A polymorphism in the promoter region of the human serotonin transporter (5-HTT)-coding SLC6A4 gene (5-HTTLPR) has been implicated in moderating susceptibility to stress-related psychopathology and to possess regulatory functions on human in vivo 5-HTT availability. However, data on a direct relation between 5-HTTLPR and in vivo 5-HTT availability have been inconsistent. Additional factors such as epigenetic modifications of 5-HTTLPR might contribute to this association. This is of particular interest in the context of obesity, as an association with 5-HTTLPR hypermethylation has previously been reported. Here, we tested the hypothesis that methylation rates of 14 cytosine-phosphate-guanine (CpG) 5-HTTLPR loci, in vivo central 5-HTT availability as measured with [11C]DASB positron emission tomography (PET) and body mass index (BMI) are related in a group of 30 obese (age: 36±10 years, BMI>35 kg/m2) and 14 normal-weight controls (age 36±7 years, BMI<25 kg/m2). No significant association between 5-HTTLPR methylation and BMI overall was found. However, site-specific elevations in 5-HTTLPR methylation rates were significantly associated with lower 5-HTT availability in regions of the prefrontal cortex (PFC) specifically within the obese group when analyzed in isolation. This association was independent of functional 5-HTTLPR allelic variation. In addition, negative correlative data showed that CpG10-associated 5-HTT availability determines levels of reward sensitivity in obesity. Together, our findings suggest that epigenetic mechanisms rather than 5-HTTLPR alone influence in vivo 5-HTT availability, predominantly in regions having a critical role in reward processing, and this might have an impact on the progression of the obese phenotype.:Introduction ............................................................................................................. 3
Homeostatic and hedonic control of food intake...................................................... 3
The obesity epidemic .............................................................................................. 4
The role of 5-HT in energy balance......................................................................... 5
The role of 5-HT in the PFC function....................................................................... 6
The role of the PFC in food intake .......................................................................... 7
The association between central 5-HT transporter (5-HTT) availability and obesity ..................................................................................................................................7
Genetics of obesity ................................................................................................. 8
Epigenetics of obesity ............................................................................................. 9
Objectives and hypothesis of the present work...................................................... 11
Manuscript ..... ....................................................................................................... 12
Summary ............................................................................................................... 20
References ............................................................................................................ 22
Appendices ............................................................................................................I
Glossary ................................................................................................................ I
Publications ........................................................................................................... IV
Selbstständigkeitserklärung................................................................................... V
Danksagung .......................................................................................................... VI
| Identifer | oai:union.ndltd.org:DRESDEN/oai:qucosa:de:qucosa:31763 |
| Date | 24 September 2018 |
| Creators | Drabe, Mandy |
| Contributors | Universität Leipzig |
| Source Sets | Hochschulschriftenserver (HSSS) der SLUB Dresden |
| Language | English |
| Detected Language | English |
| Type | info:eu-repo/semantics/publishedVersion, doc-type:doctoralThesis, info:eu-repo/semantics/doctoralThesis, doc-type:Text |
| Rights | info:eu-repo/semantics/openAccess |
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