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Genome wide methylation analysis and obesity related traits
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
2015 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The most studied form of epigenetics is DNA methylation and several studies have investigated the link between the methylome and body weight. In paper I we analyzed the methylation profile of whole blood in 46 subjects measured with Illumina 27K chip. We provide evidence that obesity influences age driven epigenetic changes. These identified markers may prove to be valuable biomarkers for the understanding of the molecular basis of aging, obesity and associated diseases. In paper II we studied the effect of bariatric surgery, and subsequent weight loss, on methylation and relating this to normal weight controls. In paper II we found 115 promoters had altered methylation after surgery. Among these promoters, an enrichment for genes involved in metabolic processes was found (n=36, p<0.05). In addition, these 51 promoters was more similar after surgery to that of normal-weight controls, than it had been at baseline (p<0.0001). One of the major comorbidities of severe obesity is obstructive sleep apnea and lack of sleep is highly correlated with obesity. Paper III shows how acute sleep deprivation increases portion size and affects food choice in 16 young men. In paper VI, whole genome DNA methylation profiles of whole blood was assessed following both conditions by the Illumina 450K methylation in the same trial as in paper III. This paper shows how sleep deprivation affects DNA methylation profiles of whole blood in a manner both dependent and independent on monocyte subpopulations. Hypothesis free genome wide analysis revealed differential methylation in ING5, a gene previously known to be differentially expressed in sleep deprivation. 

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2015. , 40 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1101
National Category
Neurosciences
Identifiers
URN: urn:nbn:se:uu:diva-248685ISBN: 978-91-554-9236-6 (print)OAI: oai:DiVA.org:uu-248685DiVA: diva2:801708
Public defence
2015-06-05, BMC C2:301, Husargatan 3, Uppsala, 13:00 (English)
Opponent
Supervisors
Available from: 2015-05-12 Created: 2015-04-07 Last updated: 2015-07-07Bibliographically approved
List of papers
1. Genome-wide analysis reveals DNA methylation markers that vary with both age and obesity
Open this publication in new window or tab >>Genome-wide analysis reveals DNA methylation markers that vary with both age and obesity
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2014 (English)In: Gene, ISSN 0378-1119, E-ISSN 1879-0038, Vol. 548, no 1, 61-67 p.Article in journal (Refereed) Published
Abstract [en]

The combination of the obesity epidemic and an aging population presents growing challenges for the healthcare system. Obesity and aging are major risk factors for a diverse number of diseases and it is of importance to understand their interaction and the underlying molecular mechanisms. Herein the authors examined the methylation levels of 27578 CpG sites in 46 samples from adult peripheral blood. The effect of obesity and aging was ascertained with general linear models. More than one hundred probes were correlated to aging, nine of which belonged to the KEGG group map04080. Additionally, 10 CpG sites had diverse methylation profiles in obese and lean individuals, one of which was the telomerase catalytic subunit (TERT). In eight of ten cases the methylation change was reverted between obese and lean individuals. One region proved to be differentially methylated with obesity (LINC00304) independent of age. This study provides evidence that obesity influences age driven epigenetic changes, which provides a molecular link between aging and obesity. This link and the identified markers may prove to be valuable biomarkers for the understanding of the molecular basis of aging, obesity and associated diseases.

Keyword
Epigenetics, Microarray, Aging, Obesity
National Category
Medical Genetics
Identifiers
urn:nbn:se:uu:diva-230920 (URN)10.1016/j.gene.2014.07.009 (DOI)000340329100010 ()
Available from: 2014-09-04 Created: 2014-09-01 Last updated: 2017-12-05Bibliographically approved
2. Roux-En Y Gastric Bypass Surgery Induces Genome-Wide Promoter-Specific Changes in DNA Methylation in Whole Blood of Obese Patients
Open this publication in new window or tab >>Roux-En Y Gastric Bypass Surgery Induces Genome-Wide Promoter-Specific Changes in DNA Methylation in Whole Blood of Obese Patients
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2015 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 2, e0115186Article in journal (Refereed) Published
Abstract [en]

Context

DNA methylation has been proposed to play a critical role in many cellular and biological processes.

Objective

To examine the influence of Roux-en-Y gastric bypass (RYGB) surgery on genome-wide promoter-specific DNA methylation in obese patients. Promoters are involved in the initiation and regulation of gene transcription.

Methods

Promoter-specific DNA methylation in whole blood was measured in 11 obese patients (presurgery BMI >35 kg/m2, 4 females), both before and 6 months after RYGB surgery, as well as once only in a control group of 16 normal-weight men. In addition, body weight and fasting plasma glucose were measured after an overnight fast.

Results

The mean genome-wide distance between promoter-specific DNA methylation of obese patients at six months after RYGB surgery and controls was shorter, as compared to that at baseline (p<0.001). Moreover, postsurgically, the DNA methylation of 51 promoters was significantly different from corresponding values that had been measured at baseline (28 upregulated and 23 downregulated, P<0.05 for all promoters, Bonferroni corrected). Among these promoters, an enrichment for genes involved in metabolic processes was found (n = 36, P<0.05). In addition, the mean DNA methylation of these 51 promoters was more similar after surgery to that of controls, than it had been at baseline (P<0.0001). When controlling for the RYGB surgery-induced drop in weight (-24% of respective baseline value) and fasting plasma glucose concentration (-16% of respective baseline value), the DNA methylation of only one out of 51 promoters (~2%) remained significantly different between the pre-and postsurgery time points.

Conclusions

Epigenetic modifications are proposed to play an important role in the development of and predisposition to metabolic diseases, including type II diabetes and obesity. Thus, our findings may form the basis for further investigations to unravel the molecular effects of gastric bypass surgery.

Clinical Trial

ClinicalTrials.gov NCT01730742

National Category
Bioinformatics and Systems Biology
Identifiers
urn:nbn:se:uu:diva-248683 (URN)10.1371/journal.pone.0115186 (DOI)000350683900003 ()25710379 (PubMedID)
Available from: 2015-04-07 Created: 2015-04-07 Last updated: 2017-12-04Bibliographically approved
3. Acute sleep deprivation increases portion size and affects food choice in young men
Open this publication in new window or tab >>Acute sleep deprivation increases portion size and affects food choice in young men
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2013 (English)In: Psychoneuroendocrinology, ISSN 0306-4530, E-ISSN 1873-3360, Vol. 38, no 9, 1668-1674 p.Article in journal (Refereed) Published
Abstract [en]

Acute sleep loss increases food intake in adults. However, little is known about the influence of acute sleep loss on portion size choice, and whether this depends on both hunger state and the type of food (snack or meal item) offered to an individual. The aim of the current study was to compare portion size choice after a night of sleep and a period of nocturnal wakefulness (a condition experienced by night-shift workers, e.g. physicians and nurses). Sixteen men (age: 23 ± 0.9 years, BMI: 23.6 ± 0.6 kg/m2) participated in a randomized within-subject design with two conditions, 8-h of sleep and total sleep deprivation (TSD). In the morning following sleep interventions, portion size, comprising meal and snack items, was measured using a computer-based task, in both fasted and sated state. In addition, hunger as well as plasma levels of ghrelin were measured. In the morning after TSD, subjects had increased plasma ghrelin levels (13%, p = 0.04), and chose larger portions (14%, p = 0.02), irrespective of the type of food, as compared to the sleep condition. Self-reported hunger was also enhanced (p < 0.01). Following breakfast, sleep-deprived subjects chose larger portions of snacks (16%, p = 0.02), whereas the selection of meal items did not differ between the sleep interventions (6%, p = 0.13). Our results suggest that overeating in the morning after sleep loss is driven by both homeostatic and hedonic factors. Further, they show that portion size choice after sleep loss depend on both an individual's hunger status, and the type of food offered.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-196214 (URN)10.1016/j.psyneuen.2013.01.012 (DOI)000325188300021 ()23428257 (PubMedID)
Note

De två sista författarna delar sistaförfattarskapet.

Available from: 2013-03-05 Created: 2013-03-05 Last updated: 2017-12-06Bibliographically approved
4. Sleep deprivation affects genome wide DNA methylation profiles and RNA expression.
Open this publication in new window or tab >>Sleep deprivation affects genome wide DNA methylation profiles and RNA expression.
(English)Manuscript (preprint) (Other academic)
National Category
Bioinformatics and Systems Biology
Identifiers
urn:nbn:se:uu:diva-248684 (URN)
Available from: 2015-04-07 Created: 2015-04-07 Last updated: 2015-05-18

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