Age-related obesity and type 2 diabetes dysregulate neuronal associated genes and proteins in humans

Abstract

// Mehran Rahimi 1, * , Manlio Vinciguerra 2, 3, * , Mojtaba Daghighi 4 , Behiye Özcan 5 , Vishtaseb Akbarkhanzadeh 6 , Fareeba Sheedfar 7 , Marzyeh Amini 8 , Tommaso Mazza 9 , Valerio Pazienza 3 , Mahdi M. Motazacker 10 , Morteza Mahmoudi 11, 12 , Felix W. M. De Rooij 13 , Eric Sijbrands 13 , Maikel P. Peppelenbosch 14 , Farhad Rezaee 14, 15 1 Faculty of Medical Science, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands 2 Institute for Liver and Digestive Health, Division of Medicine, University College London (UCL), London, UK 3 Gastroenterology Unit, IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy 4 Department of Biomedical Engineering, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands 5 Department of Endocrinology, Erasmus Medical Center, Rotterdam, The Netherlands 6 Institute Center-45, Medical Center, University of Amsterdam, The Netherlands 7 Department of Physiology, Radboud University Medical Center, Nijmegen, The Netherlands 8 Department of Epidemiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands 9 Bioinformatics Unit, IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy 10 Department of Clinical Genetics, Academic Medical Center, Amsterdam, The Netherlands 11 Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, United States 12 Department of Nanotechnology and Nanotechnology Research Center, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran 13 Department of cardiovascular genetics, Metabolism, Erasmus Medical Center, Rotterdam, The Netherlands 14 Department of Gastroenterology and Hepatology, Erasmus Medical Center, University of Rotterdam, Rotterdam, The Netherlands 15 Department of Cell Biology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands * These authors have contributed equally to this work Correspondence to: Farhad Rezaee, e-mail: F.rezaee@erasmusmc.nl , F.Rezaee@med.umcg.nl Keywords: aging, obesity, diabetes, age-related diabetes neuropathy, pancreas Received: July 12, 2015      Accepted: August 07, 2015      Published: August 18, 2015 ABSTRACT Despite numerous developed drugs based on glucose metabolism interventions for treatment of age-related diseases such as diabetes neuropathies (DNs), DNs are still increasing in patients with type 1 or type 2 diabetes (T1D, T2D). We aimed to identify novel candidates in adipose tissue (AT) and pancreas with T2D for targeting to develop new drugs for DNs therapy. AT-T2D displayed 15 (e.g. SYT4 up-regulated and VGF down-regulated) and pancreas-T2D showed 10 (e.g. BAG3 up-regulated, VAV3 and APOA1 down-regulated) highly differentially expressed genes with neuronal functions as compared to control tissues. ELISA was blindly performed to measure proteins of 5 most differentially expressed genes in 41 human subjects. SYT4 protein was upregulated, VAV3 and APOA1 were down-regulated, and BAG3 remained unchanged in 1- Obese and 2- Obese-T2D without insulin, VGF protein was higher in these two groups as well as in group 3- Obese-T2D receiving insulin than 4-lean subjects. Interaction networks analysis of these 5 genes showed several metabolic pathways (e.g. lipid metabolism and insulin signaling). Pancreas is a novel site for APOA1 synthesis. VGF is synthesized in AT and could be considered as good diagnostic, and even prognostic, marker for age-induced diseases obesity and T2D. This study provides new targets for rational drugs development for the therapy of age-related DNs.