(P31-053-23) Selenium Deficiency and Loss of Selenocysteine Lyase Activity Exacerbates Diet-Induced Obesity in Female Mice

Objectives:

Background: A healthy heart contains high levels of the micronutrient selenium (Se), signifying that this organ requires Se for proper function. Dietary deficiencies in Se have been associated with increased risk of multiple cardiometabolic disorders including type 2 diabetes and atherosclerosis. In most tissues, Se maintains redox homeostasis by controlling the levels of selenoproteins that curb reactive oxygen species. In tissues that require Se, especially when Se is limiting, a mechanism to recycle Se in order to generate Se for selenoproteins is utilized, carried out by the enzyme selenocysteine lyase (Scly). Scly also conducts the last step of the transselenation pathway to metabolize selenomethionine (SeMet) and plays a vital role in energy metabolism as male mice lacking Scly developed metabolic syndrome when given a normocaloric Se-deficient diet. However, it is unknown if Scly modulates Se and selenoprotein levels in the heart in the context of obesity and overnutrition.

Objective: To determine if Scly protects against the development of cardiometabolic disorder when dietary Se is low.

Methods: Wild-type (WT, C57BL6/N) or Scly KO (C57BL6/N background) male and female mice were supplied a high-fat diet (HFD) consisting of 45% kcal by fat and either low (0.08 ppm) or adequate selenomethionine (SeMet) (0.25 ppm) for 8 weeks. Mice were weighed weekly to assess body weight (BW) gain. After 8 weeks, cardiac function was assessed using echocardiography. Hearts were collected for protein for western blots and activity assays, or RNA for qPCR.

Results: WT and Scly KO male and female mice consistently gained weight on both a 0.25 ppm or 0.08 ppm SeMet HFD. Intriguingly however, Scly KO female mice on 0.08 ppm SeMet HFD gained significantly more weight than their WT counterpart while there was no difference in BW between WT and Scly KO female mice on a 0.25 ppm diet. Inguinal white adipose tissue and interscapular brown adipose tissue were also heavier in Scly KO females on a 0.08 ppm SeMet HFD indicating more severe obesity in the Scly KO females when Se is deficient compared with WT mice. Meanwhile, there was no difference in BW between WT and Scly KO male mice on either a 0.08 or 0.25 ppm SeMet HFD.

Conclusions: Loss of Scly activity exacerbates obesity in female mice when supplied a HFD diet deficient in SeMet.

Funding Sources: NIH - NIGMS and NIDDK