title: Insulin receptor sensitizer, dicholine succinate, prevents both Toll-like receptor 4 (TLR4) upregulation and affective changes induced by a high-cholesterol diet in mice.
abstract: BACKGROUND
  High cholesterol intake in mice induces hepatic lipid dystrophy and inflammation, signs of non-alcoholic fatty liver disease (NAFLD), depressive- and anxiety-like behaviors, and the up-regulation of brain and liver Toll-like receptor 4 (Tlr4). Here, we investigated whether dicholine succinate (DS), an insulin receptor sensitizer and mitochondrial complex II substrate would interact with these effects.
  
  
  METHODS
  C57BL/6J mice were given a 0.2%-cholesterol diet for 3 weeks, alone or along with oral DS administration, or a control feed. Outcomes included behavioral measures of anxiety/depression, and Tlr4 and peroxisome-proliferator-activated-receptor-gamma coactivator-1b (PPARGC1b) expression.
  
  
  RESULTS
  50mg/kg DS treatment for 3 weeks partially ameliorated the cholesterol-induced anxiety- and depressive-like changes. Mice were next treated at the higher dose (180mg/kg), either for the 3-week period of dietary intervention, or for the last two weeks. Three-week DS administration normalized behaviors in the forced swim and O-maze tests and abolished the Tlr4 up-regulation in the brain and liver. The delayed, 2-week DS treatment had similar effects on Tlr4 expression and largely rescued the above-mentioned behaviors. Suppression of PPARGC1b, a master regulator of mitochondrial biogenesis, by the high cholesterol diet, was prevented with the 3-week administration, and markedly diminished by the a 2-week administration of DS. None of treatments prevented hepatic dystrophy and triglyceride accumulation.
  
  
  CONCLUSIONS
  Other conditions have to be tested to define possible limitations of reported effects of DS.
  
  
  CONCLUSIONS
  DS treatment did not alter the patho-morphological substrates of NAFLD syndrome in mice, but ameliorated its molecular and behavioral consequences, likely by activating mitochondrial functions and anti-inflammatory mechanisms.
authors.affiliation: Department of Neuroscience, School for Mental Health and Neuroscience, Maastricht University, Universiteitssingel 40, 6200 MD Maastricht, The Netherlands. Electronic address: t.strekalova@maastrichtuniversity.nl.
authors.forename: Tatyana
authors.initials: T
authors.lastname: Strekalova
authors.affiliation: Department of Neuroscience, School for Mental Health and Neuroscience, Maastricht University, Universiteitssingel 40, 6200 MD Maastricht, The Netherlands; CEDOC, NOVA Medical School, Faculdade de Ciências Médicas, FCM, Universidade Nova de Lisboa, Campo Mártires da Pátria, 130, 1169-056 Lisboa, Portugal.
authors.forename: João P
authors.initials: JP
authors.lastname: Costa-Nunes
authors.affiliation: Department of Neuroscience, School for Mental Health and Neuroscience, Maastricht University, Universiteitssingel 40, 6200 MD Maastricht, The Netherlands; Institute of General Pathology and Pathophysiology, Russian Academy of Medical Sciences, Baltiyskaya 8, Moscow 125315, Russia.
authors.forename: Ekaterina
authors.initials: E
authors.lastname: Veniaminova
authors.affiliation: Institute of General Pathology and Pathophysiology, Russian Academy of Medical Sciences, Baltiyskaya 8, Moscow 125315, Russia.
authors.forename: Aslan
authors.initials: A
authors.lastname: Kubatiev
authors.affiliation: Department of Neuroscience, School for Mental Health and Neuroscience, Maastricht University, Universiteitssingel 40, 6200 MD Maastricht, The Netherlands; Division of Molecular Psychiatry, Laboratory of Translational Neuroscience, Department of Psychiatry, Psychosomatics and Psychotherapy, University of Wuerzburg, Fuechsleinstr. 15, 97080 Wuerzburg, Germany.
authors.forename: Klaus-Peter
authors.initials: KP
authors.lastname: Lesch
authors.affiliation: Serbsky National Research Center for Social and Forensic Psychiatry, Department of Fundamental and Applied Neurobiology, per. Kropotkin 23, Moscow 119034, Russian Federation.
authors.forename: Vladimir P
authors.initials: VP
authors.lastname: Chekhonin
authors.affiliation: Department of Pharmacology, Oxford University, Mansfield Road, OX1 3QT Oxford, UK.
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Evans
authors.affiliation: Department of Neuroscience, School for Mental Health and Neuroscience, Maastricht University, Universiteitssingel 40, 6200 MD Maastricht, The Netherlands.
authors.forename: Harry W M
authors.initials: HW
authors.lastname: Steinbusch
mesh_terms: D000818:Animals; D001007:Anxiety / Q000188:drug therapy / Q000209:etiology; D002784:Cholesterol / Q000009:adverse effects; D002794:Choline / Q000031:analogs & derivatives* / Q000494:pharmacology; D003863:Depression / Q000188:drug therapy / Q000209:etiology; D004032:Diet / Q000009:adverse effects; D005260:Female; D007249:Inflammation; D051379:Mice; D008810:Mice, Inbred C57BL; D065626:Non-alcoholic Fatty Liver Disease / Q000188:drug therapy* / Q000209:etiology / Q000523:psychology; D011972:Receptor, Insulin / Q000187:drug effects*; D013386:Succinates / Q000494:pharmacology*; D013390:Succinylcholine; D051197:Toll-Like Receptor 4 / Q000187:drug effects*; D014280:Triglycerides / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D013386:Succinates; D051197:Toll-Like Receptor 4; D014280:Triglycerides; D002784:Cholesterol; D011972:Receptor, Insulin; D013390:Succinylcholine; D002794:Choline
keywords: Anxiety; Depression; Insulin receptor sensitizers; Mice; Toll-like receptor four (Tlr4); Western diet