Antiobesity and antihyperglycemic effects of ginsenoside Rb1 in rats

Abstract

Objective: Obesity and type 2 diabetes are national and worldwide epidemics. Because currently available antiobesity and antidiabetic drugs have limited efficacy and/or safety concerns, identifying new medicinal agents, such as ginsenoside Rb1 (Rb1) as reported here, offers exciting possibilities for future development of successful antiobesity and antidiabetic therapies.

Research design and methods: Changes in feeding behavior after acute intraperitoneal administration of Rb1 and the effects of intraperitoneal Rb1 for 4 weeks on body weight, energy expenditure, and glucose tolerance in high-fat diet (HFD)-induced obese rats were assessed. We also examined the effects of Rb1 on signaling pathways and neuropeptides in the hypothalamus.

Results: Acute intraperitoneal Rb1 dose-dependently suppressed food intake without eliciting signs of toxicity. This inhibitory effect on feeding may be mediated by central mechanisms because Rb1 stimulated c-Fos expression in brain areas involved in energy homeostasis. Consistent with this, Rb1 activated the phosphatidylinositol 3-kinase/Akt signaling pathway and inhibited NPY gene expression in the hypothalamus. Four-week administration of Rb1 significantly reduced food intake, body weight gain, and body fat content and increased energy expenditure in HFD-induced obese rats. Rb1 also significantly decreased fasting blood glucose and improved glucose tolerance, and these effects were greater than those observed in pair-fed rats, suggesting that although Rb1's antihyperglycemic effect is partially attributable to reduced food intake and body weight; there may be additional effects of Rb1 on glucose homeostasis.

Conclusions: These results identify Rb1 as an antiobesity and antihyperglycemic agent.

FIG. 1.

Intraperitoneal administration of Rb1 dose-dependently reduced food intake in ad libitum–fed rats (A). In 24-h–fasted rats, Rb1 (10 mg/kg i.p.) significantly reduced food intake (B). No significant differences in food intake (C and D) or body weight change (E) were found in either ad libitum–fed or fasted rats after Rb1 treatment. Intraperitoneal administered LiCl, but not Rb1 (40 mg/kg i.p.), caused a conditioned taste aversion assessment in rats (F). Values are expressed as means ± SE; n = 6–8. *P < 0.05, **P < 0.01 vs. saline controls.

FIG. 2.

Rb1 (10 mg/kg i.p.) significantly increased c-Fos expression in the cells of NTS, VMH, and ARC, but not LH, areas. A–H: Images of representative brain microsections. I: Fos-like immunoreactivity counts (mean ± SE) in difference brain sections; n = 4–5, *P < 0.05, **P < 0.01 vs. saline controls. 3V, third ventricle; cc, central canal; opt, optic tract.

FIG. 3.

Chronic treatment of Rb1 in HFD-induced obese rats significantly reduced food intake (A), reduced body weight gain (B), and increased energy expenditure (C), especially during the dark phase (D), when compared with saline administration. Food intake after Rb1 treatment was significantly reduced compared with that after saline treatment since day 2, and the changes of body weight in Rb1-treated rats were significantly lower than that in saline controls since day 8. Rb1-treated rats also had significantly less body weight gain versus rats under pair-feeding since day 21. In addition, caloric restriction also has elevated energy expenditure, but the difference between saline and pair-fed group is not as prominent as the saline and Rb1 group. Data are means ± SE; n = 12. *P < 0.05, **P < 0.01 vs. saline controls; &P < 0.05, Rb1-treated vs. pair-fed rats.

FIG. 4.

Effect of chronic administration of Rb1 on body fat and plasma leptin levels in HFD-induced obese rats. Whole body weight (A and B); visceral fat tissues, including epididymal, retroperitoneal, and mesenteric fat; and inguinal fat were significantly decreased after Rb1 treatment (C). D and E: Photos of epididymal and mesenteric fat in rats treated with Rb1 or saline. F: Hematoxylin and eosin staining of epididymal and inguinal fat tissues. The size of adipocytes was calculated and represented by total adipocyte area (n = 6). Rb1 treatment resulted in reduced average adipocyte size (G). Rb1 decreased plasma leptin (H). *P < 0.05; **P < 0.01 vs. saline controls. (A high-quality digital representation of this figure is available in the online issue.)

FIG. 5.

Rb1 reduced fasting blood glucose and improved glucose tolerance in HFD-induced obese rats. A: Basal hyperglycemia was significantly reduced in Rb1-treated obese rats, compared with both saline controls and pair-fed rats. B: After intraperitoneal administration of glucose (1 g/kg), the glucose incremental area under the curve was significantly lower in the Rb1 group than in the saline group. C and D: Rb1 treatment also reduced fasting insulin level and the insulin AUC after intraperitoneal glucose. Data are means ± SE; n = 12. *P < 0.05; **P < 0.01 vs. the saline group; #P < 0.05; ##P < 0.01 vs. the pair-fed group.

FIG. 6.

Effects of Rb1 on phosphorylation of Akt in cultured primary hypothalamic neurons and in the hypothalamus of HFD-induced obese rats. A: Cells were treated with different concentrations of Rb1. B: Cells were treated with Rb1 (10 μmol/l) for the indicated times. n = 3–4. C: Hypothalamic tissues were dissected from HFD-induced obese rats. D and E: Effect of chronic Rb1 treatment on neuropeptide gene expression in HFD-induced obese rats. n = 6–7. Data are means ± SE. *P < 0.05 vs. before treatment (in vitro) or saline controls (in vivo); &P < 0.05 vs. pair-fed rats.