The ability of the body to maintain homeostasis requires constant communication between the brain and peripheral tissues. Different organs produce signals, often in the form of hormones, which are detected by the hypothalamus. In response, the hypothalamus alters its regulation of bodily processes, which is achieved through its own pathways of hormonal communication. The generation and transmission of the molecules involved in these bi-directional axes can be affected by redox balance. The essential trace element selenium is known to influence numerous physiological processes, including energy homeostasis, through its various redox functions. Selenium must be obtained through the diet and is used to synthesize selenoproteins, a family of proteins with mainly antioxidant functions. Alterations in selenium status have been correlated with homeostatic disturbances in humans and studies with animal models of selenoprotein dysfunction indicate a strong influence on energy balance. The relationship between selenium and energy metabolism is complicated, however, as selenium has been shown to participate in multiple levels of homeostatic communication. This review discusses the role of selenium in the various pathways of communication between the body and the brain that are essential for maintaining homeostasis.

The use of glucocorticoid medications is known to cause metabolic side effects such as overeating, excess weight gain, and insulin resistance. The hypothalamus, a central regulator of feeding behavior and energy expenditure, is highly responsive to glucocorticoids, and it has been proposed that it plays a role in glucocorticoid-induced metabolic defects. Glucocorticoids can alter the expression and activity of antioxidant enzymes and promote the accumulation of reactive oxygen species. Recent evidence indicates that selenium can counter the effects of glucocorticoids, and selenium is critical for proper hypothalamic function. This study sought to determine whether selenium is capable of protecting hypothalamic cells from dysfunction caused by glucocorticoid exposure. We treated mHypoE-44 mouse hypothalamic cells with corticosterone to study the effects on cellular physiology and the involvement of selenium. We found that corticosterone administration rendered cells more vulnerable to endoplasmic reticulum stress and the subsequent impairment of insulin signaling. Supplementing the cell culture media with additional selenium alleviated endoplasmic reticulum stress and promoted insulin signaling. These findings implicate a protective role of selenium against chronic glucocorticoid-induced hypothalamic dysfunction.

Long-term elevation of glucocorticoid levels is detrimental to neurological function, causing disturbances in mood and memory. Multiple molecular mechanisms of action have been implicated, including the disruption of antioxidant defense systems. This study focused on the impact of glucocorticoids on selenoproteins, which include selenoenzymes with antioxidant functions, some of which are essential for proper brain function. We exposed C57/BL6 mice to long-term glucocorticoid administration and measured changes in selenoprotein levels and gene expression. To study the underlying mechanism of selenoprotein regulation, we used an immortalized mouse hippocampal cell line. We found that Glutathione peroxidase 1 and Selenoprotein S levels are altered by glucocorticoids in a manner that is dependent on selenium availability and differential activation of the glucocorticoid and mineralocorticoid receptors. Spatial transcriptomic analysis of mouse hippocampal sections suggests spatial and cell-specific changes to the selenoprotein transcriptome. Finally, brain selenoprotein levels may be indirectly decreased by glucocorticoids due to insufficient distribution of selenium to the brain. Thus, glucocorticoids demonstrate an ability to control selenoprotein levels both by acting directly on hippocampal cells as well as indirectly by disrupting the delivery of dietary selenium to the brain. Future work will determine the impact of selenium intake on glucocorticoid-induced neurological dysfunction and damage.