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  • br Introduction Major depressive disorder MDD is a disease

    2022-09-21


    Introduction Major depressive disorder (MDD) is a disease with poorly recognized etiology. Currently used antidepressant drugs, which mainly affect synaptic neurotransmitter levels, show full clinical efficacy in only one third of patients (Rush, 2007). Thus it is now generally accepted that the pathogenesis of MDD includes not only improper monoamine transmission but disturbances in the endocrine and immunological systems, including activation of the hypothalamus-pituitary-adrenal axis (HPAA) with subsequent hypercortisolism, and upregulation of pro-inflammatory cytokines (i.e. interleukin-6 and tumor-necrosis factor-α) (Dowlati et al., 2010, Stetler and Miller, 2011). Elevated cortisol concentrations are discussed as factors underlying the development of impaired glucose metabolism and insulin resistance by impairment of insulin-mediated suppression of hepatic glucose output, impairment of insulin-mediated stimulation of glucose uptake, and enhanced lipolysis (Bjorntorp, 1999, Divertie et al., 1991, Phillips et al., 1998, Rizza et al., 1982). The alterations described above have been linked to the enhanced prevalence of the metabolic syndrome, type-2 diabetes mellitus (T2DM) and cardiovascular disorders in patients with MDD (Brown et al., 2004, Kahl et al., 2015, Mezuk et al., 2008, Moulton et al., 2015, Pan et al., 2012, Van der Kooy et al., 2007). In recent years, alterations in SCH 527123 glucose metabolism have frequently been described in MDD (reviewed in Su et al. (2014)). Glucose is the major energy resource for neuronal cells. The entry of glucose into the cell is mediated by a family of proteins, the facilitative glucose transporter proteins (Vannucci et al., 1997). In the human brain, transport of glucose across membranes is mainly mediated by the insulin-independent glucose transporter 1 (GLUT1) and glucose transporter 3 (GLUT3). The interaction among neurons, astrocytes, and endothelial cells has a central role coupling energy supply with changes in neuronal activity. GLUT1 is expressed in the nervous system predominantly in endothelial cells and astrocytes, which is essential for brain maturation and normal brain function (Klepper, 2004, Klepper et al., 2007). Astrocytes take up glucose from the blood and metabolize it to lactate, which is then delivered to neurons. The astrocytic process of providing energy is dependent on the activity of the adjacent neuron, thereby supplying the neuron with energy “on demand” (Magistretti et al., 1994). This astrocyte-to-neuron lactate shuttle is a main source of energy to sustain neuronal physiology (Benarroch, 2014, Pellerin et al., 1998). In the periphery, insulin facilitates glucose uptake in striated muscle and adipose tissue by stimulating glucose transporter 4 (GLUT4). GLUT4 activity is directly correlated with the ability to clear blood glucose and insulin sensitivity (Gannon et al., 2015). Furthermore, alterations in GLUT expression and activity have been associated with disease types such as epilepsy, dystonia and cancer (Adekola et al., 2012, De Giorgis and Veggiotti, 2013, Roubergue et al., 2011). It has been shown that the expression of various GLUT's is regulated at least in part by DNA methylation of the promoter region (Novakovic et al., 2013). The aim of our study was to examine the DNA methylation of the core promoter regions of GLUT1 and GLUT4 in depressed patients during the course of the disorder, and to compare data with healthy comparison subjects. We chose the GLUT1 as central target, because it is essential for the glucose transport from the blood into the astrocyte, and because GLUT1 protein expression is considerably higher compared to GLUT3 (Ito et al., 2011, Peters and McEwen, 2015).
    Methods and materials
    Results
    Discussion It has been postulated that inherited and acquired epigenetic dysregulation may play a role in the etiology of major depressive disorder (D'Addario et al., 2013, Oh et al., 2015). We here discovered that the enhanced promoter DNA methylation of GLUT1 is present in depressed patients compared to healthy comparison subjects. GLUT1 is the major glucose transporter in the brain and is expressed both in the endothelial cells forming the blood–brain barrier, and in astrocytes. Under normal conditions, glucose is the main source of ATP in the nervous system (Peters et al., 2004). GLUT1 is a key regulator of glucose transport into the brain across the blood brain SCH 527123 barrier, acting to maintain central nervous system homeostasis and function (Shah et al., 2012). A higher promoter DNA methylation of GLUT1 in depressed patients may be indicative for lower GLUT1 expression in brain cells, suggesting that glucose uptake from the blood vessels into the brain might be compromised.