Obesity and Metabolic Syndrome in Circadian
            <i>Clock</i>
            Mutant Mice

Turek, Fred W.; Joshu, Corinne E.; Kohsaka, Akira; Lin, Emily; Ivanova, Ganka; McDearmon, Erin L.; Laposky, Aaron D.; Losee-Olson, Sue; Easton, Amy; Jensen, Dalan R.; Eckel, Robert H.; Takahashi, Joseph S.; Bass, Joseph

doi:10.1126/science.1108750

Cited by 2,239 publications

(1,869 citation statements)

References 25 publications

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“…For example, Clock/Clock mutant mice develop metabolic syndrome and obesity [64], animals with a targeted disruption of the CLOCK transcriptional partner, BMAL1 (Bmal1 −/− knockout mice) display phenotype of premature aging [65], whereas an increase in carcinogenesis has been reported specifically for Per2 mutants [66]. These examples lead to several important conclusions.…”

Section: Non-circadian Function Of Circadian Proteinsmentioning

confidence: 99%

Pharmacological modulators of the circadian clock as potential therapeutic drugs

Antoch

Chernov

2009

Mutation Research/Genetic Toxicology and Environmental Mutagene

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Circadian clocks are molecular time-keeping systems that underlie daily fluctuations in multiple physiological and biochemical processes. It is well recognized now that dysfunctions of the circadian system (both genetically and environmentally induced) are associated with the development of various pathological conditions. Here we describe the application of high throughput screening approach designed to search for small molecules capable of pharmacological modulation of the molecular clock. We provide evidence for the feasibility and value of this approach for both scientific and therapeutic purposes.

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Section: Non-circadian Function Of Circadian Proteinsmentioning

confidence: 99%

Pharmacological modulators of the circadian clock as potential therapeutic drugs

Antoch

Chernov

2009

Mutation Research/Genetic Toxicology and Environmental Mutagene

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“…First, it has been demonstrated that altering the expression of the clock genes that coordinate seasonal and circadian rhythms leads to changes in glucose homeostasis and features of the metabolic syndrome, including hypertriglyceridaemia and hyperleptinaemia [37,38]. Second, adipocytes have fully intact clock machinery that alters in response to daytime, and which appears to correlate with the expression of a number of other genes [35].…”

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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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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“…Turek et al [15] demonstrated that Clock mutant mice are hyperphagic and develop metabolic syndrome, hyperglycaemia and hyperlipidaemia. In addition, we showed that the rhythmic expression of clock genes is blunted in the liver and visceral adipose tissues of KK-A y mice, a genetic model of type 2 diabetes [16].…”

Section: Introductionmentioning

confidence: 99%

Clock gene expression in peripheral leucocytes of patients with type 2 diabetes

et al. 2008

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Aim/hypothesis Recent studies have demonstrated relationships between circadian clock function and the development of metabolic diseases such as type 2 diabetes. We investigated whether the peripheral circadian clock is impaired in patients with type 2 diabetes. Methods Peripheral leucocytes were obtained from eight patients with diabetes and six comparatively young nondiabetic volunteers at 09:00, 15:00, 21:00 and 03:00 hours (study 1) and from 12 male patients with diabetes and 14 agematched men at 09:00 hours (study 2). Transcript levels of clock genes (CLOCK, BMAL1 [also known as ARNTL], PER1, PER2, PER3 and CRY1) were determined by real-time quantitative PCR.Results In study 1, mRNA expression patterns of BMAL1, PER1, PER2 and PER3 exhibited 24 h rhythmicity in the leucocytes of all 14 individuals. The expression levels of these mRNAs were significantly (p<0.05) lower in patients with diabetes than in non-diabetic individuals at one or more time points. Moreover, the amplitudes of mRNA expression rhythms of PER1 and PER3 genes tended to diminish in patients with diabetes. In study 2, leucocytes obtained from patients with diabetes expressed significantly (p<0.05) lower transcript levels of BMAL1, PER1 and PER3 compared with leucocytes from control individuals, and transcript expression was inversely correlated with HbA 1c levels (ρ=−0.47 to −0.55, p<0.05). Conclusions/interpretation These results suggest that rhythmic mRNA expression of clock genes is dampened in peripheral leucocytes of patients with type 2 diabetes. The impairment of the circadian clock appears to be closely associated with the pathophysiology of type 2 diabetes in humans.

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Obesity and Metabolic Syndrome in Circadian Clock Mutant Mice

Cited by 2,239 publications

References 25 publications

Pharmacological modulators of the circadian clock as potential therapeutic drugs

Pharmacological modulators of the circadian clock as potential therapeutic drugs

Neel revisited: the adipocyte, seasonality and type 2 diabetes

Clock gene expression in peripheral leucocytes of patients with type 2 diabetes

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