Ashley N. Ogawa-Wong

Selenoproteins are a class of proteins with the selenium-containing amino acid selenocysteine (Sec) in their primary structure. Sec is incorporated into selenoproteins via recoding of the stop codon UGA, with specific cis and trans factors required during translation to avoid UGA recognition as a stop codon, including a Sec-specific tRNA, tRNA^[Ser]Sec, encoded in mice by the gene Trsp. Whole-body deletion of Trsp in mouse is embryonically lethal, while targeted deletion of Trsp in mice has been used to understand the role of selenoproteins in the health and physiology of various tissues. We developed a mouse model with the targeted deletion of Trsp in brown adipocytes (Trsp^f/f-Ucp1-Cre^+/−), a cell type predominant in brown adipose tissue (BAT) controlling energy expenditure via activation of adaptive thermogenesis, mostly using uncoupling protein 1 (Ucp1). At room temperature, Trsp^f/f-Ucp1-Cre^+/− mice maintain oxygen consumption and Ucp1 expression, with male Trsp^f/f-Ucp1-Cre^+/− mice accumulating more triglycerides in BAT than both female Trsp^f/f-Ucp1-Cre^+/− mice or Trsp^f/f controls. Acute cold exposure neither reduced core body temperature nor changed the expression of selenoprotein iodothyronine deiodinase type II (Dio2), a marker of adaptive thermogenesis, in Trsp^f/f-Ucp1-Cre^+/− mice. Microarray analysis of BAT from Trsp^f/f-Ucp1-Cre^+/− mice revealed glutathione S-transferase alpha 3 (Gsta3) and ELMO domain containing 2 (Elmod2) as the transcripts most affected by the loss of Trsp. Male Trsp^f/f-Ucp1-Cre^+/− mice showed mild hypothyroidism while downregulating thyroid hormone-responsive genes Thrsp and Tshr in their BATs. In summary, modest changes in the BAT of Trsp^f/f-Ucp1-Cre ^+/− mice implicate a mild thyroid hormone dysfunction in brown adipocytes.

Selenium (Se) is an essential micronutrient known for its antioxidant properties and health benefits, attributed to its presence in selenoproteins as the amino acid, selenocysteine. Selenocysteine lyase (Scly) catalyzes hydrolysis of selenocysteine to selenide and alanine, facilitating re-utilization of Se for de novo selenoprotein synthesis. Previously, it was reported that male Scly^−/− mice develop increased body weight and body fat composition, and altered lipid and carbohydrate metabolism, compared to wild type mice. Strikingly, females appeared to present with a less severe phenotype, suggesting the relationship between Scly and energy metabolism may be regulated in a sex-specific manner. Here, we report that while body weight and body fat gain occur in both male and female Scly^−/− mice, strikingly, males are susceptible to developing glucose intolerance, whereas female Scly^−/− mice are protected. Because Se is critical for male reproduction, we hypothesized that castration would attenuate the metabolic dysfunction observed in male Scly^−/− mice by eliminating sequestration of Se in testes. We report that fasting serum insulin levels were significantly reduced in castrated males compared to controls, but islet area was unchanged between groups. Finally, both male and female Scly^−/− mice exhibit reduced hypothalamic expression of selenoproteins S, M, and glutathione peroxidase 1.

Selenium (Se) is a micronutrient that maintains biological functions through the action of Se containing proteins known as selenoproteins. Due to the known antioxidant effects of Se, supplements containing Se have been on the rise. While Se supplementation may be beneficial for Se deficient populations, few are at risk for Se deficiency due to the transportation of food from Se-rich regions and the rise of Se-enriched foods. Alarmingly, Se supplementation may have adverse effects in people who already receive an adequate Se supply. Specifically, an increased risk of type 2 diabetes has been reported in individuals with high baseline Se levels. However, this effect was restricted to males, suggesting the relationship between Se and glucose homeostasis may be sexually dimorphic. This review will discuss the current understanding of the interaction between Se and glucose homeostasis, including any sex differences that have been described.