The Circadian Clock: A Manager of Biochemical Processes Within the Organism

Holzberg, David; Albrecht, Urs

doi:10.1046/j.1365-2826.2003.00992.x

Cited by 52 publications

(39 citation statements)

References 37 publications

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“…Melatonin affects hypothalamic clock gene expression and has systemic effects on other tissues in the body [32]. Within the hypothalamus, a complex system of positive and negative feedbacks occur on the clock genes that lead to the development of an oscillating system that essentially regulates the cyclical phenotype in response to day length and the seasons [32][33][34]. One remarkable finding has been the recognition that peripheral tissues have intrinsic clock activity (critically, including the adipocyte [35]), suggesting a hierarchy of regulatory mechanisms that keep the organism in time with its environment [33].…”

Section: Seasonal and Circadian Responses In Mammalsmentioning

confidence: 99%

“…Within the hypothalamus, a complex system of positive and negative feedbacks occur on the clock genes that lead to the development of an oscillating system that essentially regulates the cyclical phenotype in response to day length and the seasons [32][33][34]. One remarkable finding has been the recognition that peripheral tissues have intrinsic clock activity (critically, including the adipocyte [35]), suggesting a hierarchy of regulatory mechanisms that keep the organism in time with its environment [33]. A second equally astonishing finding is that there appear to be two clock pathways, one involving the pineal gland, which regulates short photoperiodicity, and a second involving pituitary calendar cells, which has much longer term effects [34].…”

Section: Seasonal and Circadian Responses In Mammalsmentioning

confidence: 99%

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Neel revisited: the adipocyte, seasonality and type 2 diabetes

Scott

Grant

2006

Diabetologia

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The modern epidemic of obesity and insulin resistance with cardiovascular risk factor clustering is related to the development of type 2 diabetes and cardiovascular disease. Over 40 years ago, Neel postulated that insulin resistance should confer survival benefit. Extrapolating Neel's hypothesis, we propose that the cluster of associated abnormalities also confers survival benefit and is related to metabolic responses seen in seasonally responsive animals. Weight gain in preparation for winter is accompanied by a range of acute metabolic changes virtually identical to the long-term changes seen in type 2 diabetes. In seasonal animals the responses are acute, physiological and protective. In man, similar responses that would once have conferred survival benefit have become chronic, pathological and harmful in modern life. We hypothesise that type 2 diabetes and cardiovascular disease in man are the result of chronic and inappropriate pinealhypothalamic-adipocyte interactions biologically related to seasonal change.Keywords Adipocyte . Cardiovascular disease . Circadian and circannual rhythm . Clock genes . Hypothalamus . Inflammation . Insulin resistance . Melatonin . Metabolic syndrome . Seasonality . Type 2 diabetes Neel revisitedThe world is currently in the midst of an epidemic of type 2 diabetes, and around 300 million individuals are predicted to develop this disorder by the year 2025 [1]. The close biological relationship between diabetes and cardiovascular disease has focused attention on the common genetic and environmental antecedents of these conditions-the common soil hypothesis [2]-but the pathophysiological basis of these associations remains obscure. In 1962, Neel proposed the thrifty genotype hypothesis, which postulated that insulin overproduction must at one time have had a beneficial effect, in that it would provide 'an important energy conserving mechanism when food intake was irregular and obesity rare' [3]. Although Neel recognised insulin antagonism rather than insulin resistance, he hypothesised that the combination of obesity with increased insulin (or the presence of insulin antagonists) would lead to the development of diabetes. With hindsight, Neel was essentially speculating on the potential metabolic benefits of insulin resistance. The recognition in the last 20 years of an insulin resistance risk cluster [4] indicates that, under certain circumstances, elements of the risk cluster should also be beneficial to the survival of the organism, a response that, by analogy with Neel's original hypothesis, may coincidentally lead to the development of cardiovascular disease in times of plenty. The development of both insulin resistance and inflammation are physiological responses to increasing adiposity that, by definition, should be beneficial to the survival of the organism. The observation that the chronic metabolic milieu associated with type 2 diabetes is harmful raises the possibility that the adipocyte response to fat loading is beneficial when acute and short-lived, as is o...

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Section: Seasonal and Circadian Responses In Mammalsmentioning

confidence: 99%

Section: Seasonal and Circadian Responses In Mammalsmentioning

confidence: 99%

Neel revisited: the adipocyte, seasonality and type 2 diabetes

Scott

Grant

2006

Diabetologia

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“…Adult (4-mo-old) female Sprague-Dawley rats were randomly assigned to either control, 6 h MV (MV6), or 18 h MV (MV18; n ϭ 5/group). Animals were killed around the same time (Ϯ 2 h) of the day to minimize possible influences of circadian rhythm on gene expression levels (27). A brief outline of the experimental methods follows, with methodologic details for each procedure provided in the online supplement.…”

Section: Animals and Experimental Designmentioning

confidence: 99%

Diaphragm Unloading via Controlled Mechanical Ventilation Alters the Gene Expression Profile

DeRuisseau

Shanely

Akunuri

et al. 2005

Am J Respir Crit Care Med

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Rationale: Prolonged controlled mechanical ventilation results in diaphragmatic inactivity and promotes oxidative injury, atrophy, and contractile dysfunction in this important inspiratory muscle. However, the impact of controlled mechanical ventilation on global mRNA alterations in the diaphragm remains unknown. Objectives: In these experiments, we used an Affymetrix oligonucleotide array to identify the temporal changes in diaphragmatic gene expression during controlled mechanical ventilation in the rat. Methods: Adult Sprague-Dawley rats were assigned to either control or mechanical ventilation groups (n ϭ 5/group). Mechanically ventilated animals were anesthetized, tracheostomized, and ventilated with room air for 6 or 18 h. Animals in the control group were acutely anesthetized but not exposed to mechanical ventilation. Measurements and Main Results: Compared with control diaphragms, microarray analysis identified 354 differentially expressed, unique gene products after 6 and 18 h of mechanical ventilation. In general, genes in the cell growth/cell maintenance, stress response, and nucleic acid metabolism categories showed predominant upregulation, whereas genes in the structural protein and energy metabolism categories were predominantly downregulated. Conclusions: We conclude that mechanical ventilation results in rapid changes in diaphragmatic gene expression, and subsequently, many of these changes may contribute to atrophy and muscle fiber remodeling associated with unloading this primary inspiratory muscle. Importantly, this study also provides new insights into why the diaphragm, after the onset of contractile inactivity, atrophies more rapidly than locomotor skeletal muscles and also highlights unique differences that exist between these muscles in the mRNA response to inactivity. Keywords: gene expression; microarray; muscle atrophy; respiratory muscle; weaning from mechanical ventilation Mechanical ventilation (MV) is used clinically to maintain blood gas homeostasis in patients who are incapable of maintaining adequate alveolar ventilation on their own. For many of these patients, an unfortunate consequence of prolonged MV is the ensuing development of respiratory muscle weakness (1). It is now clear that prolonged MV is associated with significant atrophy and contractile dysfunction of the diaphragm (2-6). Recent animal studies indicate that controlled MV leads to significantly greater respiratory muscle weakness than assisted MV (7) because controlled MV results in complete loss of neural activation and mechanical activity of the diaphragm (3,7,8). Therefore, controlled MV is a useful physiologic model to investigate the effects of prolonged inactivity of the diaphragm (2, 3).The diaphragm experiences remarkable physiologic and biochemical alterations during periods of unloading. The time frame of phenotypic changes that the diaphragm undergoes during MV occurs on the order of hours (3, 9), whereas diaphragmatic inactivity imposed by phrenic nerve denervation and cervical spinal cord hemisectio...

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“…12,13 There are several core clock proteins (CLOCK, BMAL1, Per1, Per2, Per3, Cry1 and Cry2), which drive the feedback loops leading to the development of an oscillating system that regulates the cyclical phenotype in response to day length and the seasons. 12,13 Their expression plays an important role regulating the physiological function of the cell and organism, particularly regarding metabolism and energy homeostasis, 1,4,5,14,15 indeed 3-10% of transcripts from all tissues are under circadian control. 1 Recent evidence in animals links disruption of synchronous clock activity with the pathogenesis of features of the metabolic syndrome.…”

Section: Introductionmentioning

confidence: 99%

Association between polymorphisms in the Clock gene, obesity and the metabolic syndrome in man

2007

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Objective: Accumulating evidence raises the hypothesis that dysregulation of intrinsic clock mechanisms are involved in the development of the metabolic syndrome, type 2 diabetes mellitus and cardiovascular disease. The aim of the present study was to investigate the relationship between three known common polymorphisms in the Clock gene and features of the metabolic syndrome in man. Methods: Genotype and haplotype analysis was carried out in a cohort of 537 individuals from 89 families characterized for inflammatory, atherothrombotic and metabolic risk associated with insulin resistance. Results: Heritability of the metabolic syndrome, defined according to International Diabetes Federation criteria, was 0.40. Haplotype analysis indicated three common haplotypes: CAT, TGT and CGC (rs4864548-rs3736544-rs1801260) with frequencies of 31, 33 and 28%, respectively. The CGC haplotype was less prevalent in subjects with the metabolic syndrome (P ¼ 0.0015) and was associated with lower waist circumference (P ¼ 0.007), lower hip circumference (P ¼ 0.023), lower body mass index (P ¼ 0.043) and lower leptin levels (P ¼ 0.028). The CAT haplotype was significantly associated with the presence of the metabolic syndrome (P ¼ 0.020). Conclusions: These findings suggest that the Clock gene CGC haplotype may be protective for the development of obesity and support the hypothesis that genetic variation in the Clock gene may play a role in the development of the metabolic syndrome, type 2 diabetes and cardiovascular disease.

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The Circadian Clock: A Manager of Biochemical Processes Within the Organism

Cited by 52 publications

References 37 publications

Neel revisited: the adipocyte, seasonality and type 2 diabetes

Neel revisited: the adipocyte, seasonality and type 2 diabetes

Diaphragm Unloading via Controlled Mechanical Ventilation Alters the Gene Expression Profile

Association between polymorphisms in the Clock gene, obesity and the metabolic syndrome in man

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