Targeted Disruption of Selenocysteine Lyase in Brown Adipocytes Controls Glutathione Peroxidase 1 and 4 Expression in...

Brown adipocytes (BA), the predominant cell type in brown adipose tissue (BAT), are essential for adaptive thermogenesis in response to environmental temperature or diets that impact energy expenditure. BAT thermogenic activation is regulated by thyroid hormones (TH) and norepinephrine, with TH activation carried out by the selenoprotein class of deiodinases, making BAT reliant on the micronutrient selenium (Se). Se is utilized to synthesize selenocysteine (Sec), incorporated into selenoproteins. The enzyme Sec lyase (Scly) decomposes Sec to provide selenide for selenoprotein synthesis. Besides deiodinases, glutathione peroxidases (GPXs) are critical selenoproteins for antioxidant defense and redox balance in BAT. Whole-body Scly knockout (KO) mice exhibit obesity, glucose intolerance, fatty liver, and BAT whitening. However, the specific tissue where Scly loss drives this phenotype remains unclear. As BAT regulates energy expenditure and glucose metabolism, we hypothesized either hepatocyte or BA Scly deletion drives the observed phenotype in Scly KO mice. We generated hepatocyte-specific and BA-specific Scly KO mice and assessed metabolic and thermogenic outcomes. Hepatocyte-specific Scly KO mice showed no metabolic phenotype, suggesting hepatic Scly is dispensable. BA-specific Scly KO mice exhibited normal glucose and insulin tolerance. Under Se-deficiency, male BA-specific Scly KO mice recovered body temperature after initial cold-induced thermogenic impairment. Only male mice showed reduced expression of GPX1 and GPX4 in BAT across diets, without TH impairments. These findings demonstrate that Scly in BA supports local Se homeostasis and selenoprotein expression in a sex- and Se-dependent manner, with its loss leading to transient thermoregulatory impairment, contributing to the Scly KO phenotype.