Brown adipocytes exposed to cold dissipate heat via adaptive thermogenesis. Adaptive thermogenesis is a physiological response that contributes to energy homeostasis and restricts obesity development in rodents and humans. Activation of adaptive thermogenesis by cold exposure depends on sympathetic/beta-adrenergic signals and thyroid hormones (TH) and is induced by glutathione (GSH) depletion via elevation of reactive oxygen species. TH levels in BAT are locally regulated by iodothyronine deiodinase 2 (DIO2), while GSH is enzymatically converted into its reduced form by GSH peroxidase 1 (GPX1). Besides their crucial role in the activation of BAT adaptive thermogenesis, both DIO2 and GPX1 are selenoproteins, i.e. a class of proteins containing in their active site selenium (Se) as the amino acid selenocysteine (Sec). Sec is decomposed by the enzyme Sec lyase (Scly) into H2Se. Sec comes from either dietary sources or selenoprotein degradation. Hence Scly-mediated Sec decomposition triggers a Se recycling process required to maintain optimal levels of selenoproteins, particularly when Se is limiting. Se recycling is key for energy balance, as disruption of the Scly gene in mice (Scly KO) leads to weight gain worsened by Se deficiency. In wild-type rodents, Se deficiency upregulates Scly and decreases BAT Se levels, DIO2 and GPX1 activities. It is unknown if Se recycling modulates BAT Se levels, impacting DIO2 and GPX1 synthesis and activities, ultimately contributing to cold- induced adaptive thermogenesis. Our long-term research goal is to determine the molecular mechanisms through which Se metabolism regulates energy homeostasis. The overall objective of this research proposal is to determine the role of Se and Scly-mediated Se recycling in linking selenoprotein degradation and synthesis with adaptive thermogenesis in brown adipocytes. In Aim 1, we will determine if dietary Se intake regulates Se metabolism, especially Scly-mediated Se recycling, impacting responses to cold exposure in BAT. In Aim 2, we will determine if Scly is required for cold-induced adaptive thermogenesis in BAT. In Aim 3, we will determine if Scly participates in selenoprotein degradation in brown adipocytes. By studying both Se intake and metabolism, especially Se recycling, using novel in vitro and in vivo models, this conceptually and technically innovative project will clarify the modulatory effect of dietary Se on brown adipocyte physiology, providing new insights into the mechanistic role of Scly in the control of energy expenditure in mammals.

R01DK128390

2021-04-22

2026-03-31