RF36 | PSUN77 Female Dexras1 WT & KO Mice Fed a High Fat Diet Do Not Have Different Body Compositions nor Bone Densities

Glucocorticoids are a frequently prescribed class of medications, widely used for their anti-inflammatory and immunosuppressive effects. However, long term usage of glucocorticoids is associated with a variety of adverse effects, including adrenal suppression, increased adiposity, and decreased bone density. DEXRAS1, also known as RASD1, is a member of the Ras family of GTPases that is upregulated by glucocorticoids. In in vitro experiments, DEXRAS1 has been shown to promote differentiation of adipocytes and decrease differentiation of osteoblasts. Studies conducted in male Dexras1 knockout (KO) and wild type (WT) mice treated with dexamethasone found decreased body weight and visceral fat, and increased bone density in KO mice when compared to WT mice; together, these experiments suggest that the removal of the Dexras1 gene can prevent glucocorticoid-induced osteoporosis and fat-accumulation.A major limitation of the aforementioned studies is that they were performed using only male mice, despite well-known sex related differences in body composition and bone density. On average, females have a higher percentage of body fat and lower bone density. While obesity is prevalent across all sexes, osteoporosis is 4 times more common in females. Therefore, in order to better understand sex as a biological variable on the effects of the Dexras1 gene, we compared female Dexras1 KO and WT mice fed a high-fat diet (HFD) containing 45 kcal% fat over the course of 14 weeks. Body composition was assessed by quantitative magnetic resonance. Bone morphometry was analyzed with micro-CT, and bone density was analyzed with micro-CT and dual-energy x-ray absorptiometry (DXA) scans of female murine femurs. Interestingly, there were no differences in the overall body weight, fat mass, nor lean mass over this period between WT and KO female mice. Similarly, the female Dexras1 KO and WT mice mice showed no differences in their bone density, cortical thickness, and average trabecular separation. Since there was no difference in the fat mass, it is not surprising that there was also no difference in bone density, as they are often inversely related. These data in conjunction with previous experiments on male mice suggest that sex strongly impacts the phenotype observed as a result of knocking out the Dexras1 gene. The mechanisms underlying differential regulation between the sexes is unclear, and could include differences in sex hormones, the presence of estrus cycle in females, differences in stress response, or even differences in microbiome. Consequently, more studies are necessary to fully understand the function and regulation of Dexras1.

Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m., Monday, June 13, 2022 12:36 p.m. - 12:41 p.m.