGL), phosphoenolpyruvate carboxykinase (PEPCK), glucokinase (GCK), glucose-6-phosphatase (GLC-6-Pase), and the glucose trans- expressed liver genes revealed by ge- porter GLUT2. (A) In wild-type animals, the SCN drives feeding rhythms and, thus, rhythms of glucose nome-wide transcriptome profiling stud- supply from nutrients. These cycles are counteracted by antiphasic rhythms of hepatic glucose export. (B) ies are associated with the metabolism In L-Bmal1Ϫ/Ϫ mice, the ﬂoxed Bmal1 alleles have been disrupted only in hepatocytes. Because the SCN of fatty acids, cholesterol, bile acids, master clock is intact in these animals, their activity and feeding rhythms are normal. However, because amino acids, and xenobiotics (2–4, 16). the disabled liver clock can no longer compensate the lack of food-derived glucose by a burst of GLUT2 It will be a challenging but enticing task expression during the fasting phase, L-Bmal1Ϫ/Ϫ mice display a circadian hypoglycemia. (C)InBmal1Ϫ/Ϫ mice, the circadian clocks are disabled in all tissues. These arrhythmic animals eat throughout the day, and to evaluate the contribution of liver the nutrient-derived glucose supply is nearly invariable over time. Although GLUT2 is expressed at low clocks to the coordination of these vari- levels, it is sufﬁcient to keep blood glucose at nearly normal (and invariable) concentrations. ous metabolic processes.

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14754 ͉ www.pnas.org͞cgi͞doi͞10.1073͞pnas.0807861105 Gatﬁeld and Schibler Downloaded by guest on September 30, 2021