Low Bone Turnover Due to Hypothyroidism or Anti-Resorptive Treatment Does Not Affect Whole-Body Glucose Homeostasis in Male Mice

Bone is a large and dynamic tissue and its maintenance requires high amounts of energy as old or damaged bone structures need to be replaced during the process of bone remodeling. Glucose homeostasis is an essential prerequisite for a healthy bone and vice versa, the skeleton can act as an endocrine organ on energy metabolism. We recently showed that hypothyroidism in mice leads to an almost complete arrest of bone remodeling. Here, we aimed to investigate whether the profound suppression of bone remodeling affects whole-body glucose homeostasis. To that end, male C57BL/6JRj mice were rendered hypothyroid over 4 weeks using methimazole and sodium perchlorate in the drinking water. We confirmed trabecular bone gain due to decreased bone turnover in hypothyroid mice with decreased cortical but increased vertebral bone strength. Further, we found impaired glucose handling but not insulin resistance with hypothyroidism. In hypothyroid bone, glucose uptake and expression of glucose transporter Glut4 were reduced by 44.3% and 13.9%, respectively, suggesting lower energy demands. Nevertheless, hypothyroidism led to distinct changes in glucose uptake in muscle, liver, and epididymal white adipose tissue (eWAT). Reduced glucose uptake (−30.6%) and Glut1/Glut4 transcript levels (−31.9%/−67.5%) were detected in muscle tissue. In contrast, in liver and eWAT we observed increased glucose uptake by 25.6% and 68.6%, respectively, and upregulated expression of glucose transporters with hypothyroidism. To more specifically target bone metabolism and discriminate between the skeletal and systemic effects of hypothyroidism on energy metabolism, male mice were treated with zoledronate (ZOL), a bisphosphonate, that led to decreased bone turnover, trabecular bone gain, and reduced local glucose uptake into bone (−40.4%). However, ZOL-treated mice did not display alterations of systemic glucose handling nor insulin tolerance. Despite the close mutual crosstalk of bone and glucose metabolism, in this study, we show that suppressing bone remodeling does not influence whole-body glucose homeostasis in male mice.