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Molecular clocks, type 2 diabetes and cardiovascular disease

Madhu J Prasai, Jyothis T George and Eleanor M Scott Diabetes and Vascular Disease Research 2008 5: 89 DOI: 10.3132/dvdr.2008.015 The online version of this article can be found at: http://dvr.sagepub.com/content/5/2/89

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Molecular clocks, type 2 diabetes and cardiovascular disease

MADHU J PRASAI, JYOTHIS T GEORGE, ELEANOR M SCOTT
Abstract he westernised world is in the midst of an epidemic of type 2 diabetes and associated cardiovascular disease. These closely interlinked conditions have a common pathophysiological basis underpinned by insulin resistance and the metabolic syndrome. Contemporary changes in environmental factors on a background of genetic susceptibility are thought to account for the increases seen. Life on earth is governed by the 24-hour environment of light and darkness cycling with the rotation of the earth. Numerous metabolic and physiological pathways are coordinated to this 24-hour cycle by an endogenous clock. Recent epidemiological evidence and animal data suggest that disturbance of circadian rhythms through genetic and environmental influences on the molecular clock is pivotal in the pathogenesis of obesity, type 2 diabetes and cardiovascular disease. This review describes current knowledge on the topic. Diabetes Vasc Dis Res 2008;5:8995 doi:10.3132/dvdr.2008.015

tion. They are generated by an endogenous oscillator, which is composed of a central clock in the suprachiasmic nucleus (SCN) of the hypothalamus, known as the master clock or circadian pacemaker, and numerous peripheral clocks in peripheral tissues.1,2 The central clock consists of multiple, autonomous, selfsustaining, single cell circadian oscillators which are linked to produce a co-ordinated, in-phase, circadian signal.1,3,4 The SCN oscillations are not exactly 24 hours and so they are synchronised and entrained every day by the external light/dark signal transmitted through the retinohypothalamic tract.1,4 Thus, light is the primary environmental Zeitgeber or timegiver. This gives information not only about the 24hour day but also about the change in the relative proportion of light/dark (the photoperiod) and the amplitude of light intensity that tracks the seasons.5 Similar oscillations are found in the cells of most (if not all) peripheral tissues.6 These too are autonomous and self-sustaining but are entrained to the SCN by neurohumoral information and also respond to their own peripheral Zeitgebers, most notably feeding and local changes in energy status (figure 1).3,4 Molecular organisation of the endogenous clock The molecular mechanisms that underlie these circadian oscillators and control these daily rhythms have recently been elucidated (for reviews see1,3-9) and are outlined in the article by Duez et al. in this edition of the Journal (pages 828). As an indication of its wide-ranging importance, the molecular clock is ubiquitous to all mammals and indeed most other organisms; it has been demonstrated recently that at least 20%, and possibly up to 100%, of transcripts from all tissues are under circadian control.9-12 In brief, each cell contains a set of core clock genes Clock, Bmal1, Cry 1-2, Per 1-3 and nuclear receptors (Rev-erb, ROR). Through complex positive and negative transcriptional and translational feedback loops, they generate an endogenous rhythm of intracellular protein expression, leading to rhythmic cell and tissue function that oscillates over approximately 24 hours.1,4,11 The molecular clock has been demonstrated to regulate metabolism and energy homeostasis by controlling the expression and activity of numerous enzymes, transport systems and nuclear receptors involved in lipid and carbohydrate metabolism.11,13,14 Is there a role for the endogenous clock in obesity, type 2 diabetes and cardiovascular disease? Type 2 diabetes (T2DM) and cardiovascular disease share common pathophysiological mechanisms that are underpinned by the development of insulin resistance and a

Key words: adipose tissue, cardiovascular disease, circadian rhythms, molecular clock, shift work, sleep deprivation, type 2 diabetes. Organisation of circadian and seasonal rhythms Life on earth is governed by the 24-hour environment of light and dark. Adaptation to this 24-hour cycle enables an organism to anticipate environmental fluctuations over the day and to optimise the timing of relevant biological processes. These wide-ranging circadian rhythms (circa = around; dies = one day) of behaviour, physiology and metabolism include the sleepwake cycle, feeding behaviour, control of body temperature, as well as numerous aspects of cardiovascular, endocrine, gastrointestinal, hepatic and renal func-

Division of Cardiovascular and Diabetes Research, The Leeds Institute of Genetics Health and Therapeutics, Clarendon Way, University of Leeds, Leeds, LS2 9JT, UK. Madhu J Prasai, Senior House Officer Jyothis T George, Specialist Registrar Eleanor M Scott, Senior Lecturer in Medicine, Consultant in Diabetes and Endocrinology Correspondence to: Dr Eleanor M Scott Division of Cardiovascular and Diabetes Research, Leeds Institute of Genetics, Health and Therapeutics, Clarendon Way, University of Leeds, Leeds, LS2 9JT, UK. Tel: +44 (0)113 343 7721; Fax: +44 (0)113 343 7738 E-mail: e.m.scott@leeds.ac.uk

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Figure 1. Organisation of circadian rhythms and the endogenous clock

SCN Central oscillator

Light/dark

Neural/hormonal signals Melatonin MT receptors on many tissues

Pars tuberalis Adipocytes Endothelial cells

Food

Peripheral cells Peripheral oscillator

Regulates metabolism of cell and organism in response to day length and the seasons
(20100% of transcripts under circadian control)

Key: SCN = suprachiasmic nucleus

cluster of cardiovascular risk factors known as the metabolic syndrome. Obesity plays a major role in this process, as fat-laden adipose tissue becomes an active endocrine organ, secreting a variety of substances that actively promote the development of the metabolic syndrome and vascular disease. There has been an increasing awareness of the importance of the biological clock in mans physiology and concern over disruption of its rhythms.11,15-19 Mans body clock is tightly regulated to keep his physiology and metabolism in time with day length. Glucose, lipids, insulin, adiponectin, leptin, plasminogen activator inhibitor-1 (PAI-1) and blood pressure normally exhibit diurnal variation in man.18 There is evidence to suggest that not only are many of these variables increased in the metabolic syndrome but that the normal physiological variation between day and night is lost, so that the increase is sustained over the full 24-hour day.18,20-24 This continuous increase, with loss of diurnal variation, contributes to the development of vascular disease and end-organ damage.18,20-22 The clinical presentation of cardiovascular disease is also recognised to have a diurnal distribution, with myocardial infarction and angina occurring more commonly in the early hours of the morning.25 The central and peripheral molecular clock system sits at the absolute core of synchronising an organisms metabolism and physiology to its external day/night 24-hour environment. Obesity, T2DM and cardiovascular disease are recognised to develop as a result of the effect of disturbance of environmental factors on a genetic predisposition. It is important, therefore, to consider the role of the molecular clock in this process by looking at the impact that disruption of core genetic components and environmental inputs (light, feeding) to the molecular clock have on glucose metabolism, adipocyte and vascular function.

Genetic disruption of the molecular clock Glucose and metabolism Various studies that have examined the impact of disruption of core clock genes on glucose metabolism, adipocyte and vascular function have been reported recently. The most prominent of these was a study by Turek et al., who examined the effect of a loss of sense mutation in Clock and showed that homozygous Clock mutant mice, on a C57BL/6J background, lose circadian rhythmicity, become obese and develop the metabolic syndrome with hepatic steatosis, hyperglycaemia, hypertriglyceridaemia, hypercholesterolaemia and hyperleptinaemia.26 A subsequent study examined Clock mutant mice on an ICR background at three months but did not confirm these findings due to fat malabsorption.27 However, this group then went on to look at the effect of Clock disruption in genetically obese leptin-deficient mice (ob/ob) and found that it led to more weight gain, raised triglycerides, cholesterol and adipocyte hypertrophy than leptin deficiency alone.28 Concerned about the impact that melatonin deficiency might be having in the Clock mutant mice on a C57BL/6J background, Kennaway examined Clock19+MEL mice and showed that there was reduced hepatic expression and rhythmicity of glycolytic and gluconeogenic regulatory components, with impaired glucose tolerance but enhanced insulin sensitivity, suggesting that abnormalities in glucose metabolism associated with the Clock mutation could not be attributed to melatonin deficiency.29 In support of this, mutations in Bmal and Clock have been shown to modify circadian variation in glucose and triglycerides and to influence the development of insulin resistance in response to a high-fat diet.30 Additionally, Panda et al. have performed transcriptome analysis of the suprachiasmic nucleus and liver of Clock mutant mice and shown

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global changes in metabolic pathways, particularly those encoding glycolysis and lipid metabolism.31 Adipose tissue function Given the central role that adipose tissue is considered to play in the development of the metabolic syndrome, T2DM and cardiovascular disease, it is interesting that core components of the molecular clock have been shown to have a role to play in adipocyte development and function.32 BMAL1 is usually highly expressed during adipogenesis.33 Mice deficient in BMAL1 lose fat mass and the normal diurnal variation in plasma triglycerides.30 In vitro studies of BMAL1deficient embryonic fibroblast cells and BMAL1 knockdown 3T3-L1 cells show a failure to differentiate into adipocytes, and re-introduction of BMAL1 into these cells increases lipid synthesis and accumulation.33 Overexpressing BMAL1 in 3T3-L1 cells induces factors involved in lipid metabolism and adipocyte differentiation such as Rev-erb and SREBP1.33 Impaired adipocyte differentiation and increased adipocyte hypertrophy are seen in obesity, raising the possibility of a role for the molecular clock in this disturbance. In mouse adipose tissue, circadian rhythmicity of expression of adipokines is lost when the expression of clock genes is attenuated by obesity.34 In addition, as outlined above, leptindeficient ob/ob mice lacking functional CLOCK protein gain more weight and have significantly increased adipocyte hypertrophy compared to ob/ob mice.28 Vascular function The possible role of the clock in vascular function has been reviewed previously.35-37 Of particular relevance to insulin resistance and the metabolic syndrome is the effect the clock has on blood pressure, endothelial and haemostatic function. Blood pressure (BP) varies diurnally, dipping at night; however, loss of this pattern is seen with insulin resistance and is associated with increased end-organ damage.20 Bmal1 and Clock have been shown to be indispensable for generating this circadian rhythm: mice with loss of Bmal1 have loss of diurnal BP variation whereas mice with a mutation in Clock have attenuation of the normal diurnal rhythm.38 It has been shown that the vascular endothelium plays a key role in vascular homeostasis, with endothelial dysfunction a critical factor in the initiation and progression of atherosclerosis.39,40 There is a closely coupled inverse relationship between insulin sensitivity and endothelial dysfunction, suggesting it is a likely pathogenic factor in the development of vascular disease in the setting of insulin resistance and obesity.39,41 Recent studies demonstrate that endotheliumdependent vasodilatation, a reproducible measure of endothelial nitric oxide production, varies diurnally, although this variation is lost with coronary artery disease,42 and that mice with a mutation in Per2 have aortic endothelial dysfunction associated with reduced production of nitric oxide.43 Plasminogen activator inhibitor 1 (PAI-1) is the major inhibitor of fibrinolysis in vivo. It is produced by the liver, adipocyte and vascular endothelium. PAI-1 levels in the circulation fluctuate diurnally, with a peak first thing in the morning. Sustained, increased levels of PAI-1 are observed

in association with insulin resistance, the metabolic syndrome, T2DM and cardiovascular disease and it is thought to contribute significantly to atherothrombotic events.44 Perhaps explaining its diurnal rhythm, the CLOCK:BMAL heterodimer has been demonstrated to activate the PAI-1 promoter through E-box enhancers45,46 and Rev-erb represses PAI-1 gene expression through ROREs and competitively blocks ROR-mediated activation.47 Clock mutant mice lose plasma PAI-1 diurnal rhythmicity and PAI-1 mRNA expression from adipose tissue is augmented, whilst that from liver is attenuated.48 Taken together, these studies support an involvement of the molecular clock system in the metabolic and vascular changes associated with obesity, T2DM and vascular disease. However, they represent global disruption of central and peripheral clocks. Key areas for future research will be to determine the role of the molecular clock in metabolism independently from its role in altering circadian behaviour (activity and feeding patterns) and to distinguish the potential differential effects of central versus tissue-specific peripheral molecular clock disruption. Environmental disruption of the molecular clock It is clear from outlining the organisation of the molecular clock that there are two main environmental Zeitgebers. The first is light intensity/photoperiod, which directly entrains the central clock. The second is feeding, which directly entrains peripheral clocks. A key question therefore is whether disruption of these timekeepers has an impact on metabolism, T2DM, obesity and vascular disease and whether such disruption is mediated through the molecular clock. There are two increasingly common situations affecting man which cause disruption of the circadian system through altered timing of exposure to the light/dark cycle and feeding: these are shift work and a gradual decline in the amount of time spent asleep. Both situations are worth examining in more detail before outlining how light and food disruption affect metabolism through the molecular clock. Shift work Shift work is a way of life for more than 20% of the work force in Europe. It is well recognised to disrupt circadian rhythms, with loss of the normal synchrony that exists between light/dark phase, sleeping and eating. Numerous studies have demonstrated an increased prevalence of obesity, T2DM and features of the metabolic syndrome in nightshift workers.49-55 Shift work has also been associated with an increased risk of cardiovascular disease, reported in one study as a 1.6- and 3.0-fold increased risk for men and women, respectively, in the 4555-year age group.55,56 Sleep deprivation The amount of sleep that we have each night has been declining in the westernised world. On average, we sleep 6.8 hours a night, which is 1.5 hours less than we did a century ago, with a third of adults sleeping less than six hours a night.57 Numerous population-based studies have shown a relationship between short sleep duration, increasing obesity and T2DM, but it is only with prospective studies that the

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Figure 2. A role for disruption of the molecular clock in diabetes, obesity and cardiovascular disease, through novel genetic and environmental factors
Clock gene mutations 24/7 society High-fat feeding Constant snacking

Artificial light Molecular clock disruption

Diabetes

Metabolic disruption Adipocyte dysfunction Vascular dysfunction

Cardiovascular disease

cause and effect is becoming clearer (for review see ref 58). A UK study looked at early life risk factors for obesity in children and demonstrated that short sleep duration at 30 months was independently associated with prevalence of obesity at the age of seven years.59 The Japanese Prospective Study followed 2,649 male employees with no history of diabetes for eight years and found that difficulties falling asleep and staying asleep were associated with an increased risk of developing T2DM.60 This was confirmed in the Massachusetts Male Ageing study, which found that men who slept only 56 hours per night were twice as likely to develop T2DM subsequently.61 Investigating the mechanisms behind this, Spiegel et al. restricted 11 healthy young men to four hours sleep a night for a week and found decreased glucose tolerance and increased insulin resistance.62 Another study demonstrated that sleep restriction was associated with abnormalities in the hormones ghrelin and leptin.63 Sleep loss appears to be a novel risk factor for insulin resistance, therefore, and it would seem likely that the molecular clock is involved in its manifestation. In support of this, polymorphisms in the Clock gene have been associated with sleep dysregulation in humans in many studies.64-71 Light disrupting the clock The extent to which light influences the endogenous clock and metabolism is well illustrated in seasonal mammals (e.g. hibernators) and is outlined in the article by Martin in this issue of the Journal (pages 7681). To summarise, their clock is synchronised to the day/night cycle but also to relative lengths of day/night (photoperiod), allowing coordination of physiology and metabolism over 24 hours and in response to seasonal change.5 During long summer days the seasonal mammal gains weight and by the autumn it becomes insulin- and leptin-resistant.72-75 In response to the short day

lengths of autumn/winter it spontaneously reduces its food intake, irrespective of adequate supply, and enters hibernation during which its body weight declines. By the time spring arrives with longer day lengths, the animal is insulinand leptin-sensitive again.72-75 It is clear that melatonin is vital to this process, mediating the seasonal photoperiodic information through the clock system.76-84 Disrupting the melatonin signal or increasing the duration of light leads to changes in metabolism and adiposity consistent with the summer/autumn phenotype, with fat storage and insulin resistance.79,80,85 Persistent phase shifting of the light/dark cycle in other animals disrupts sleep/wake cycles and eating patterns, mimicking shift work.86,87 Not only has this been shown to disrupt peripheral clock gene expression86 but it is associated with weight gain87 and premature death.88 These observations are physiologically relevant to man as it has been demonstrated that man has conservation of photoperiodic mechanisms able to influence circadian rhythms but these seasonally changing photoperiodic responses have been suppressed by modern artificial lighting.89,90 Indeed, it has been proposed that humans live in a state of constant summer, due to artificial lighting, with a metabolism that reflects this and encourages obesity.16,91 The findings also support the notion that the clock system may be an important mechanistic link between shift work and the development of obesity, T2DM and cardiovascular disease. High-fat feeding and obesity When it comes to the Zeitgeber of feeding, the main area of interest in relation to T2DM and cardiovascular disease is the effect that high-fat feeding and obesity has on the clock. In genetically obese and obese diabetic mice, clock gene expression is attenuated in adipose tissue, with loss of the circadian rhythmicity of expression of adipocytokines

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(adiponectin, resistin and visfatin).34 This attenuated pattern is also seen in the livers of these mice.92 This could suggest that developing obesity and diabetes itself disrupts the molecular clock system. Two studies have attempted to address this question. The first published study showed that high-fat feeding alone in C57BL/6J mice for eight weeks induced a mild metabolic syndrome but did not alter clock gene expression in visceral adipose tissue or liver.93 The second study produced a much greater degree of obesity with highfat feeding and showed that there was indeed attenuation of the diurnal variation in clock gene expression (Clock, Bmal1 and Per2).94 Interestingly, this study failed to show attenuation of clock gene expression in the hypothalamus, showing the main changes in adipose tissue and liver. This suggests that high-fat feeding leading to obesity affects molecular clock function in peripheral tissues but not centrally. These changes were associated with altered diurnal profiles of leptin, gluocse, insulin, free fatty acids and corticosterone as well as impaired regulation of nuclear receptor networks (ROR, RXR, PPAR and PPAR), suggesting that this disruption of peripheral clocks directly alters metabolic function.94 Thus, it appears that feeding, one of the key risk factors for obesity, T2DM and cardiovascular disease, exerts its effects in part by altering molecular clock function and, importantly, it appears that there is a new potentially modifiable risk factor for these conditions light. Studies in man Studies of the molecular clock in relation to insulin resistance, diabetes and cardiovascular disease in man are in their infancy. Clock components have been identified in some human tissues, including adipose tissue and peripheral blood cells.95,96 It has recently been reported that the expression of several components of the molecular clock (Per2, Cry1 and Bmal1) in adipose tissue is associated with features of the metabolic syndrome in man96 and we have just demonstrated an association between polymorphisms in the Clock gene and features of the metabolic syndrome in man, particularly weight and obesity.97 Supporting this relationship to the metabolic syndrome, another study has shown associations between Clock polymorphisms and nonalcoholic fatty liver disease.98 It will be extremely interesting to see how this rapidly burgeoning research field develops over the next decade and whether it will be able to provide us with answers to help control the epidemic of obesity and prevent T2DM and cardiovascular disease in man. Summary The molecular clock sits at the absolute core of synchronising mans metabolism with his external environment and is involved in physiological processes crucial to his wellbeing. Current evidence suggests that interactions between the central and peripheral molecular clocks are important in metabolic, adipocyte and vascular function and that disrupting this process through mutations in the core clock genes or by interfering with the environmental Zeitgebers that entrain the central clock, such as altered photoperiod with artificial lighting late into the evenings and during night-shift work, or

the peripheral clock by constant snacking/high fat feeding may modulate the function of the cell and tissue, with loss of the synchrony that normally exists between the environment and physiology leading to the development of insulin resistance (figure 2). Ultimately, a closer understanding of the roles of the central and peripheral molecular clocks in the pathogenesis of systemic insulin resistance and the metabolic syndrome may help to develop novel therapeutic approaches to combat obesity, type 2 diabetes and associated cardiovascular disease. Conflicts of interest statement None declared. References
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