Grant Abstract: Mechanism of Selenoprotein Synthesis

Grant Number: 5R01DK047320-22
PI Name: Berry
Project Title: Mechanism of Selenoprotein Synthesis

Abstract: Human selenium (Se) supplementation studies indicate an increased risk of type 2 diabetes (T2D) in men taking Se supplements, but not in women. Se is an essential trace element, present in selenoproteins as selenocysteine (Sec). Sec is recycled in the body via Sec lyase (Scly). Knockout (KO) of the Scly gene in mice results in sex-specific differences in energy metabolism, with males exhibiting hyperinsulinemia, glucose intolerance, and hepatic steatosis, whereas females do not. Upon dietary Se restriction, male Scly KO mice exhibit characteristics of metabolic syndrome (MetS), including obesity, fatty liver, and hypercholesterolemia, and exacerbation of symptoms seen on normal chow. The overall objectives of the parent R01 are to elucidate the pathways and mechanisms underlying the sex-specific differences seen upon Scly KO that lead to development of MetS. The proposed studies will also establish whether castration (CAST) attenuates the phenotype in the Scly KO mouse, and investigate the contribution of testosterone (TST) to development of MetS when Se recycling is disrupted. The long-term goals are to understand the mechanisms and regulatory pathways governing Se distribution, selenoprotein synthesis, and the sex differences described above. Our central hypothesis is that development of MetS in male Scly KO mice is due to sex-specific effects on energy metabolism, and possibly sex hormone regulation of certain selenoprotein genes. Tissue specific Scly KO mice and in vitro studies will allow us to focus on specific tissues and genes, respectively, that contribute to the Scly KO male phenotype. Our hypotheses will be tested via the following specific aims: Aim 1: Identify changes in metabolic pathways and selenoprotein gene expression that occur in male and female mice in response to whole body Scly KO, and which of these are affected by CAST and/or TST replacement. Aim 2: Generate and characterize effects of liver, pancreatic islet and hypothalamic Scly KO in male and female mice, and effects of CAST and TST replacement. Aim 3: Establish cell culture models to further investigate which of the changes identified in aims 1 and 2 contribute to MetS in male versus female Scly KO mice. In this Administrative Supplement, we propose to expand our studies to include dietary supplementation with high Se, with or without a high fat diet. We further propose to include brown adipose tissue in our studies in specific aims 1 and 2. The significance of the proposed work for human health is that the knowledge will provide new insights into the sex specific differences in the mechanisms of Se utilization in health and disease, and contribute new information to nutritional guidelines on Se requirements, and effects of supplementation in people with metabolic disorders.

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