Global loss of selenocysteine lyase in mice drives lipid accumulation in brown adipocytes

The enzyme selenocysteine (Sec) lyase (SCLY) decomposes Sec, releasing selenide for the synthesis of selenoproteins, which contain Sec in their primary structure and participate in strong redox reactions, maintaining redox balance. We previously showed that global disruption of the <i>Scly</i> gene (Scly KO) in mice leads to obesity. Targeted deletion of <i>Scly</i> in agouti-related peptide neurons enhances energy expenditure and brown adipose tissue (BAT) activation, augmenting leanness. We hypothesized that Scly KO mice develop obesity due to failure of BAT-controlled mechanisms of energy expenditure due to redirection of Sec to an alternative pathway. We analyzed BAT from male Scly KO mice on selenium (Se)-adequate [0.25 parts per million (ppm)] and Se-deficient (0.08 ppm) diets for morphology, Se content, selenoprotein expression, thyroid hormones, and additional Sec-using pathways. We found that the BAT of Scly KO mice was enlarged, with lower Se levels, and substantial whitening on a Se-adequate diet. This phenotype worsened on low Se and coincided with a mild impairment in adapting to cold exposure. BAT whitening coincided with an increase in triglycerides and reduced 3-hydroxy-3-methylglutaryl coenzyme A and cholesterol. BAT selenoproteins regulating energy metabolism, type 2 iodothyronine deiodinase (DIO2), glutathione peroxidase 1 (GPX1), and glutathione peroxidase 1 (GPX4), were significantly decreased. DIO2 reduction corresponded with an increase in thyroxine and thyroid-stimulating hormone and a reduction in heat-producing uncoupling protein 1. Downregulation of GPX4 did not affect ferroptosis in the BAT. Therefore, the whitened BAT of the <i>Scly</i> KO mouse is a multifactorial process involving the disruption of BAT function through changes to selenoproteins involved in energy metabolism.<b>NEW & NOTEWORTHY</b> Global loss of the selenocysteine-decomposing enzyme selenocysteine lyase in mice leads to lipid accumulation and whitening of the brown adipose tissue, with consequent obesity development. Selenocysteine lyase modulates selenium levels and selenoprotein expression, specifically GPX1, GPX4, and DIO2, in brown adipocytes. Selenocysteine metabolic fate hinges on the actions of selenocysteine lyase.