Selenium Protects Mouse Hypothalamic Cells from Glucocorticoid-Induced Endoplasmic Reticulum Stress Vulnerability and Insulin Signaling Impairment.

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.

Selenium in Bodily Homeostasis: Hypothalamus, Hormones, and Highways of Communication.

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.

Metabolism of Selenium, Selenocysteine, and Selenoproteins in Ferroptosis in Solid Tumor Cancers.

A potential target of precision nutrition in cancer therapeutics is the micronutrient selenium (Se). Se is metabolized and incorporated as the amino acid selenocysteine (Sec) into 25 human selenoproteins, including glutathione peroxidases (GPXs) and thioredoxin reductases (TXNRDs), among others. Both the processes of Se and Sec metabolism for the production of selenoproteins and the action of selenoproteins are utilized by cancer cells from solid tumors as a protective mechanism against oxidative damage and to resist ferroptosis, an iron-dependent cell death mechanism. Protection against ferroptosis in cancer cells requires sustained production of the selenoprotein GPX4, which involves increasing the uptake of Se, potentially activating Se metabolic pathways such as the trans-selenation pathway and the TXNRD1-dependent decomposition of inorganic selenocompounds to sustain GPX4 synthesis. Additionally, endoplasmic reticulum-resident selenoproteins also affect apoptotic responses in the presence of selenocompounds. Selenoproteins may also help cancer cells adapting against increased oxidative damage and the challenges of a modified nutrient metabolism that result from the Warburg switch. Finally, cancer cells may also rewire the selenoprotein hierarchy and use Se-related machinery to prioritize selenoproteins that are essential to the adaptations against ferroptosis and oxidative damage. In this review, we discuss both the evidence and the gaps in knowledge on how cancer cells from solid tumors use Se, Sec, selenoproteins, and the Se-related machinery to promote their survival particularly via resistance to ferroptosis.

Selenium and selenoproteins in thermogenic adipocytes.

Selenium (Se) is involved in energy metabolism in the liver, white adipose tissue, and skeletal muscle, and may also play a role in thermogenic adipocytes, i.e. brown and beige adipocytes. Thereby this micronutrient is a key nutritional target to aid in combating obesity and metabolic diseases. In thermogenic adipocytes, particularly in brown adipose tissue (BAT), the selenoprotein type 2 iodothyronine deiodinase (DIO2) is essential for the activation of adaptive thermogenesis. Recent evidence has suggested that additional selenoproteins may also be participating in this process, and a role for Se itself through its metabolic pathways is also envisioned. In this review, we discuss the recognized effects and the knowledge gaps in the involvement of Se metabolism and selenoproteins in the mechanisms of adaptive thermogenesis in thermogenic (brown and beige) adipocytes.

New insights on selenoproteins and neuronal function.

Fifty years have passed since the discovery of the first selenoprotein by Rotruck and colleagues. In that time, the essential nature of selenium has come to light including the dependence of the brain on selenium to function properly. Animal models have shown that a lack of certain selenoproteins in the brain is detrimental for neuronal health, sometimes leading to neurodegeneration. There is also potential for selenoprotein-mediated redox balance to impact neuronal activity, including neurotransmission. Important insights on these topics have been gained over the past several years. This review briefly summarizes the known roles of specific selenoproteins in the brain while highlighting recent advancements regarding selenoproteins in neuronal function. Hypothetical models of selenoprotein function and emerging topics in the field are also provided.