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

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 (TIr4). Here, we investigated whether dicholine succinate (DS), an insulin receptor sensitizer and mitochondrial complex II substrate would interact with these effects. Methods: C57BL/6 J 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-lb (PPARGClb) expression. Results: 50 mg/kg DS treatment for 3 weeks partially ameliorated the cholesterol-induced anxiety- and depressive-like changes. Mice were next treated at the higher dose (180 mg/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 0-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 PPARGC1 b, 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.