Obese mice exposed to psychosocial stress display cardiac and hippocampal dysfunction associated with local brain-derived neurotrophic factor depletion Jacopo Agrimi a,b,1 , Cristina Spalletti c,1 , Carlotta Baroni a , Gizem Keceli b , Guangshuo Zhu b , Angela Caragnano e , Marco Matteucci a , Stephen Chelko b , Genaro A. Ramirez-Correa d , Djahida Bedja b , Valentina Casieri a , Nicole Di Lascio a,f , Arianna Scalco b,g , Antonio Paolo Beltrami e , Nazareno Paolocci b,h , Matteo Caleo c,h , Vincenzo Lionetti a,i, ⁎ a Institute of Life Sciences, Scuola Superiore Sant'Anna, Pisa 56127, Italy b Division of Cardiology, Johns Hopkins University, Baltimore, MD, USA c CNR Neuroscience Institute, Pisa 56124, Italy d Department of Molecular Science, UT Health Rio Grande Valley 5300 N L Street/Office 1.48 McAllen, Texas 78502, USA e Department of Medicine (DAME), University of Udine, Udine 33100, Italy f CNR Institute of Clinical Physiology, Pisa 56124, Italy g Department of Cardiac, Thoracic, Vascular Sciences and Public Health, University of Padova, via Giustiniani 2, 35128 Padova, Italy h Department of Biomedical Sciences, University of Padova, Padova 35131, Italy i UOS Anesthesiology and Intensive Care Medicine, Fondazione Toscana G. Monasterio, Pisa 56124, Italy abstract article info Article history: Received 13 July 2019 Received in revised form 13 August 2019 Accepted 20 August 2019 Available online 3 September 2019 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 mea- sured 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, ox- idative 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 reduced hippocampal volume, neurogenesis, local BDNF and TrkB content and augmented astrogliosis. Interpretation: PS and obesity synergistically deteriorate myocardial structure and function by depleting cardiac BDNF/TrkB content, leading to augmented oxidative stress. This comorbidity triggers behavioral deficits and in- duces hippocampal remodeling, potentially via lower BDNF and TrkB levels. Fund: J.A. was in part supported by Rotary Foundation Global Study Scholarship. G.K. was supported by T32 Na- tional Institute of Health (NIH) training grant under award number 1T32AG058527. S.C. was funded by American Heart Association Career Development Award (19CDA34760185). G.A.R.C. was funded by NIH (K01HL133368- 01). APB was funded by a Grant from the Friuli Venezia Giulia Region entitled: “Heart failure as the Alzheimer disease of the heart; therapeutic and diagnostic opportunities”. M.C. was supported by PRONAT project (CNR). N.P. was funded by NIH (R01 HL136918) and by the Magic-That-Matters fund (JHU). V.L. was in part supported by institutional funds from Scuola Superiore Sant'Anna (Pisa, Italy), by the TIM-Telecom Italia (WHITE Lab, Pisa, Italy), by a research grant from Pastificio Attilio Mastromauro Granoro s.r.l. (Corato, Italy) and in part by Keywords: Brain-heart axis Brain-derived neurotrophic factor (BDNF) Obesity Psychosocial stress Left ventricle Hippocampus Tropomyosin receptor kinase B (TrkB) Oxidative stress EBioMedicine 47 (2019) 384–401 ⁎ Corresponding author at: Unit of Translational Critical Care Medicine, Institute of Life Sciences, Scuola Superiore Sant'Anna, via G. Moruzzi, 1, 56124 Pisa, Italy. E-mail address: v.lionetti@santannapisa.it (V. Lionetti). 1 J.A. and C.S. have equally contributed to this work. https://doi.org/10.1016/j.ebiom.2019.08.042 2352-3964/© 2019 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Contents lists available at ScienceDirect EBioMedicine journal homepage: www.ebiomedicine.com