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

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


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anxiety / drug therapy
  • Anxiety / etiology
  • Cholesterol / adverse effects
  • Choline / analogs & derivatives*
  • Choline / pharmacology
  • Depression / drug therapy
  • Depression / etiology
  • Diet / adverse effects
  • Female
  • Inflammation
  • Mice
  • Mice, Inbred C57BL
  • Non-alcoholic Fatty Liver Disease / drug therapy*
  • Non-alcoholic Fatty Liver Disease / etiology
  • Non-alcoholic Fatty Liver Disease / psychology
  • Receptor, Insulin / drug effects*
  • Succinates / pharmacology*
  • Succinylcholine
  • Toll-Like Receptor 4 / drug effects*
  • Triglycerides / metabolism
  • Up-Regulation / drug effects


  • Succinates
  • Toll-Like Receptor 4
  • Triglycerides
  • Cholesterol
  • Receptor, Insulin
  • Succinylcholine
  • Choline