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J Affect Disord. 2016 May 15;196:109-16. doi: 10.1016/j.jad.2016.02.045. Epub 2016 Feb 18.

Insulin receptor sensitizer, dicholine succinate, prevents both Toll-like receptor 4 (TLR4) upregulation and affective changes induced by a high-cholesterol diet in mice.

Author information

1
Department of Neuroscience, School for Mental Health and Neuroscience, Maastricht University, Universiteitssingel 40, 6200 MD Maastricht, The Netherlands. Electronic address: t.strekalova@maastrichtuniversity.nl.
2
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.
3
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.
4
Institute of General Pathology and Pathophysiology, Russian Academy of Medical Sciences, Baltiyskaya 8, Moscow 125315, Russia.
5
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.
6
Serbsky National Research Center for Social and Forensic Psychiatry, Department of Fundamental and Applied Neurobiology, per. Kropotkin 23, Moscow 119034, Russian Federation.
7
Department of Pharmacology, Oxford University, Mansfield Road, OX1 3QT Oxford, UK.
8
Department of Neuroscience, School for Mental Health and Neuroscience, Maastricht University, Universiteitssingel 40, 6200 MD Maastricht, The Netherlands.

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.

LIMITATIONS:

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.

KEYWORDS:

Anxiety; Depression; Insulin receptor sensitizers; Mice; Toll-like receptor four (Tlr4); Western diet

PMID:
26921863
DOI:
10.1016/j.jad.2016.02.045
[Indexed for MEDLINE]

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