Obese mice exposed to psychosocial stress display cardiac and hippocampal dysfunction associated with local brain-derived neurotrophic factor depletion

作者：Jacopo Agrimi, Cristina Spalletti, Carlotta Baroni, Gizem Keceli, Guangshuo Zhu, Angela Caragnano, Marco Matteucci, Stephen P. Chelko, Genaro A. Ramirez‐Correa, Djahida Bedja, Valentina Casieri, Nicole Di Lascio, Arianna Scalco, Antonio Paolo Beltrami, Nazareno Paolocci, Matteo Caleo, Vincenzo Lionetti · 发表于：EBioMedicine · 年份：2019 · DOI：10.1016/j.ebiom.2019.08.042 · 被引用次数：83 · 研究领域：Nerve injury and regeneration、Cardiac Fibrosis and Remodeling、Neurogenesis and neuroplasticity mechanisms

INTRODUCTION: Obesity and psychosocial stress (PS) co-exist in individuals of Western society. Nevertheless, how PS impacts cardiac and hippocampal phenotype in obese subjects is still unknown. Nor is it clear whether changes in local brain-derived neurotrophic factor (BDNF) account, at least in part, for myocardial and behavioral abnormalities in obese experiencing PS. METHODS: In adult male WT mice, obesity was induced via a high-fat diet (HFD). The resident-intruder paradigm was superimposed to trigger PS. In vivo left ventricular (LV) performance was evaluated by echocardiography and pressure-volume loops. Behaviour was indagated by elevated plus maze (EPM) and Y-maze. LV myocardium was assayed for apoptosis, fibrosis, vessel density and oxidative stress. Hippocampus was analyzed for volume, neurogenesis, GABAergic markers and astrogliosis. Cardiac and hippocampal BDNF and TrkB levels were measured by ELISA and WB. We investigated the pathogenetic role played by BDNF signaling in additional cardiac-selective TrkB (cTrkB) KO mice. FINDINGS: When combined, obesity and PS jeopardized LV performance, causing prominent apoptosis, fibrosis, oxidative stress and remodeling of the larger coronary branches, along with lower BDNF and TrkB levels. HFD/PS weakened LV function similarly in WT and cTrkB KO mice. The latter exhibited elevated LV ROS emission already at baseline. Obesity/PS augmented anxiety-like behaviour and impaired spatial memory. These changes were coupled to reduce...