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, 21 (3), 1059-1070

Ginsenosides Reduce Body Weight and Ameliorate Hepatic Steatosis in High Fat Diet‑induced Obese Mice via Endoplasmic Reticulum Stress and p‑STAT3/STAT3 Signaling

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Ginsenosides Reduce Body Weight and Ameliorate Hepatic Steatosis in High Fat Diet‑induced Obese Mice via Endoplasmic Reticulum Stress and p‑STAT3/STAT3 Signaling

Yin Yao. Mol Med Rep.

Abstract

Obesity has been increasing globally for over three decades. According to previous studies, dietary obesity is usually associated with endoplasmic reticulum stress (ERS) and STAT3 signaling, which result in interference with the homeostatic control of energy and lipid metabolism. Ginsenosides (GS) administered to mice will modulate adiposity and food intake; however, the mechanism of food inhibition is unknown. The aim of the present study was to investigate whether GS may inhibit ERS and regulate STAT3 phosphorylation in GT1‑7 cells (a mouse hypothalamus gonadotropin‑releasing hormone neuron cell line) and the hypothalamus in order to reduce the body weight and ameliorate hepatic steatosis in high fat diet (HFD)‑induced obese mice. In the present study, GS inhibited the appetite, reduced the body weight, visceral fat, body fat content and blood glucose, and ameliorated the glucose tolerance of the obese mice compared with HFD mice. In addition, the levels of aspartate aminotransferase and alanine aminotransferase, triglyceride (TG), leptin and insulin in the serum were reduced compared with HFD mice. There was less TG in the liver, but more in the feces compared with HFD mice. Using hematoxylin and eosin staining of HepG2 cells and liver tissues, GS were demonstrated to improve the non‑alcoholic fatty liver of the HFD‑induced obese mice and reduce the diameter of the fat cells compared with HFD mice. GS also increased oxygen consumption and carbon dioxide emissions in the metabolic cage data compared with HFD mice. In the GT1‑7 cells, GS alleviated the ERS induced by tunicamycin and enhanced the activation of the STAT3 phosphorylation pathway. Furthermore the ERS of the liver was relieved to achieve the aforementioned pharmacological effects. GS were used in the homeostatic control of the energy and lipid metabolism of a diet‑induced obesity model. In conclusion, present studies suggest that GS exert these effects by increasing STAT3 phosphorylation expression and reducing the ERS. Thus, GS reduce body weight and ameliorate hepatic steatosis in HFD‑induced obese mice.

Figures

Figure 1.
Figure 1.
GS administration reduces food intake and reverses the obesity induced by a HFD. (A) Body weight n=5 per group. (B) Percentage reduction in body weight. (C) Food intake of the HFD-fed mice during the four weeks of treatment. The mice were subjected to a 4-weeks treatment of standard chow, HFD or GS (120 mg/kg; daily, intraperitoneal injection). (D) Hemoxylin and eosin staining of the adipose tissue. (E) Relative area of the adipocytes. (F) Lean weight. (G) Lean percentage of body weight. (H) Fat weight. (I) Fat percentage of body weight. The HFD-fed mice were analyzed with by magnetic resonance imaging following 3 weeks of treatment. (J) Liver weight. (K) Abdominal, (L) perirenal and (M) epididymis adipose tissues. Error bars present the mean ± standard error of the mean. P-values were determined by one-way ANOVA. *P<0.05 and **P<0.01 vs. HFD group; #P<0.05 and ##P<0.01 vs. CHOW group; n=5 for all groups. GS, ginsenosides; HFD, high-fat diet; CHOW, mice administered a standard chow diet.
Figure 2.
Figure 2.
GS increases glucose tolerance, reduces insulin resistance and reduces blood leptin and insulin levels in HFD-fed mice. (A) Glucose tolerance test. The mice were fasted for 12 h and the tail vein blood was used to measure the blood glucose levels. (B) Insulin tolerance test. (C) Serum leptin. (D) Serum insulin. Error bars represent the mean ± standard error of the mean. P-values were determined using one-way ANOVA. **P<0.01 vs. HFD group; ##P<0.01 vs. CHOW group; n=5 for all groups. GS, ginsenosides; HFD, high-fat diet; CHOW, mice administered a standard chow diet; IPGTT, intraperitoneal glucose tolerance test; ITT, insulin tolerance test.
Figure 3.
Figure 3.
GS improve the lipid metabolism of HFD-fed mice. (A) Serum ALT, (B) serum AST, (C) serum TG, (D) serum TC, (E) serum HDL-c, (F) serum LDL-c, (G) liver TG levels and (H) feces TG levels. Error bars present the mean ± standard error of the mean. P-values were determined by one-way ANOVA. *P<0.05 and **P<0.01. vs. HFD group; #P<0.05 and ##P<0.01 vs. CHOW group; n=5 for all groups. GS, ginsenosides; HFD, high-fat diet; CHOW, mice administered a standard chow diet; ALT, alanine aminotransferase; AST, aspartate aminotransferase; TG, triglyceride; TC, total cholesterol; HDL-c, high-density lipoprotein cholesterol; LDL-c, low-density lipoprotein cholesterol; NS, no significance.
Figure 4.
Figure 4.
GS alleviates lipid droplet accumulation in vivo and in vitro. (A) Oil red O staining of HepG2 cells (magnification, ×400). (B) Hemoxylin and eosin and (C) oil red O staining of liver sections (magnification, ×200). Scoring of (D) inflammation injury, (E) steatosis injury and (F) ballooning injury. (G) Lipid accumulation in HepG2 cells. Error bars present the mean ± standard error of the mean. P-values were determined by a one-way ANOVA. Scale bars, 25 or 50 µm. *P<0.05, vs. HFD group (D-F); *P<0.05 vs. PA + OA group (G); n=5 for all groups. GS, ginsenosides; HFD, high-fat diet; CHOW, mice administered a standard chow diet; PA, palmitic acid; OA, oleic acid.
Figure 5.
Figure 5.
Effect of GS on metabolic measures. (A) Oxygen consumption. (B) Carbon dioxide elimination. (C) RER. (D) Ambulatory count (physical activity). Error bars present the mean ± standard error of the mean. P-values were determined by a one-way ANOVA. *P<0.05, **P<0.01 vs. HFD group; n=5 for all groups. NS, no significance; GS ginsenoside; HFD, high-fat diet; RER, respiratory exchange ratio; VCO2, carbon dioxide consumption; VO2, oxygen consumption.
Figure 6.
Figure 6.
Effect of GS on p-STAT3/STAT3 and ERS. Following treatment for 24 h (ERS)/12 h (p-STAT3/STAT3), western blotting was performed to determine the relative expression of ERS-associated proteins. (A) Expression of GRP78, CHOP, total PERK and p-PERK in GT1-7 cells treated with 5 µg/ml TM, 5 µg/ml TM + 25 µg GS, 5 µg/ml TM + 50 µg GS, 5 µg/ml TM + 100 µg GS or 5 µg/ml TM + 200 µg GS. *P<0.05 vs. TM. (B) Expression of GRP78, CHOP and ATF4 in the liver. *P<0.05 vs. HFD group. (C) Expression of p-STAT3 and total STAT3 in GT1-7 cells treated with GS (12.5, 25, 50, 100 and 200 µg). *P<0.05 vs. 0 µg. (D) Expression of p-STAT3 and total STAT3 in the hypothalamus. **P<0.01 vs. HFD group. GS, ginsenosides; HFD, high-fat diet; CHOW, mice administered a standard chow diet; STAT3, signal transducer and activator of transcription 3; p-, phosphorylated; ERS, endoplasmic reticulum stress; GRP78, glucose regulation protein 78; CHOP, C/EBP homologous protein; PERK, protein kinase-like endoplasmic reticulum kinase; ATF4, activating transcription factor 4; TM, tunicamycin.

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