8446 Thermoneutral Housing has Limited Effects on Social Isolation-Induced Bone Loss in Male C57BL/6J Mice

Abstract Disclosure: R. Mountain: None. A. Langlais: None. C. Lary: None. K.J. Motyl: None. Social isolation stress has numerous known negative health effects, including increased risk for cardiovascular disease, dementia, as well as overall mortality. The impacts of social isolation on skeletal health, however, have not been thoroughly investigated. We previously found that four weeks of social isolation through single housing led to a significant reduction in trabecular and cortical bone in male, but not female, mice. In addition to evidence of reduced bone remodeling, we found a significant elevation of Pdk4 and reduced brown adipocyte and lipid droplet size in the brown fat of isolated male mice, suggesting increased brown fat activation and thermal stress. Single housing at room temperature (∼20-25°C)—below the thermoneutral range of mice (∼26-34°C)—can lead to cold stress, which has known negative effects on bone. Therefore, the aim of this study was to test the hypothesis that housing mice at thermoneutrality, thereby ameliorating cold-stress, will prevent social isolation-induced bone loss in male C57BL/6J mice. 16-week-old mice were randomized into social isolation (1 mouse/cage) or grouped housing (4 mice/cage) at either room temperature (∼23°C) or in a warm temperature incubator (∼28°C) for four weeks (N=16/group). As seen in our previous studies, isolated mice at room temperature had significantly reduced bone parameters, including femoral bone volume fraction (BV/TV), bone mineral density (BMD), and cortical thickness (p < 0.001). Contrary to our hypothesis, these effects were not ameliorated by thermoneutral housing. In fact, 28°C housing tended to reduce BV/TV (p = 0.0711) and BMD (p = 0.0883), and significantly reduced cortical thickness (p = 0.0492) within the grouped mice relative to 23°C housing. There were no differences in serum bone resorption or formation markers between the groups, nor were there any differences in fat or lean mass. Social isolation did significantly increase gene expression of the glucocorticoid receptor Nr3c1 (p = 0.0288) and tended to increase expression of Hsd11b1 (p = 0.0947), an enzyme critical for corticosterone activation, across housing temperatures. Increased glucocorticoid activity can enhance brown fat activation, including increased Pdk4 expression. Overall, our data suggest social isolation-induced bone loss is not a result of thermal stress from single housing. These results provide key insights into the potential mechanisms mediating the effects of social isolation on skeletal health and will inform future studies investigating the role of glucocorticoid signaling. Presentation: 6/1/2024