Orexin expression and promoter-methylation in peripheral blood of patients suffering from major depressive disorder

Orexins are endogenous neuropeptides synthesized in hypothalamic neurones; they play a major role in the regulation of feeding, drinking, endocrine function and sleep/wakefulness that is often disturbed in major depression. The aim of this study was to explore Orexin A expression and promotermethylation in peripheral blood cells of 29 patients (14 male and 15 female patients at three different time points during antidepressive treatment) suffering from major depressive disorder (MDD) by quantitative RT-PCR and bisulfite sequencing. There was a measurable difference between Orexin A expression on admission in comparison to the Orexin mRNA expression in the healthy control group (T = 1.53; df = 39; p = 0.135) that failed to reach statistical significance. An inverse correlation between Orexin A mRNA expression on admission and the HAMD scores at all measurement dates each week over 6 weeks could be detected. A cluster of methylated CPG sites within the promoter region of the Orexin A gene could be identified that was positively correlated with Delta CT values of the mRNA expression 14 days after hospital admission (r = 0.625; p = 0.072) and 4 weeks afterwards (r = 0.582; p = 0.1). Considering only the methylation of the 7 CPGs within the CPG island in the promoter 4 weeks after treatment onset a statistically significant relation between the cluster of CPG sites within the island and body weight (r = 0.55; p = 0.034) as well as BMI (r = 0.474; p = 0.074) could be detected. Furthermore, this methylation pattern 4 weeks after treatment onset was positively associated with mRNA expression on admission, 2 and 4 weeks afterwards. In sum, these results are an indicator of a link between social stresses, disruptions in energy homeostasis and changes in body weight in relation to depressive disorders that are possibly linked to Orexin dysregulation.