SAT-293 Osteocalcin and Exercise Improve Mood and Cognition in Female Mice with High-Fat Diet Induced Type 2 Diabetes

The skeleton has been characterized as an endocrine organ, demonstrating a capacity to modulate cognition, mood and energy homeostasis (1,2). These endocrine actions of the skeleton have been attributed to the osteoblast-derived peptide osteocalcin. In mice, uncarboxylated osteocalcin (ucOCN) decreased the acquisition of type 2 diabetes mellitus (T2DM) and ameliorated depressive- and anxiety-like behaviours (1,2). Clinically, T2DM patients present with reduced serum osteocalcin levels and approximately 1 in 4 also suffer from co-morbid depression (3,4). The cognitive and metabolic benefits of ucOCN are similar to the beneficial effects of exercise that is recommended in treatment of both depression and T2DM. Here we compared the effects of ucOCN or exercise in female C57-BL/6J mice under two different metabolic conditions. Mice were fed either a high-fat diet (60% calories from fat) to induce T2DM or a control diet (10% calories from fat). Groups of mice were either sedentary or exercised daily by 30 min treadmill running for two months, with or without daily administration of ucOCN (30 ng/g/day). Mice with T2DM displayed depressive behaviours marked by a higher immobile time in tail suspension tests compared to control mice (97±25 n=11 vs 207±9.0 s n=12; t(21)=4.21, P=0.0004). Exercise and osteocalcin both improved depressive behaviour (137±8 n=12; t(22)=5.85, P<0.0001 & 127±15 s n=12; t(22)=4.46, P=0.0002). Anxiety, measured by the elevated-plus maze revealed the mice with T2DM displayed increased anxiety spending less time in the open arms and had a lower ratio of open to closed arm entries than the control group (0.37±0.03 n=10 vs 0.21±0.032 n=11; t(19)=3.56, P=0.0021). Neither exercise nor osteocalcin improved anxiety in the T2DM mice. The puzzle box test revealed the negative effects of the high-fat diet in problem solving and memory, where the sedentary mice displayed greater latencies to solve each task compared to control mice. Exercised and mice receiving osteocalcin displayed performances comparable to that of the control group. Under normal metabolic conditions (low fat diet), neither osteocalcin nor exercise altered responses in any of the behavioural tests. Together, these results: 1. The effects of osteocalcin on behaviour and cognition are comparable to that of the effects of exercise in female mice with T2DM; 2. Behaviour and cognition did not improve from exercise or osteocalcin in female mice on a low-fat diet. References: (1) Ferron et al., Bone. 2012 Feb;50(2):568–575. (2) Oury et al., Cell. 2013 Sep 26:155(1):228–241. (3) Liu et al., Horm Metab Res. 2015 Oct;47(11):813–9. (4) Khaledi et al., Acta Diabetol. 2019 June;56(6):631–650.