The Role of Circadian Rhythms in the Hypertension of Diabetes Mellitus and the Metabolic Syndrome

Purpose of the Review

Cellular circadian clocks regulate physiological functions during day and night. It has been convincingly demonstrated that hypertension in patients suffering from diabetes mellitus or metabolic syndrome is characterized in most cases by a disturbed 24-h profile resulting in a nondipper pattern. We consider possible correlation between biological clocks and symptoms of the metabolic syndrome.

Recent Findings

Changes in circadian clock function have been linked to metabolic disorders in genome-wide association studies. Epidemiological studies have shown that a loss of nocturnal decline in blood pressure increases the risk of cardiovascular morbidity and mortality and end-organ damage. Looking at clock genes, however, there is no obvious association between symptoms of diabetes or metabolic syndrome and clock gene expression.

Summary

Emerging data suggest that circadian rhythm disruption is a risk factor for metabolic and cardiovascular disorders, while disease feedback on clock function is limited.

     

Circadian clock and cardiovascular disease

Both the physiological and pathological functions of cardiovascular organs are closely related to circadian rhythm, an endogenously driven 24-h cycle. Heart rate, blood pressure, and endothelial function show diurnal variations within a day. The onset of cardiovascular disorders such as acute coronary syndrome, atrial arrhythmia, and subarachinoid hemorrhage also exhibits diurnal oscillation. Recent progress in studying the functions and molecular mechanisms of the biological clock brought forth the idea that intrinsic circadian rhythms are tightly related to cardiovascular pathology. The center of the biological clock exists in the suprachiasmatic nucleus in the hypothalamus. In addition to this central clock, each organ has its own biological clock system, termed the peripheral clock. Each cardiovascular tissue or cell, including heart and aortic tissue, cardiomyocyte, vascular smooth muscle cell, and vascular endothelial cell also has intrinsic biological rhythm. Until recently, little was known about the roles of peripheral clocks in cardiovascular organs. However, studies using genetically engineered mice revealed their contributions during the process of disease progression. Loss of synchronization between the internal clock and external stimuli can induce cardiovascular organ damage. Discrepancy in the phases between the central and peripheral clocks also seems to contribute to progression of the disorders. Elucidation of the precise roles of biological clocks in cardiovascular organs will provide us with more profound insights into the relevance of the circadian rhythm in cardiac pathology. Moreover, identification of the modalities with which we can manipulate the phase of each peripheral clock will enable us to establish a novel chronotherapeutic approach. This time-of-day based strategy may innovate a new paradigm in the prevention and treatment of cardiovascular disorders.     

An intrinsic circadian clock of the pancreas is required for normal insulin release and glucose homeostasis in mice

Aims/hypothesis  

Loss of circadian clocks from all tissues causes defective glucose homeostasis as well as loss of feeding and activity rhythms. Little is known about peripheral tissue clocks, so we tested the hypothesis that an intrinsic circadian clock of the pancreas is important for glucose homeostasis.     

Relationship between calorie restriction and the biological clock: lessons from long-lived transgenic mice

The master clock located in the brain regulates circadian rhythms in mammals. Similar clocks are found in peripheral tissues. Life span has been independently increased by reset circadian rhythms and caloric restriction (CR). The mechanisms by which CR extends life span are not well understood. We found that alphaMUPA transgenic mice that exhibit reduced eating and live longer show high amplitude, appropriately reset circadian rhythms in clock gene expression, and clock-controlled output systems, such as feeding time and body temperature. As CR resets circadian rhythms, and the circadian clock controls many physiological and biochemical systems, we suggest that the biological clock could be an important mediator of longevity in calorically restricted animals.     

Alterations of the circadian clock in the heart by streptozotocin-induced diabetes

The heart, like other organs, possesses an internal circadian clock. These clocks provide the selective advantage of anticipation, enabling the organ to prepare for a given stimulus, thereby optimizing the appropriate response. The heart in diabetes is associated with alterations in morphology, gene expression, metabolism and contractile performance. The present study investigated whether diabetes also alters the circadian clock in the heart. Insulin-dependent diabetes mellitus was induced in rats by treatment with streptozotocin (STZ; 65 mg/kg). STZ increased humoral (glucose and non-esterified fatty acids) and heart gene expression (myosin heavy chain beta, pyruvate dehydrogenase kinase 4 and uncoupling protein 3) markers of diabetes. The circadian patterns of gene expression of seven components of the mammalian clock (bmal1, clock, cry1, cry2, per1, per2 and per3), as well as three clock output genes (dbp, hlf and tef), were compared in hearts isolated from control and STZ-induced diabetic rats. All components of the clock investigated possessed circadian rhythms of gene expression. In the hearts isolated from STZ-induced diabetic rats, the phases of these circadian rhythms were altered (approximately 3 h early) compared to those observed for control hearts. The clock in the heart has therefore lost normal synchronization with its environment during diabetes. Whether this loss of synchronization plays a role in the development of contractile dysfunction of the heart in diabetes remains to be determined.     

The regulation of central and peripheral circadian clocks in humans

Many circadian rhythms are controlled by the central clock of the suprachiasmatic nucleus of the hypothalamus, as well as clocks located in other brain regions and most peripheral tissues. These central and peripheral clocks are based on clock genes and their protein products. In recent years, the expression of clock genes has started to be investigated in human samples, primarily white blood cells, but also skin, oral mucosa, colon cells, adipose tissue as well as post-mortem brain tissue. The expression of clock genes in those peripheral tissues offers a way to monitor human peripheral clocks and to compare their function and regulation with those of the central clock, which is followed by markers such as melatonin, cortisol and core body temperature. We have recently used such an approach to compare central and peripheral rhythms in subjects under different lighting conditions. In particular, we have monitored the entrainment of the clock of blood cells in subjects undergoing a simulated night shift protocol with bright light treatment, known to efficiently reset the central clock. This line of research will be helpful for learning more about the human circadian system and to find ways to alleviate health problems of shift workers, and other populations experiencing altered circadian rhythms.     

The melatonin-sensitive circadian clock of the enteric bacterium Enterobacter aerogenes

Circadian clocks are fundamental properties of all eukaryotic organisms and at least some prokaryotic organisms. Recent studies in our laboratory have shown that the gastrointestinal system contains a circadian clock that controls many, if not all, aspects of gastrointestinal function. We now report that at least one species of intestinal bacteria, Enterobacter aerogenes, responds to the pineal and gastrointestinal hormone melatonin by an increase in swarming activity. This swarming behavior is expressed rhythmically, with a period of approximately 24 hrs. Transformation of E. aerogenes to express luciferase with a MotA promoter reveals circadian patterns of bioluminescence that are synchronized by melatonin and whose periods are temperature compensated from 26°C to 40°C. Bioinformatics suggest similarities between the E. aerogenes and cyanobacterial clocks, suggesting the circadian clock may have evolved very early in the evolution of life. They also point to a coordination of host circadian clocks with those residing in the microbiota themselves.     

The diurnal tick-tockery of platelet biology

Circadian (～24?hours) clocks are ubiquitous in nature and are important regulators of behaviour, physiology and metabolism. Circadian clocks can synchronise biological processes with environmental cycles, buffer biological systems to maintain homeostasis and partition mutually antagonistic processes to different temporal spaces within the daily cycle. Clocks act cell-autonomously (intrinsically) and systemically (extrinsically) to coordinate whole organism biology and there is epidemiological evidence indicating that chronic disruption of behavioural rhythms increases the risk of developing cancer and cardiovascular disease. Although the genetic mechanism of the mammalian clock has been largely deciphered, the physiological relevance of clocks often remains elusive. Findings from humans and animal models suggest that the circadian clock and diurnal rhythms have an important role in megakaryopoiesis and the risk of a cardiovascular event. This short review will introduce the mammalian circadian clock and discuss how circadian clocks and diurnal rhythms influence platelet production and function.     

Deconstructing circadian disruption: Assessing the contribution of reduced peripheral oscillator amplitude on obesity and glucose intolerance in mice

Disturbing the circadian regulation of physiology by disruption of the rhythmic environment is associated with adverse health outcomes but the underlying mechanisms are unknown. Here, the response of central and peripheral circadian clocks to an advance or delay of the light-dark cycle was determined in mice. This identified transient damping of peripheral clocks as a consequence of an advanced light-dark cycle. Similar depression of peripheral rhythm amplitude was observed in mice exposed to repeated phase shifts. To assess the metabolic consequences of such peripheral amplitude depression in isolation, temporally chimeric mice lacking a functional central clock (Vgat-Cre⁺ Bmal1^fl/fl) were housed in the absence of environmental rhythmicity. In vivo PER2::LUC bioluminescence imaging of anesthetized and freely moving mice revealed that this resulted in a state of peripheral amplitude depression, similar in severity to that observed transiently following an advance of the light-dark cycle. Surprisingly, our mice did not show alterations in body mass or glucose tolerance in males or females on regular or high-fat diets. Overall, our results identify transient damping of peripheral rhythm amplitude as a consequence of exposure to an advanced light-dark cycle but chronic damping of peripheral clocks in isolation is insufficient to induce adverse metabolic outcomes in mice.     

Differential entrainment of peripheral clocks in the rat by glucocorticoid and feeding

The suprachiasmatic nucleus is the master circadian clock and resets the peripheral clocks via various pathways. Glucocorticoids and daily feeding are major time cues for entraining most peripheral clocks. However, recent studies have suggested that the dominant timing factor differs among organs and tissues. In our current study, we reveal differences in the entrainment properties of the peripheral clocks in the liver, kidney, and lung through restricted feeding (RF) and antiphasic corticosterone (CORT) injections in adrenalectomized rats. The peripheral clocks in the kidney and lung were found to be entrained by a daily stimulus from CORT administration, irrespective of the meal time. In contrast, the liver clock was observed to be entrained by an RF regimen, even if daily CORT injections were given at antiphase. These results indicate that glucocorticoids are a strong zeitgeber that overcomes other entrainment factors regulating the peripheral oscillators in the kidney and lung and that RF is a dominant mediator of the entrainment ability of the circadian clock in the liver.     

Tissue-intrinsic dysfunction of circadian clock confers transplant arteriosclerosis

The suprachiasmatic nucleus of the brain is the circadian center, relaying rhythmic environmental and behavioral information to peripheral tissues to control circadian physiology. As such, central clock dysfunction can alter systemic homeostasis to consequently impair peripheral physiology in a manner that is secondary to circadian malfunction. To determine the impact of circadian clock function in organ transplantation and dissect the influence of intrinsic tissue clocks versus extrinsic clocks, we implemented a blood vessel grafting approach to surgically assemble a chimeric mouse that was part wild-type (WT) and part circadian clock mutant. Arterial isografts from donor WT mice that had been anastamosed to common carotid arteries of recipient WT mice (WT:WT) exhibited no pathology in this syngeneic transplant strategy. Similarly, when WT grafts were anastamosed to mice with disrupted circadian clocks, the structural features of the WT grafts immersed in the milieu of circadian malfunction were normal and absent of lesions, comparable to WT:WT grafts. In contrast, aortic grafts from Bmal1 knockout (KO) or Period-2,3 double-KO mice transplanted into littermate control WT mice developed robust arteriosclerotic disease. These lesions observed in donor grafts of Bmal1-KO were associated with up-regulation in T-cell receptors, macrophages, and infiltrating cells in the vascular grafts, but were independent of hemodynamics and B and T cell-mediated immunity. These data demonstrate the significance of intrinsic tissue clocks as an autonomous influence in experimental models of arteriosclerotic disease, which may have implications with regard to the influence of circadian clock function in organ transplantation.     

Daily oscillations in liver function: diurnal vs circadian rhythmicity.

The rodent suprachiasmatic nucleus (SCN), a site in the brain that contains a light-entrained biological (circadian) clock, has been thought of as the master oscillator, regulating processes as diverse as cell division, reproductive cycles, sleep, and feeding. However, a second circadian system exists that can be entrained by meal feeding and has an influence over metabolism and behavior. Recent advances in the molecular genetics of circadian clocks are revealing clock characteristics such as rhythmic clock gene expression in a variety of non-neural tissues such as liver. Although little is known regarding the function of these clock genes in the liver, there is a large literature that addresses the capabilities of this organ to keep time. This time-keeping capability may be an adaptive function allowing for the prediction of mealtime and therefore improved digestion and energy usage. Consequently, an understanding of these rhythms is of great importance. This review summarizes the results of studies on diurnal and circadian rhythmicity in the rodent liver. We hope to lend support to the hypothesis that there are functionally important circadian clocks outside of the brain that are not light- or SCN-dependent. Rather, these clocks are largely responsive to stimuli involved in nutrient intake. The interaction between these two systems may be very important for the ability of organisms to synchronize their internal physiology.     

Peripheral circadian clocks in the vasculature

Living organisms have adapted to the daily rotation of the earth and regular changes in the light environment. Life forms anticipate environmental transitions, adapt their own physiology, and perform activities at behaviorally advantageous times during the day. This is achieved by means of endogenous circadian clocks that can be synchronized to the daily changes in external cues, most notably light and temperature. For many years it was thought that neurons of the suprachiasmatic nucleus (SCN) uniquely controlled circadian rhythmicity of peripheral tissues via neural and humoral signals. The cloning and characterization of mammalian clock genes revealed that they are expressed in a circadian manner throughout the body. It is now accepted that peripheral cells, including those of the cardiovascular system, contain a circadian clock similar to that in the SCN. Many aspects of cardiovascular physiology are subject to diurnal variation, and serious adverse cardiovascular events including myocardial infarction, sudden cardiac death, and stroke occur with a frequency conditioned by time of day. This has raised the possibility that biological responses under the control of the molecular clock might interact with environmental cues to influence the phenotype of human cardiovascular disease.     

Circadian rhythms and the liver

This narrative review briefly describes the mammalian circadian timing system, the specific features of the liver clock, also by comparison with other peripheral clocks, the role of the liver clock in the preparation of food intake, and its relationship with energy metabolism. It then goes on to provide a chronobiological perspective of the pathophysiology and management of several types of liver disease, with a particular focus on metabolic-associated fatty liver disease (MAFLD), decompensated cirrhosis and liver transplantation. Finally, it provides some insight into the potential contribution of circadian principles and circadian hygiene practices in preventing MAFLD, improving the prognosis of advanced liver disease and modulating liver transplantation outcomes.     

Physiological significance of a peripheral tissue circadian clock

Mammals have circadian clocks in peripheral tissues, but there is no direct evidence of their physiological importance. Unlike the suprachiasmatic nucleus clock that is set by light and drives rest–activity and fasting–feeding cycles, peripheral clocks are set by daily feeding, suggesting that at least some contribute metabolic regulation. The liver plays a well known role in glucose homeostasis, and we report here that mice with a liver-specific deletion of Bmal1, an essential clock component, exhibited hypoglycemia restricted to the fasting phase of the daily feeding cycle, exaggerated glucose clearance, and loss of rhythmic expression of hepatic glucose regulatory genes. We conclude that the liver clock is important for buffering circulating glucose in a time-of-day-dependent manner. Our findings suggest that the liver clock contributes to homeostasis by driving a daily rhythm of hepatic glucose export that counterbalances the daily cycle of glucose ingestion resulting from the fasting–feeding cycle.