Geraniol, alone and in combination with pioglitazone, ameliorates fructose-induced metabolic syndrome in rats via the modulation of both inflammatory and oxidative stress status.

Geraniol (GO) potent antitumor and chemopreventive effects are attributed to its antioxidant and anti-inflammatory properties. In the current study, the potential efficacy of GO (250 mg/kg) in ameliorating metabolic syndrome (MetS) induced by fructose in drinking water was elucidated. Moreover, the effect of pioglitazone (5 and 10 mg/kg; PIO) and the possible interaction of the co-treatment of GO with PIO5 were studied in the MetS model. After 4 weeks of treatment, GO and/or PIO reduced the fasting blood glucose and the glycemic excursion in the intraperitoneal glucose tolerance test. GO and PIO5/10 restrained visceral adiposity and partly the body weight gain. The decreased level of peroxisome proliferator activated receptor (PPAR)-γ transcriptional activity in the visceral adipose tissue of MetS rats was increased by single treatment regimens. Though GO did not affect MetS-induced hyperinsulinemia, PIO5/10 lowered it. Additionally, GO and PIO5/10 suppressed glycated hemoglobin and the receptor for advanced glycated end products (RAGE). These single regimens also ameliorated hyperuricemia, the disrupted lipid profile, and the elevated systolic blood pressure evoked by MetS. The rise in serum transaminases, interleukin-1β, and tumor necrosis factor-α, as well as hepatic lipid peroxides and nitric oxide (NO) was lowered by the single treatments to different extents. Moreover, hepatic non-protein thiols, as well as serum NO and adiponectin were enhanced by single regimens. Similar effects were reached by the combination of GO with PIO5; however, a potentiative interaction was noted on fasting serum insulin level, while synergistic effects were reflected as improved insulin sensitivity, as well as reduced RAGE and triglycerides. Therefore, GO via the transcriptional activation of PPAR-γ reduces inflammation and free radical injury produced by MetS. Thereby, these effects provide novel mechanistic insights on GO management of MetS associated critical risk factors. Moreover, the co-administration of GO to PIO5 exalted the antidiabetic drug anti-MetS efficacy

Effect of 4 weeks daily oral administration of geraniol (GO; 250 mg/kg), pioglitazone (PIO; 5 and 10 mg/kg), and GO with PIO5 on serum alanine amino transferase (ALT) and aspartate amino transferase (AST) levels in fructose-induced metabolic syndrome (MetS) in rats.

<p>Effect of 4 weeks daily oral administration of geraniol (GO; 250 mg/kg), pioglitazone (PIO; 5 and 10 mg/kg), and GO with PIO5 on serum alanine amino transferase (ALT) and aspartate amino transferase (AST) levels in fructose-induced metabolic syndrome (MetS) in rats.</p

Effect of 4 weeks daily oral administration of geraniol (GO; 250 mg/kg), pioglitazone (PIO; 5 and10 mg/kg), and GO with PIO5 on serum (a) interleukin (IL)-1β, (b) tumor necrosis factor (TNF)-α, and (c) adiponectin levels in fructose-induced metabolic syndrome (MetS) in rats. Values are mean (6–8 animals) ± SEM. <i>P</i>< 0.05, as compared to control (CONT) (*) and MetS (^#) groups using one-way ANOVA followed by Tukey–Kramer test.

<p>Effect of 4 weeks daily oral administration of geraniol (GO; 250 mg/kg), pioglitazone (PIO; 5 and10 mg/kg), and GO with PIO5 on serum (a) interleukin (IL)-1β, (b) tumor necrosis factor (TNF)-α, and (c) adiponectin levels in fructose-induced metabolic syndrome (MetS) in rats. Values are mean (6–8 animals) ± SEM. <i>P</i>< 0.05, as compared to control (CONT) (*) and MetS (^#) groups using one-way ANOVA followed by Tukey–Kramer test.</p

Effect of 4 weeks daily oral administration of geraniol (GO; 250 mg/kg), pioglitazone (PIO; 5 and10 mg/kg), and GO with PIO5 on plasma (a) glycated haemoglobin (HbA1c) and (b) receptor for advanced glycated end product (RAGE) in fructose-induced metabolic syndrome (MetS) in rats.

<p>Values are mean (6–8 animals) ± SEM. <i>P</i>< 0.05, as compared to control (CONT) (*) and MetS (^#) groups using one-way ANOVA followed by Tukey–Kramer test. Significant potentiative and synergistic interactions (^o) when GO and PIO5 were combined using the factorial design test.</p

Effect of 4 weeks daily oral administration of geraniol (GO; 250 mg/kg), pioglitazone (PIO; 5 and10 mg/kg), and GO with PIO5 on hepatic (a) thiobarbituric acid reactive substance and (b) non protein thiols (NPSH), as well as hepatic (c) and serum (d) nitric oxide (NO) levels in fructose-induced metabolic syndrome (MetS) in rats. Values are mean (6–8 animals) ± SEM. <i>P</i>< 0.05, as compared to control (CONT) (*) and MetS (^#) groups using one-way ANOVA followed by Tukey–Kramer test.

<p>Effect of 4 weeks daily oral administration of geraniol (GO; 250 mg/kg), pioglitazone (PIO; 5 and10 mg/kg), and GO with PIO5 on hepatic (a) thiobarbituric acid reactive substance and (b) non protein thiols (NPSH), as well as hepatic (c) and serum (d) nitric oxide (NO) levels in fructose-induced metabolic syndrome (MetS) in rats. Values are mean (6–8 animals) ± SEM. <i>P</i>< 0.05, as compared to control (CONT) (*) and MetS (^#) groups using one-way ANOVA followed by Tukey–Kramer test.</p

Adult male Wistar rats (45 days; 170±20 g) were randomly divided into 2 experimental subsets, namely, control group (free access to water for 16 weeks then vehicle for 4 weeks) or metabolic syndrome (MetS; 10% fructose solution in drinking water for 16 weeks) subset.

<p>After 16 weeks, all animals were exposed to the intraperitoneal glucose tolerance test (IPGTT) after an overnight fast; and MetS was verified in the fructose fed rats. In the MetS experimental subset, rats were subdivided into MetS (1% Tween 80; 4 weeks; p.o), geraniol (GO; 250 mg/kg/day; 4 weeks; p.o); pioglitazone (PIO; 5 and 10 mg/kg/day; 4 weeks; p.o), and GO/PIO5 groups. These animals were further supplied with 10% fructose solution in drinking water for 4 weeks. Insulin resistance was tested using IPGTT 24 h after last treatments or vehicle administration and after an overnight fast in all groups. Body weight was recorded at baseline and after 20 weeks of the beginning of the experiments. Blood was collected and then rats were euthanized to dissect the liver and visceral fat for different assessments.</p

Effect of 4 weeks daily oral administration of geraniol (GO; 250 mg/kg), pioglitazone (PIO; 5 and10 mg/kg), and GO with PIO5 on (a) systolic blood pressure and (b) serum uric acid level in fructose-induced metabolic syndrome (MetS) in rats.

<p>Values are mean (6–8 animals) ± SEM. <i>P</i>< 0.05, as compared to control (CONT) (*) and MetS (^#) groups using one-way ANOVA followed by Tukey–Kramer test.</p

Effect of 4 weeks daily oral administration of geraniol (GO; 250 mg/kg), pioglitazone (PIO; 5 and 10 mg/kg), and GO with PIO5 on serum total cholesterol (TC), triglycerides (TGs), very low density lipoprotein-triglycerides (VLDL-TG), low density lipoprotein-cholesterol (LDL-C), and high density lipoprotein-cholesterol (HDL-C) in fructose-induced metabolic syndrome (MetS) in rats.

<p>Effect of 4 weeks daily oral administration of geraniol (GO; 250 mg/kg), pioglitazone (PIO; 5 and 10 mg/kg), and GO with PIO5 on serum total cholesterol (TC), triglycerides (TGs), very low density lipoprotein-triglycerides (VLDL-TG), low density lipoprotein-cholesterol (LDL-C), and high density lipoprotein-cholesterol (HDL-C) in fructose-induced metabolic syndrome (MetS) in rats.</p

Effect of 4 weeks daily oral administration of geraniol (GO; 250 mg/kg), pioglitazone (PIO; 5 and10 mg/kg), and GO with PIO5 on (a) body weight gain, (b) visceral index, and (c) adipose PPAR-γ transcriptional activity in fructose-induced metabolic syndrome (MetS) in rats.

<p>Values are mean (6–8 animals) ± SEM. <i>P</i>< 0.05, as compared to control (CONT) (*) and MetS (^#) groups using one-way ANOVA followed by Tukey–Kramer test.</p