Hepatic energy parameters in male Wistar rats after three weeks of treatment.

<p>(A) Energy charge (ATP + 0.5 ADP)/(AMP + ADP + ATP). (B) Ratio of AMP and ATP. Values are shown as mean ± SD (n = 6–8). One-Way ANOVA with p<0.05 was followed by Fisher LSD to determine significant difference between all three groups: Different letters above bars indicate significant difference between group mean values, p<0.05; same letters above bars indicate no significant difference between group mean values p>0.05. C–Control, M–Mildronate (550 mg/kg body weight), MT–combination of Mildronate (550 mg/kg body weight) and 1-triple TTA (100 mg/ kg body weight).</p

Hepatic gene expression in Wistar male rats after three weeks of treatment.

<p>Hepatic gene expression in Wistar male rats after three weeks of treatment.</p

Hepatic enzyme activities involved in lipid anabolism in male Wistar rats after three weeks of treatment.

<p>(A) Enzyme activity of acetyl-CoA carboxylase (ACC). (B) Enzyme activity of fatty acid synthase (FAS). (C) Enzyme activity of citrate-ATP lyase. (D) Enzyme activity of glycerol-3-phosphate transferase (GPAT). Values are shown as mean± SD (n = 6–8). One-Way ANOVA with p<0.05 was followed by Fisher LSD to determine significant difference between all three groups: Different letters above bars indicate significant difference between group mean values, p<0.05; same letters above bars indicate no significant difference between group mean values p>0.05. C–Control, M–Mildronate (550 mg/kg body weight), MT–combination of Mildronate (550 mg/kg body weight) and 1-triple TTA (100 mg/ kg body weight).</p

Hepatic β-oxidation and enzyme activities involved in lipid catabolism in male Wistar rats after three weeks of treatment.

<p>(A) Total β-oxidation of palmitoyl-CoA in liver; (B) Total β-oxidation of palmitoyl-CoA with addition of malonyl-CoA in liver; (C) Enzyme activity of acyl-CoA synthetase; (D) Enzyme activity of carnitine palmitoyltransferase (CPT) 2; (E) Enzyme activity of 3-ketothiolase; (F) Enzyme activity of malonyl-CoA decarboxylase (MCD); (G) Enzyme activity of acyl-CoA oxidase (ACOX); (H) Enzyme activity of citrate synthase. Values are shown as means ± SD (n = 6–8). One-Way ANOVA with p<0.05 was followed by Fisher LSD to determine significant difference between all three groups: Different letters above bars indicate significant difference between group mean values, p<0.05; same letters above bars indicate no significant difference between group mean values p>0.05. C–Control, M–Mildronate (550 mg/kg body weight), MT–combination of Mildronate (550 mg/kg body weight) and 1-triple TTA (100 mg/ kg body weight).</p

Plasma and liver lipids in male Wistar rats after three weeks of treatment.

<p>Plasma and liver lipids in male Wistar rats after three weeks of treatment.</p

Plasma levels of carnitine derivatives and carnitine precursors in male Wistar rats after three weeks of treatment.

<p><b>A.</b> Plasma L-carnitine; <b>B.</b> Plasma acetylcarnitine; <b>C.</b> Plasma γ-butyrobetaine; <b>D.</b> Plasma trimethyllysine; <b>E.</b> Protein expression of carnitine translocase (CACT). Values are shown as mean ± SD (n = 6–8). One-Way ANOVA with p<0.05 was followed by Fisher LSD to determine significant difference between all three groups. Different letters above bars indicate significant difference between group mean values, p<0.05; same letters above bars indicate no significant difference between group mean values p>0.05. C–Control, M–Mildronate (550 mg/kg body weight), MT–combination of Mildronate (550 mg/kg body weight) and 1-triple TTA (100 mg/ kg body weight).</p

Selected genes with drug exposure-related, differential expression in liver in the subchronic experiment.

<p>Data are given as fold change relative to vehicle, and presented as mean±SEM. Data shown are normalised to P0 (Arbp), with comparable results when normalised to β-actin.</p>*<p>P≤0.05 vs vehicle.</p>**<p>P≤0.01 vs vehicle.</p>***<p>P≤0.001 vs vehicle. Subchronic data for the VEH, OLZ, and APZ groups have been reported in a previous article <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0050853#pone.0050853-Skrede1" target="_blank">[23]</a>. Gene abbreviations: <i>Scd1</i>; stearoyl-CoA desaturase. <i>Fasn</i>; fatty acid synthase. <i>Srebp1</i>; sterol regulatory element binding protein 1, <i>Srebp2</i>; sterol regulatory element binding protein 2. <i>Hmgcr</i>; 3-hydroxy-3-methylglutaryl-CoA reductase. <i>Ppara</i>: peroxisome proliferator activated receptor α, <i>Pparg</i>: peroxisome proliferator activated receptor γ. <i>Cpt2</i>: carnitine O-palmitoyltransferase 2. <i>Acox1</i>: acyl-Coenzyme A oxidase 1.</p

Serum levels of antipsychotic agents.

<p>Fasting serum levels of antipsychotic agents, given in nM, after 2 or 8 weeks of treatment, respectively.</p

Fasting lipids in serum and liver at 8 weeks.

<p>Serum and liver lipids after chronic treatment with vehicle (VEH), olanzapine (OLZ), clozapine (CLZ), tetradecylthioacetic acid (TTA), or a combination of OLZ/CLZ+TTA. * P≤0.05, ** P≤0.01, *** P≤0.001.</p

Relevant genes examined in brown adipose tissue (BAT) in the chronic study.

<p>Data are given as fold change relative to vehicle, and presented as mean±SEM. Data shown are normalised to P0 (<i>Arbp</i>), with comparable results when normalised to <i>β-actin</i>.</p>*<p>P≤0.05 vs vehicle.</p>**<p>P≤0.01 vs vehicle.</p>***<p>P≤0.001 vs vehicle.</p