Genetic variants of Clock transcription factor are associated with individual susceptibility to obesity

Sookoian, Silvia; Gemma, Carolina; Gianotti, Tomás Fernández; Burgueño, Adriana Laura; Castaño, Gustavo Osvaldo; Pirola, Carlos José

doi:10.1093/ajcn/87.6.1606

Cited by 223 publications

(165 citation statements)

References 32 publications

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“…Additionally, the importance of individual differences in phase and amplitude of lipid rhythms has yet to be explored. Several epidemiologic studies suggest that genetic variation in clock genes modulates risk for obesity and type 2 diabetes (116)(117)(118)(119) , but the underlying mechanisms are poorly understood. Therefore, future studies should examine the interaction of genetic and environmental factors on diurnal regulation of lipids and postprandial responses.…”

Section: Limitations and Future Directionsmentioning

confidence: 99%

Circadian regulation of lipid metabolism

Gooley

2016

Proc. Nutr. Soc.

130

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The circadian system temporally coordinates daily rhythms in feeding behaviour and energy metabolism. The objective of the present paper is to review the mechanisms that underlie circadian regulation of lipid metabolic pathways. Circadian rhythms in behaviour and physiology are generated by master clock neurons in the suprachiasmatic nucleus (SCN). The SCN and its efferent targets in the hypothalamus integrate light and feeding signals to entrain behavioural rhythms as well as clock cells located in peripheral tissues, including the liver, adipose tissue and muscle. Circadian rhythms in gene expression are regulated at the cellular level by a molecular clock comprising a core set of clock genes/proteins. In peripheral tissues, hundreds of genes involved in lipid biosynthesis and fatty acid oxidation are rhythmically activated and repressed by clock proteins, hence providing a direct mechanism for circadian regulation of lipids. Disruption of clock gene function results in abnormal metabolic phenotypes and impaired lipid absorption, demonstrating that the circadian system is essential for normal energy metabolism. The composition and timing of meals influence diurnal regulation of metabolic pathways, with food intake during the usual rest phase associated with dysregulation of lipid metabolism. Recent studies using metabolomics and lipidomics platforms have shown that hundreds of lipid species are circadian-regulated in human plasma, including but not limited to fatty acids, TAG, glycerophospholipids, sterol lipids and sphingolipids. In future work, these lipid profiling approaches can be used to understand better the interaction between diet, mealtimes and circadian rhythms on lipid metabolism and risk for obesity and metabolic diseases.

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Section: Limitations and Future Directionsmentioning

confidence: 99%

Circadian regulation of lipid metabolism

Gooley

2016

Proc. Nutr. Soc.

130

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“…In this sense, the work performed by Sookoian et al in 2008 was the first to demonstrate that several variants at CLOCK were associated with obesity, especially with abdominal obesity (12) . In addition, in the same year, Scott et al confirmed these results by showing that CLOCK could play a relevant role in the development of MetS, type 2 diabetes and CVD (13) .…”

Section: Failures In the Central Clock: Mutations In Experimental Animentioning

confidence: 99%

Circadian rhythms, food timing and obesity

2016

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It is known that our physiology changes throughout the day and that several physiological hormones display circadian rhythmicity. The alteration of this normal pattern is called chronodisruption (CD). In recent years, it has been demonstrated that CD is related to obesity. Although several factors may be causing CD, one important aspect to consider is the failure in our internal clock. Indeed, studies performed in mutant animals have demonstrated that mutations in clock genes are related to obesity. In human subjects, mutations are rare (<1 % of the population). Nevertheless, it is rather common to have genetic variations in one SNP, which underlie differences in our vulnerability to disease. Several SNP in clock genes are related to obesity and weight loss. Taking into account that genetics is behind CD, as has already been demonstrated in twins’ models, the question is: Are we predestinated? We will see along these lines that nutrigenetics and epigenetics answer: ‘No, we are not predestinated’. Through nutrigenetics we know that our behaviours may interact with our genes and may decrease the deleterious effect of one specific risk variant. From epigenetics the message is even more positive: it is demonstrated that by changing our behaviours we can change our genome. Herein, we propose modifying ‘what, how, and when we eat’ as an effective tool to decrease our genetic risk, and as a consequence to diminish CD and decrease obesity. This is a novel and very promising area in obesity prevention and treatment.

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“…Two remarkable findings that were also found in the liver programming search are worth mentioning. One of them, the CLOCK gene, a master regulator of circadian function associated with MS in humans as already mentioned (29,30) and rodent studies (31), was connected to corticotropin releasing hormone and proopiomelanocortin-related nodes. The second one, the SLC7A5-related nodes, predicted thyrotropin-releasing hormone, which was associated with hypertension, obesity-related hypertension, and control of body weight in rodents (32,33) and in humans (34).…”

Section: Reviewmentioning

confidence: 89%

“…Others, such as PER1, constitute key components of the circadian mechanism, which controls the entire cell metabolism. Mutations in PER1 and other family members make mice more prone to gain weight under HFD (28), and normal variants of the CLOCK promoter are associated with nonalcoholic fatty liver disease or obesity in humans (29,30).…”

Section: Reviewmentioning

confidence: 99%

Fetal metabolic programming and epigenetic modifications: a systems biology approach

et al. 2013

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A growing body of evidence supports the notion that epigenetic changes such as DNA methylation and histone modifications, both involving chromatin remodeling, contribute to fetal metabolic programming. We use a combination of gene-protein enrichment analysis resources along with functional annotations and protein interaction networks for an integrative approach to understanding the mechanisms underlying fetal metabolic programming. systems biology approaches suggested that fetal adaptation to an impaired nutritional environment presumes profound changes in gene expression that involve regulation of tissue-specific patterns of methylated cytosine residues, modulation of the histone acetylation-deacetylation switch, cell differentiation, and stem cell pluripotency. The hypothalamus and the liver seem to be differently involved. In addition, new putative explanations have emerged about the question of whether in utero overnutrition modulates fetal metabolic programming in the same fashion as that of a maternal environment of undernutrition, suggesting that the mechanisms behind these two fetal nutritional imbalances are different. In conclusion, intrauterine growth restriction is most likely to be associated with the induction of persistent changes in tissue structure and functionality. conversely, a maternal obesogenic environment is most probably associated with metabolic reprogramming of glucose and lipid metabolism, as well as future risk of metabolic syndrome (Ms), fatty liver, and insulin (INs) resistance.L arge amounts of epidemiological data showed that impaired intrauterine growth and adult metabolic and cardiovascular disorders, including coronary heart disease, type 2 diabetes, and insulin (INS) resistance, are strongly associated (1-4). Actually, the first exploration of a putative connection between environmental influence in early life and the risk of cardiovascular disease in adulthood was done by David Barker and coworkers, who followed-up a cohort of 499 men and women born in Preston (Lancashire, UK) during 1935-1943, and observed that as adults the highest blood pressures occurred in people who had been small babies with large placentas (5).Of note, the concept of a relationship between birth weight and adult chronic diseases initially described in low-birthweight babies was further extended to large-for-gestational age (LGA) babies, and the term of inappropriate gestational weight gained acceptance to better illustrate changes in earlylife metabolic environment that contribute to the risk of metabolic syndrome (MS) in adulthood (6).Barker and Hales also provided the initial answer to the question of how birth weight and adult chronic diseases are connected. They explained that fetuses adapt to an impaired supply of nutrients by changing their physiology and metabolism, and altering the sensitivity of tissues causes an abnormal structure and function in adult life; thereby, they formulated the "thrifty phenotype hypothesis" (7,8).Altogether, the above-mentioned clinico-epidemiological evidence str...

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Genetic variants of Clock transcription factor are associated with individual susceptibility to obesity

Abstract: The present study suggests a putative role of the CLOCK polymorphism and related haplotypes in susceptibility to obesity. The haplotype of rs1554483G and rs4864548A was associated with a 1.8-fold risk of overweight or obesity.

Cited by 223 publications

References 32 publications

Circadian regulation of lipid metabolism

Circadian regulation of lipid metabolism

Circadian rhythms, food timing and obesity

Fetal metabolic programming and epigenetic modifications: a systems biology approach

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