title: ATF3 expression in cardiomyocytes preserves homeostasis in the heart and controls peripheral glucose tolerance.
abstract: Obesity and type 2 diabetes (T2D) trigger a harmful stress-induced cardiac remodeling process known as cardiomyopathy. These diseases represent a serious and widespread health problem in the Western world; however the underlying molecular basis is not clear. ATF3 is an 'immediate early' gene whose expression is highly and transiently induced in response to multiple stressors such as metabolic, oxidative, endoplasmic reticulum and inflammation, stressors that are involved in T2D cardiomyopathy. The role of ATF3 in diabetic cardiomyopathy is currently unknown. Our research has aimed to study the effect of ATF3 expression on cardiomyocytes, heart function and glucose homeostasis in an obesity-induced T2D mouse model.
  
  
  
  We used wild type mice (WT) as well as mutant mice with a cardiac-specific ATF3 deficiency (ATF3-cKO). Mice were fed a high-fat diet (HFD) for 15 weeks. HFD induced high ATF3 expression in cardiomyocytes. Mice were examined for cardiac remodeling processes and the diabetic state was assessed. HFD-fed ATF3-cKO mice exhibited severe cardiac fibrosis, higher levels of heart hypertrophic markers, increased inflammation and worse cardiac function, as compared to WT mice. Interestingly, HFD-fed ATF3-cKO mice display increased hyperglycemia and reduced glucose tolerance, despite higher blood insulin levels, as compared to HFD-fed WT mice. Elevated levels of the cardiac inflammatory cytokines IL-6 and TNFα leading to impaired insulin signalling may partially explain the peripheral glucose intolerance.
  
  
  
  Cardiac ATF3 has a protective role in dampening the HFD-induced cardiac remodeling processes. ATF3 exerts both local and systemic effects related to T2D-induced cardiomyopathy. This study provides a strong relationship between heart remodeling processes and blood glucose homeostasis.
authors.affiliation: Department of Cell Biology and Cancer Science, B. Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, 7th Efron St., Bat-Galim, Haifa 31096, Israel.
authors.forename: Roy
authors.initials: R
authors.lastname: Kalfon
authors.affiliation: Department of Cell Biology and Cancer Science, B. Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, 7th Efron St., Bat-Galim, Haifa 31096, Israel.
authors.forename: Lilach
authors.initials: L
authors.lastname: Koren
authors.affiliation: Department of Cell Biology and Cancer Science, B. Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, 7th Efron St., Bat-Galim, Haifa 31096, Israel.
authors.forename: Sharon
authors.initials: S
authors.lastname: Aviram
authors.affiliation: Biomedical Core Facility, B. Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
authors.forename: Ortal
authors.initials: O
authors.lastname: Schwartz
authors.affiliation: Departments of Biological Chemistry and Pharmacology, Ohio State University, 1060 Carmack road, Columbus, OH 43210, USA.
authors.forename: Tsonwin
authors.initials: T
authors.lastname: Hai
authors.affiliation: Department of Cell Biology and Cancer Science, B. Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, 7th Efron St., Bat-Galim, Haifa 31096, Israel; aronheim@tx.technion.ac.il.
authors.forename: Ami
authors.initials: A
authors.lastname: Aronheim
mesh_terms: D051700:Activating Transcription Factor 3 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism*; D006332:Cardiomegaly / Q000097:blood / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D003924:Diabetes Mellitus, Type 2 / Q000097:blood* / Q000209:etiology; D058065:Diabetic Cardiomyopathies / Q000097:blood* / Q000209:etiology / Q000473:pathology / Q000503:physiopathology; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D005230:Fatty Acids, Nonesterified / Q000494:pharmacology; D005355:Fibrosis; D020022:Genetic Predisposition to Disease; D006706:Homeostasis; D018836:Inflammation Mediators / Q000378:metabolism; D007328:Insulin / Q000097:blood; D019426:Integrases / Q000235:genetics; D015850:Interleukin-6 / Q000097:blood; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D018995:Myosin Heavy Chains / Q000235:genetics; D010641:Phenotype; D011401:Promoter Regions, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000097:blood; D020257:Ventricular Remodeling / Q000187:drug effects
chemical_list: D051700:Activating Transcription Factor 3; C103002:Atf3 protein, mouse; D001786:Blood Glucose; D005230:Fatty Acids, Nonesterified; D018836:Inflammation Mediators; D007328:Insulin; D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha; C577686:interleukin-6, mouse; C045073:Cre recombinase; D019426:Integrases; D018995:Myosin Heavy Chains
keywords: Type 2 diabetes • Cardiac remodeling • Cytokines • High fat diet • ATF3