Obese Mice Exposed to Psychosocial Stress Display Cardiac and Hippocampal Impairment Associated With Local Brain-Derived Neurotrophic Factor Depletion

Introduction: Obesity and psychosocial stress (PS), two stigmata of Western society increasingly coexisting in the same individual, are risk factors for cardiovascular disease and cognitive deficits. However, the effects of PS on cardiac and hippocampal phenotype of obese subjects are still unknown. Furthermore, Brain-Derived Neurotrophic Factor (BDNF) can regulate the hippocampal and cardiac homeostasis; thus, its depletion may explain PS/obesity-induced dysfunction at both levels. Hypothesis: Obese mice exposed to PS display cardiac and hippocampal impairment associated to local BDNF depletion. Methods: Forty adult male C57BL6/J mice were subjected to: 1) normocaloric diet (ND) for 18 weeks (Control); 2) high-fat diet (HFD) for 18 weeks (Ob); 3) ND and resident-intruder paradigm (RIP) to trigger PS (PS); 4) HFD and RIP (Ob+PS). Left ventricular (LV) function was evaluated by pressure-volume loops. Spatial memory was assessed by Y-maze. LV ROS levels were measured by EPR. Myocardial apoptosis, fibrosis and vascular density were histologically evaluated. Hippocampus was assayed to evaluate volume, neurogenesis and synaptic plasticity. Tissue BDNF levels were measured by ELISA. Results: Preload recruitable stroke work and LV elastance, load-independent indexes of LV contractility, were impaired only in Ob+PS group (-44% and -41%, respectively, both p<0.01 vs. Control). Moreover, combined regimen jeopardized also myocardial relaxation (tau), (p<0.05 vs. Control), without affecting arterial elastance. Obesity/PS significantly increased LV oxidative stress, apoptosis and fibrosis, without changing vascular density, while halving cardiac BDNF (-48%, p<0.01 vs. all groups). Spatial memory was compromised only in Ob+PS group (p<0.05 vs. Control) consistent with reduced hippocampal volume (-27%, p<0.05 vs. all groups), neurogenesis (-33%, p<0.001 vs. Control), synaptic plasticity (-29%, p<0.05 vs. Control) and local BDNF levels (-52%, p<0.01 vs. Control; p<0.05 vs. PS and Ob). Conclusions: PS triggers prominent myocardial and hippocampal dysfunction in obese mice. PS-challenged obese mice exhibit BDNF depletion in both remodeled tissues. Therefore, PS may jam heart-brain communication of obese mice though local BDNF exhaustion.