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Obesity alters the peripheral circadian clock in the aorta and microcirculation.

ABSTRACT: Perturbation of daily rhythm increases cardiovascular risk. The aim of this study was to determine whether obesity alters circadian gene expression and microvascular function in lean mice and obese (db/db) mice.Mice were subjected to normal LD or DD to alter circadian rhythm. Metabolic parameters and microvascular vasoreactivity were evaluated. Array studies were conducted in the am and pm cycles to assess the rhythmicity of the entire genomics. Rhythmic expression of specific clock genes (Bmal1, Clock, Npas2, Per1, Per2, and Cry1), clock output genes (dbp), and vascular relaxation-related genes (eNOS, GTPCH1) were assessed.Obesity was associated with metabolic dysfunction and impaired endothelial dilation in the microvasculature. Circadian rhythm of gene expression was suppressed 80% in both macro- and microcirculations of obese mice. Circadian disruption with DD increased fasting serum glucose and HbA1c in obese but not lean mice. Endothelium-dependent dilation was attenuated in obese mice and in lean mice subjected to DD. Rhythmic expression of per1 and dbp was depressed in obesity. Expression of eNOS expression was suppressed and GTPCH1 lost rhythmic expression both in obesity and by constant darkness.These results suggest that obesity reduces circadian gene expression in concert with impaired endothelial function. The causal relationship remains to be determined.

SUBMITTER: Nernpermpisooth N

PROVIDER: S-EPMC4532430 | biostudies-literature | 2015 May

REPOSITORIES: biostudies-literature

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Obesity alters the peripheral circadian clock in the aorta and microcirculation.

Nernpermpisooth Nitirut N Qiu Shuiqing S Mintz James D JD Suvitayavat Wisuda W Thirawarapan Suwan S Rudic Daniel R DR Fulton David J DJ Stepp David W DW

Microcirculation (New York, N.Y. : 1994) 20150501 4

<h4>Objective</h4>Perturbation of daily rhythm increases cardiovascular risk. The aim of this study was to determine whether obesity alters circadian gene expression and microvascular function in lean mice and obese (db/db) mice.<h4>Methods</h4>Mice were subjected to normal LD or DD to alter circadian rhythm. Metabolic parameters and microvascular vasoreactivity were evaluated. Array studies were conducted in the am and pm cycles to assess the rhythmicity of the entire genomics. Rhythmic express ...[more]

PMID: 25660131

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Project description:MotivationPersonalized medicine aims at providing patient-tailored therapeutics based on multi-type data toward improved treatment outcomes. Chronotherapy that consists in adapting drug administration to the patient's circadian rhythms may be improved by such approach. Recent clinical studies demonstrated large variability in patients' circadian coordination and optimal drug timing. Consequently, new eHealth platforms allow the monitoring of circadian biomarkers in individual patients through wearable technologies (rest-activity, body temperature), blood or salivary samples (melatonin, cortisol) and daily questionnaires (food intake, symptoms). A current clinical challenge involves designing a methodology predicting from circadian biomarkers the patient peripheral circadian clocks and associated optimal drug timing. The mammalian circadian timing system being largely conserved between mouse and humans yet with phase opposition, the study was developed using available mouse datasets.ResultsWe investigated at the molecular scale the influence of systemic regulators (e.g. temperature, hormones) on peripheral clocks, through a model learning approach involving systems biology models based on ordinary differential equations. Using as prior knowledge our existing circadian clock model, we derived an approximation for the action of systemic regulators on the expression of three core-clock genes: Bmal1, Per2 and Rev-Erbα. These time profiles were then fitted with a population of models, based on linear regression. Best models involved a modulation of either Bmal1 or Per2 transcription most likely by temperature or nutrient exposure cycles. This agreed with biological knowledge on temperature-dependent control of Per2 transcription. The strengths of systemic regulations were found to be significantly different according to mouse sex and genetic background.Availability and implementationhttps://gitlab.inria.fr/julmarti/model-learning-mb21eccb.Supplementary informationSupplementary data are available at Bioinformatics online.

Dataset Information

Obesity alters the peripheral circadian clock in the aorta and microcirculation.

Publications

Obesity alters the peripheral circadian clock in the aorta and microcirculation.

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