Treatment with an SSRI antidepressant restores hippocampo-hypothalamic corticosteroid feedback and reverses insulin resistance in low-birth-weight rats

Abstract

is associated with type 2 diabetes and depression, which may be related to prenatal stress and insulin resistance as a result of chronic hypothalamic-pituitary-adrenal (HPA) axis hyperactivity. We examined whether treatment with a selective serotonin reuptake inhibitor [escitalopram (ESC)] could downregulate HPA axis activity and restore insulin sensitivity in LBW rats. After 4 -5 wk of treatment, ESC-exposed LBW (SSRI-LBW) and saline-treated control and LBW rats (Cx and LBW) underwent an oral glucose tolerance test or a hyperinsulinemic euglycemic clamp to assess whole body insulin sensitivity. Hepatic phosphoenolpyruvate carboxykinase (PEPCK) mRNA expression and red skeletal muscle PKB Ser 473 phosphorylation were used to assess tissue-specific insulin sensitivity. mRNA expression of the hypothalamic mineralocorticoid receptor was fivefold upregulated in LBW (P Ͻ 0.05 vs. Cx), accompanied by increased corticosterone release during restraint stress and total 24-h urinary excretion (P Ͻ 0.05 vs. Cx), whole body insulin resistance (P Ͻ 0.001 vs. Cx), and impaired insulin suppression of hepatic PEPCK mRNA expression (P Ͻ 0.05 vs. Cx). Additionally, there was a tendency for reduced red muscle PKB Ser 473 phosphorylation. The ESC treatment normalized corticosterone secretion (P Ͻ 0.05 vs. LBW), whole body insulin sensitivity (P Ͻ 0.01) as well as postprandial suppression of hepatic mRNA PEPCK expression (P Ͻ 0.05), and red muscle PKB Ser 473 phosphorylation (P Ͻ 0.01 vs. LBW). We conclude that these data suggest that the insulin resistance and chronic HPA axis hyperactivity in LBW rats can be reversed by treatment with an ESC, which downregulates HPA axis activity, lowers glucocorticoid exposure, and restores insulin sensitivity in LBW rats.selective serotonin reuptake inhibitors STRESS MAY BE INVOLVED IN THE DEVELOPMENT of major Western lifestyle disorders such as cardiovascular disease and the metabolic syndrome (53,59,61). Particularly in humans born with low birth weight (LBW) (e.g., birth weight Ͻ2,500 g), stressrelated psychiatric illness and metabolic disturbances seem to coexist, and the prevalence of conditions associated with psychological stress, such as melancholic depression, is increased in subjects born with LBW (35). In addition, these individuals also have a higher prevalence of type 2 diabetes (23, 57, 80) that is potentially due to early development of insulin resistance. Hence, the LBW condition can be considered as both a predepressive and a prediabetic state. However, the exact mechanisms responsible for these changes and whether they are associated are still debated.Recently, impairments in hippocampal structure and function have been proposed to account for some of the phenotypic characteristics of LBW (21,40,63). Hippocampus regulates the overall circadian tonus of the hypothalamic-pituitary-adrenal (HPA) axis, and accordingly, the processes involved in corticosteroid regulation in LBW have been studied extensively. At this point the HPA axis in LBW has been studied at various developmental ...

Impaired miR449a-induced downregulation of Crhr1 expression in low-birth-weight rats

“…This study demonstrated impaired restoration of ACTH and corticosterone secretion and Pomc and Gr mRNA expression during restraint in the anterior pituitary of LBW offspring in accordance with previous reports (Buhl et al 2007(Buhl et al , 2010. Although several research groups have attempted to elucidate the mechanism underlying the dysfunction of the HPA axis in LBW offspring by analyzing GRs in the hypothalamus, hippocampus, and amygdala , Sebaai et al 2002, the details of this mechanism remain unclear.…”

“…These disorders are associated with abnormalities of the hypothalamicpituitary-adrenal (HPA) axis such as disturbed circadian rhythm, impaired cortisol suppression by dexamethasone (Holsboer-Trachsler et al 1987, Hoshino et al 1987, Vreeburg et al 2009, Hempel et al 2010, and abnormal adrenocorticotropin (ACTH) and cortisol responses to corticotropin-releasing factor (CRF) or stress (Young et al 2000, Ehnvall et al 2004, Corbett et al 2006. Recent animal studies have indicated that maternal malnutritioninduced impairment of fetal programing of the HPA axis function is associated with adult-onset dysregulation of the axis (Chadio et al 2007, Rumball et al 2008, Buhl et al 2010. Dysregulation of the HPA axis function is the most common and consistently reported abnormality in depression (Reus et al 1985).…”

A Review of the Association Between Depression and Insulin Resistance: Pitfalls of Secondary Analyses or a Promising New Approach to Prevention of Type 2 Diabetes?

“…Trial data in populations with pre-diabetes are limited but promising and suggest that SSRIs may enhance insulin sensitivity in depressed patients who achieve symptomatic remission [23]. Animal studies clearly show that the use of SSRIs increases insulin sensitivity [31]. Collectively, existing evidence indicates that the remission of depressive and anxiety symptoms and/ or the increase in central serotonin activity are associated with increased peripheral insulin sensitivity, possibly via the above-mentioned biological mechanisms.…”

Escitalopram affects spexin expression in the rat hypothalamus, hippocampus and striatum

“…The dose used at the experiment were taken from the publications where authors examine the influence of the escitalopram on the neuropeptide expression in the rat brain [19,23]. 24 hours after the last drug administration, animals were anaesthetized with isoflurane and quickly sacrificed.…”