SUN-237 Sex Differences in the Effect of Osteocalcin and Exercise on Memory and Cognition

Abstract Osteocalcin is a protein produced in the osteoblasts of bone and found both in the bone matrix and in circulation1. Mouse studies have demonstrated that osteocalcin administration improves type II diabetes through increased insulin release and sensitivity2. Further, osteocalcin can cross the blood-brain barrier and has been shown to restore memory and cognition in mice3. To date, experiments testing the effects of osteocalcin in mice have almost exclusively been conducted in only one sex and could not account for sex as a biological variable. We hypothesized that osteocalcin and exercise would improve behavioral outcomes and aimed to record any difference in response between sexes. In this study, we compare the effects of daily osteocalcin treatment, with or without daily treadmill exercise, in male and female mice (C57BL/6) on a high-fat diet induced model of type II diabetes. Mice were fed high-fat diet for eight weeks, followed by eight weeks of daily osteocalcin injections and/or treadmill exercise. During the final two weeks of treatment behavioural testing for depressive-like behaviour, anxiety-like behaviour, problem-solving, and memory was completed, and the results obtained in male and female mice were compared. The high-fat diet increased depressive-like behaviour and impaired problem solving in both sexes. Significant interactions between sex and exercise and sex and diet were observed. High-fat diet increased anxiety-like behaviour in females, but not males, while exercise increased anxiety-like behaviour in males. Both treatments improved behavioural outcomes, though no difference could be attributed to the combination of treatments. Exercise and osteocalcin decreased depressive-like behaviour in both sexes. Osteocalcin improved problem solving in both sexes, but exercise only improved problem solving in females. The effects of osteocalcin were similar in both male and female mice, however exercise improved problem-solving only in female mice. This suggests that both sexes benefit from osteocalcin treatment and exercise may be more beneficial in females. The results indicate that osteocalcin and exercise have similar but not identical effects on behaviour that may be reflected in overlapping mechanisms of action. References: (1) Lee et al., Cell. 2007; 130(3): 456-469. (2) Ferron et al., Bone. 2012; 50(2): 568–575. (3) Khrimian et al., J Exp Med. 2017; 214(10): 2859-2873.