Skip to main content
NCBI home page
Saudi Pharmaceutical Journal : SPJ logoLink to Saudi Pharmaceutical Journal : SPJ
. 2023 Jan 13;31(3):351–358. doi: 10.1016/j.jsps.2023.01.003

6-gingerol ameliorates weight gain and insulin resistance in metabolic syndrome rats by regulating adipocytokines

Shirly Gunawan a,b, Eka Munika c, Endah Tri Wulandari c, Frans Ferdinal d, Erni H Purwaningsih e, Puspita Eka Wuyung f,g, Melva Louisa h, Vivian Soetikno h,⁎
PMCID: PMC10071327  PMID: 37026043

Abstract

Metabolic syndrome (MetS) can lead to increase of insulin resistance (IR) and visceral adipose tissue production of adipocytokines. 6-gingerol is known to have antioxidant and anti-inflammatory activities. Aim of this study is to investigate the effects of 6-gingerol on high-fat high-fructose (HFHF) diet-induced weight gain and IR in rats through modulation of adipocytokines. To induce MetS, male Sprague-Dawley rats were fed with a HFHF diet for 16 weeks and at Week 8, single-dose low-dose streptozotocin (22 mg/kg) were intraperitoneally injected. After 8 weeks of HFHF diet feeding, the rats were treated orally with 6-gingerol (50, 100, and 200 mg/kg/day) once daily for 8 weeks. At the end of the study, all animals were terminated, serum, liver, and visceral adipose tissues were harvested for biochemical analysis including the measurements of total cholesterol, triglycerides, HDL-cholesterol, fasting plasma glucose, insulin, leptin, adiponectin, proinflammatory cytokines (TNF-α and IL-6) and liver and adipose tissue histopathology. Biochemical parameters namely serum total cholesterol (243.7 ± 127.6 vs 72.6 ± 3 mg/dL), triglycerides (469.2 ± 164.9 vs 49.3 ± 6.3 mg/dL), fasting plasma glucose (334 ± 49.5 vs 121 ± 8.5 mg/dL), HOMA-IR (0.70 ± 0.24 vs 0.32 ± 0.06), and leptin (6.19 ± 1.24 vs 3.45 ± 0.33 ng/mL) were significantly enhanced, whereas HDL-cholesterol (26.2 ± 5.2 vs 27.9 ± 1.1 mg/dL) and adiponectin level (14.4 ± 5.5 vs 52.8 ± 10.7 ng/mL) were lowered in MetS vs normal control. Moreover, MetS were marked a significant increase in body weight and proinflammatory cytokines. Treatment with 6-gingerol dose-dependently restored all of those alterations towards normal values as well as the accumulation of lipid in liver and adipose tissues. These findings demonstrate that 6-gingerol, in a dose-dependent mode, showed capability of improving weight gain and IR in MetS rats through modulation of adipocytokines.

Keywords: Adiponectin, Diabetes mellitus type 2, Ginger, Lipidemia, Diet

1. Introduction

Metabolic syndrome (MetS) is one of the leading global health issue. It is a cluster of metabolic abnormalities that includes hypertension, central obesity, insulin resistance (IR), and dyslipidemia (Grundy et al., 2004, Alberti et al., 2009). MetS could be considered as a systemic disease since its pathology involves the interplay of multiple organs, including adipose tissue, an important organ which plays a crucial role in the pathogenesis of MetS (Chait and den Hartigh, 2020, Cheng and Yu, 2022, Jung and Choi, 2014). Adipose tissue was initially classified as an energy storage organ, but today, it is known to function as a major endocrine system that secretes adipocytokines or adipokines, growth factors, cytokines, and chemokines (Chait and den Hartigh, 2020). Adipocytokines secreted by the adipose tissue plays a critical role in storage, food intake, energy expenditure, lipid and glucose metabolism (Albaraccin and Torres, 2020). Alterations in the levels of adipocytokines are associated with the risk of obesity, IR, and type 2 diabetes mellitus (T2DM). In obesity, the adipocytes are dysfunctional with excessive secretion of multiple pro-inflammatory adipocytokines, contributing to a chronic inflammatory reaction and promote the progression of MetS complications (Lopez-Jaramillo et al., 2014). Two major adipocytokines, leptin and adiponectin, are thought to play important roles in the regulation of metabolic homeostasis. Leptin is a 16-kDa protein hormone, which is primarily involved in regulating food intake, body weight and energy homeostasis through neuroendocrine functions (Kim et al., 2022). Some research suggests that leptin also influences insulin sensitivity and lipid metabolism. High leptin concentrations are directly associated with the obesity subsequent development of metabolic disease sequelae such as IR and type 2 diabetes (Ghadge and Khaire, 2019). Adiponectin is an adipose tissue specific cytokine which regulates glucose and lipid metabolism by targeting the liver and skeletal muscle. It has a protective role against IR and anti-inflammatory activity and seems to protect against metabolic diseases (von Frankenberg et al., 2017). Previous studies have shown that leptin upregulates proinflammatory cytokines such as TNF-α and IL-6 whereas, adiponectin has anti-inflammatory properties and downregulates the expression and release of a number of proinflammatory immune mediators (Cheng and Yu, 2022).

Many pharmacological treatments are available for treating metabolic disorders, while present drugs pose many adverse effects with prolonged use. Natural products have always maintain as a valuable source for the discovery of new drugs. Zingiber officinale ROSCOE (family Zingiberaceae) is one of the plants with medicinal potencial (Mao et al., 2019). 6-gingerols, a major bioactive component of ginger, has been found to possess a variety of interesting pharmacological effects, for example, antioxidant activity, antiinflammatory effects, anti-obese activity, antidiabetic activity, and cardioprotective effects (Mao et al., 2019, Choy et al., 2018, Rahimlou et al., 2019). Tzeng et al., have demonstrated that 6-gingerol has a protective effect on ameliorating nutritional steatohepatitis in mice by inducing PPARα expression (Tzeng et al., 2015a, Tzeng et al., 2015b). Moreover, 6-gingerol has also capability to lower plasma fasting glucose, LDL-cholesterol, TG, aspartate aminotransferase, and alanine aminotransferase in rat model of non-alcoholic fatty liver disease (Sarrafan et al., 2021). Knowing the beneficial effects of 6-gingerol holding anti-inflammatory as well as other healing effects, the therapeutic properties of 6-gingerol in ameliorating IR and to overcome weight gain were evaluated in the present study in high-fat high-fructose (HFHF)-induced MetS rat model.

2. Materials and methods

2.1. Reagents

Commercially available purified 6-gingerol was obtained from Actin Chemicals®, Chengdu, China. Streptozotocin (CAS 18883-66-4) was obtained from Santa Cruz Biotechnology, Texas, USA. ELISA kits for the assay of inflammation, namely rat TNF-α (E-EL-R2856) and rat IL-6 (E-EL-R0015) were procured from Elabscience Biotechnology Inc, Houston, Texas, USA. ELISA kits for the assay of rat insulin (E-EL-R3034), rat leptin (E-EL-R0582), and rat adiponectin (E-EL-R3012) were also purchased from Elabscience Biotechnology Inc, Houston, Texas, USA. High purity grade of all supplementary chemicals used in this study were obtained from commercial sources.

2.2. Animal models

Eight-week-old healthy male Sprague-Dawley rats weighing 180–220 g were procured from the National Agency of Drug and Food Control, Jakarta, Indonesia. The animals were housed in plastic cages with a top grill, according to the Animal Research Facility in our institution standards, in a controlled environment with 65–75 % relative humidity and a 12: 12 light–dark cycle. Body weight and food intake were measured every week and every day, respectively during the study period. To calculate daily food intake, the amount of food given each day (25 g/rat) is subtracted by the leftovers the next day. All laboratory animal procedures were conducted per the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. This study was approved by the Institutional Animal Care and Use Committee of Universitas Indonesia (approval number: KET-945/UN2.F1/ETIK/PPM.00.02/2021).

2.3. Experimental design

The rats were divided into five groups, with five animals per group. Group 1 is the healthy control group that was fed a standard commercial diet (ND) contains 304 kcal/100 g with 4 % fat, 20 % protein, 47 % carbohydrate, 12 % water, and 17 % mineral. The other four groups (Group 2 – 5) received HFHF diets contains 474 kcal/100 g with 29.02 % fat, 21.31 % protein, 31.92 % carbohydrate, 12.60 % water, and 5.15 % ash from University of Brawijaya Laboratory, Malang, Indonesia during the study, namely for 16 weeks. After consuming a HFHF diet for 8 weeks, rats in Group 3 – 5 were administered 6-gingerol by oral gavage once daily at doses of 50 (Group 3: 6-G 50), 100 (Group 4: 6-G 100), and 200 (Group 5: 6-G 200) mg/kg in 1.5 mL/kg of corn oil for another 8 weeks. The dose of 6-gingerol was obtained from a previous study in HFD/STZ-induced diabetic rats and toxicity study (Song et al., 2019, Benny et al., 2021). At Week 8, Group 2 – 5 were induced with a single intraperitoneal dose of streptozotocin (STZ) at a dose of 22 mg/kgBW. At the end of the study (16 weeks), all rats were weighed, fasted for 12 h, anesthetized with ketamine, and sacrificed by exsanguination. Blood from the ventricle were collected for analysis, after which the adipose tissue, which collected from the abdomen and the liver were taken for analysis.

2.4. Biochemical evaluations

Fasting serum glucose was measured using Autocheck® Glucare glucometer (Medical Technology Promedr, St. Ingbert, Germany). The homeostasis model assessment for insulin resistance (HOMA-IR) was calculated as an indicator of IR, according to the formula HOMA-IR = fasting serum glucose (mg/dL) × fasting serum insulin (IU/mL)/ 405 (Wallace et al. 2004). Total serum cholesterol (TC), high-density lipoprotein (HDL) cholesterol, and triglycerides (TG) were measured using the colorimetric method (DiaSys Diagnosis Systems GmbH, Holzheim, Germany). The absorbance of the coloured solution was measured at 546 nm.

2.5. Measurements of serum and liver and adipose tissues proinflammatory cytokines

TNF-α and IL-6 levels were measured in duplicate using commercially available rat ELISA kits from Elabscience Biotechnology Inc, Houston, Texas, USA according to the manufactures protocol and results were interpreted accordingly.

2.6. Measurements of adipocytokines

Adipocytokines namely adipokine and leptin in the serum and adipose tissues of experimental group rats were determined by assaying in ELISA reader in duplicate, and the results were interpreted accordingly.

2.7. Histopathological assessment of liver and adipose tissues

The samples of the liver and adipose tissue were preserved in 10 % neutral buffer formalin solution followed by tissue dehydration with alcohol and xylene. Each sample was then embedded in paraffin wax, sectioned at 5 μm, and mounted on slides prior to staining. Hematoxylin and eosin (HE) stains were used. The slides were observed under the light microscope, and the observations were recorded using 10x and 40x lenses. The size of fat cells was calculated using ImageJ software (Media Cybernetics, Maryland, USA).

2.8. Oil Red O staining

Frozen liver sections (10 μm) were fixed in 10 % formaldehyde for 10 min. To measure lipid accumulation, slides containing the cryosections were washed in water, immersed in 60 % isopropanol for 5 min, followed by incubated in 0.5 % Oil Red O working solution (Sigma-Aldrich MAK194) for 30 min at room temperature. Slides washed in distilled water for 5 min and then incubate in Hematoxylin for 1 min. The slides were washed with distilled water for 3 times and then mounted in aqueous mounting medium.

2.9. Statistical analysis

All the results were expressed as the mean ± SD of five animals in each group. All the grouped data were statistically evaluated with SPSS ver. 21. Hypothesis testing methods included one-way ANOVA followed by Tukey’s multiple comparison post-test. Significance level at P < 0.05, was considered to indicate statistical significance difference.

3. Results

3.1. Effect of 6-gingerol on body weight, liver weight, food intake, and calorie intake

In comparison with rats with standard diet (ND group), there was a significant increase of body weight and ratio of liver weight to body weight in HFHF rats. Treating HFHF rats with 6-gingerol at a dose of 50 mg/kg/day did not results in significant effects on body weight, while the body weight was significantly attenuated by treatment with 6-gingerol at a dose of 100 and 200 mg/kg/day with p = 0.018 and p = 0.033, respectively as compared to the HFHF rats (Table 1 and Fig. 1A). After MetS induction week (Week 8) there were no significant differences of food intake observed for all groups. Food intake appeared to be significantly reduced in the group that received 6-gingerol in all doses when compared to the HFHF group without treatment and the ND group at Week 16 (Table 2). Accordingly, the caloric intake also decreased significantly in the HFHF plus 6-gingerol group as compared to HFHF group (Table 2 and Fig. 1B).

Table 1.

The change of body weight, liver weight, and fat weight, n = 5/group.

Parameters ND HFHF 6-G 50 6-G 100 6-G 200
Body weight (BW) (gram) 347.5 ± 10 484.5 ± 44* 460 ± 38 416 ± 33# 406 ± 22#
Liver weight (LW) (gram) 10.3 ± 0.2 24.3 ± 3.5* 19.6 ± 2.4# 17.8 ± 1.3# 16 ± 1.2#
LW/BW ratio 2.9 ± 0.1 5 ± 0.3* 4.2 ± 0.2# 4.3 ± 0.1# 3.9 ± 0.1#
Epididymal fat (gram) 2.5 ± 0.4 13.9 ± 3.3* 7.1 ± 2.2# 3.4 ± 0.4# 5.3 ± 2.3#
Subcutaneous fat (gram) 1.2 ± 0.5 9.9 ± 4.3* 6.7 ± 2.6 1.4 ± 0.5# 5 ± 3.1
Open in a new tab
*

p < 0.05 vs ND.

#

p < 0.05 vs HFHF.

Fig. 1.

Fig. 1

Open in a new tab

6-gingerol administration in rats given HFHF led to decrease of body weight (A) and caloric intake (B) at Week 8, Week 12, and Week 16 near to rats in ND group. *p < 0.05 HFHF vs ND; #p < 0.05 HFHF vs 6-G 50; †p < 0.05 HFHF vs 6-G 100; ‡p < 0.05 HFHF vs 6-G 200. Changes in the levels of serum leptin (C) and adipose leptin (D) were reduced by 6-gingerol in HFHF-induced obesity and IR rats. Changes in the levels of serum adiponectin (E) and adipose adiponectin (F) were increased by 6-gingerol in HFHF-induced obesity and IR rats. Values are reported as mean ± SD. N = 5 rats/group. *p < 0.05 vs ND; #p < 0.05 vs HFHF analyzed by one-way ANOVA followed by a Tukey’s post-hoc test.

Table 2.

Mean of food and caloric intake of rats after metabolic syndrome induction week (Week 8) and after treatment week (Week 16), n = 5/group.

Group Food intake (g)
 Caloric intake (kcal)
After Week 8 After Week 16 After Week 8 After Week 16
ND 19 ± 0.7 19 ± 0.4 57.8 ± 2.1 57.8 ± 1.2
HFHF 19 ± 1 19 ± 2 90.1 ± 4.7** 90.1 ± 9.5**
6-G 50 19 ± 1 16 ± 2*, # 90.1 ± 9.5** 75.8 ± 9.5**, #
6-G 100 19 ± 1 15 ± 1*, # 90.1 ± 4.7** 71.1 ± 4.7**, #
6-G 200 19 ± 2 16 ± 1*, # 90.1 ± 9.5** 75.8 ± 4.7**, #
Open in a new tab
*

p < 0.05 vs ND.

**

p < 0.01 vs ND.

#

p < 0.05 vs HFHF.

3.2. Effect of 6-gingerol on serum glucose levels

To evaluate fasting plasma glucose (FPG), all rats were allowed to fast for 12 h. The FPG level in HFHF group was significantly higher as compared to ND group. As compared to HFHF group, the FPG in the HFHF plus 6-gingerol group were significantly decreased in doses 50 and 200 mg/kg/day, but not in 100 mg/kg/day dose (Table 3). Next, to assess insulin resistance, we evaluated the HOMA-IR. We showed that the HOMA-IR was markedly increased in HFHF group compared to ND group. The administration of 6-gingerol doses 50 and 200 mg/kg/day could significantly normalized HOMA-IR toward normal value. The administration of 6-gingerol at a dose of 100 mg/kg/day although there was a tendency to reduce HOMA-IR but the difference was not statistically significant when compared to the HFHF group (Table 3).

Table 3.

Changes in lipid profile and glucose levels in rats receiving standard diet, HFHF diet, and 6-gingerol, n = 5/group.

Parameters ND HFHF 6-G 50 6-G 100 6-G 200
TC (mg/dL) 73 ± 3 244 ± 13* 114 ± 31 99 ± 23 94 ± 39#
TG (mg/dL) 49 ± 6 469 ± 17* 156 ± 25 145 ± 52 103 ± 52#
HDL (mg/dL) 28 ± 1 26 ± 5 31 ± 4 28 ± 3 35 ± 12
FPG (mg/dL) 121 ± 8 334 ± 49* 166 ± 24# 281 ± 10 174 ± 10#
Insulin (mg/dL) 1 ± 0.2 1 ± 0.4 1 ± 0.3 1 ± 0.3 1.2 ± 0.3
HOMA-IR 0.3 ± 0.1 0.7 ± 0.2* 0.4 ± 0.1# 0.5 ± 0.1 0.4 ± 0.1#
Open in a new tab
*

p < 0.05 vs ND.

#

p < 0.05 vs HFHF.

3.3. Effect of 6-gingerol on lipid profile

As shown in Table 3, the levels of total cholesterol (TC) and triglyceride (TG) in the HFHF group showed a significant increase as compared to the ND group, whereas the level of HDL-cholesterol was lowered in the HFHF group, though not significantly different to that of ND group. Rats treated with 6-gingerol showed attenuated the TC and TG, tough only 6-gingerol 200 mg/kg/day showed a statistically significant difference compared to ND group. Administration of HFHF diet for 16 weeks caused the HDL-cholesterol levels to decrease in the HFHF group when compared to the ND group. Treatment with 6-gingerol for 8 weeks at doses of 50, 100, and 200 mg/kg/day could increase HDL-cholesterol levels although there were no statistically significant difference when compared to the HFHF group.

3.4. Effect of 6-gingerol on adipocytokines

To investigate the role of adipocytokines in the regulation of IR and inflammation, adiponectin and leptin were examined in the serum as well as in the adipose tissues. As shown in the Fig. 1B and 1C, HFHF diet-fed rats had higher serum and adipose leptin as compared to those of ND-fed rats. On the contrary, serum and adipose adiponectin were reduced in the HFHF diet-fed rats as compared to those of ND diet-fed rats (Fig. 1D and E). Interestingly, 6-gingerol administration to HFHF rats dose-dependently reduced the serum and adipose leptin levels significantly as compared to those of vehicle-treated HFHF rats. However, although 6-gingerol could increase serum and adipose adiponectin levels but there was no statistically significant difference when compared to vehicle-treated HFHF rats (Fig. 1B-E).

3.5. Effect of 6-gingerol on IL-6 and TNF-α

Serum IL-6 and TNF-α in the vehicle-treated HFHF rats were increased significantly as compared to the ND-fed rats. In line to serum results, IL-6 and TNF-α levels in adipose tissue and liver were also significantly increased in the HFHF diet-fed rats as compared to the ND-fed rats. 6-gingerol treatment reduced both of pro-inflammatory cytokines although there were difference in 6-gingerol dose in reducing serum levels as well as adipose tissue and liver of IL-6 and TNF-α in the treated rats as compared to the HFHF diet-fed rats (Fig. 2A-F).

Fig. 2.

Fig. 2

Open in a new tab

Changes in the levels of pro-inflammatory cytokines in the serum, liver, and adipose tissues of HFHF-induced obesity and IR rats treated by 6-gingerol. (A) IL-6 levels in serum, (B) IL-6 levels in the adipose tissues, and (C) IL-6 levels in the liver tissues were reduced by 6-gingerol treatment for 8 weeks. (D) TNF-α levels in serum, (E) TNF-α levels in the adipose tissues, and (F) TNF-α levels in the liver tissues were also reduced by 6-gingerol treatment for 8 weeks. Values are reported as mean ± SD. N = 5 rats. *p < 0.05 vs ND; #p < 0.05 vs HFHF analyzed by one-way ANOVA followed by a Tukey’s post-hoc test.

3.6. 6-gingerol decreased HFHF-induced hepatic and adipose tissues lipid accumulation

To investigate the role of 6-gingerol in hepatic and adipose tissue lipid accumulation, HE-stained liver and adipose tissue sections of 6-gingerol-treated rats was examined from HFHF diet-fed rats. As shown in Fig. 3A and 3B i-ii, significant adipose and hepatic lipid accumulation were observed in HFHF diet-fed rats as compared to those in ND diet-fed rats. In contrast, 6-gingerol at doses of 50 mg, 100 mg, and 200 mg/kg/day administration to HFHF diet-fed rats, showed a clearly reduced level of lipid accumulation in adipose tissue as well as in hepatic tissue (Fig. 3A and 3B iii-iv). In line with HE-staining results, Oil Red O staining of liver tissues also showed an increase in lipid accumulation in the HFHF diet-fed rats as compared to the ND-fed rats and the administration of 6-gingerol appeared to reduce lipid accumulation at doses 50, 100, and 200 mg/kg/day (Fig. 3C i-v).

Fig. 3.

Fig. 3

Open in a new tab

HFHF-induced hepatic and adipose lipid accumulation were attenuated in 6-gingerol-treated HFHF diet-fed rats. (A) Images of HE staining for adipose tissues sections of ND (i), HFHF diet-fed rats (ii), and 6-gingerol-treated HFHF diet-fed rats (iii – v) for 8 weeks, N = nucleus; AC = adipose cells; FD = fat deposition. (B) Images of HE staining for liver tissues sections of ND (i), HFHF diet-fed rats (ii), and 6-gingerol-treated HFHF diet-fed rats (iii – v) for 8 weeks. (C) Images of Oil Red O staining for liver tissues sections of ND (i), HFHF diet-fed rats (ii), and 6-gingerol-treated HFHF diet-fed rats (iii – v) for 8 weeks. Bars, 50 μm. The magnification of objective was x40.

4. Discussion

In the present study, a HFHF diet and low-dose injection of STZ was used to induce MetS in rats and to create a lipid accumulation in the hepatic and adipose tissues. After 16 weeks of receiving HFHF diet, the results demonstrated that the parameters of MetS including weight gain as demonstrated by increased of body weight, hyperlipidemia as demonstrated by increased of TC and TG as well as reduced of HDL-cholesterol, and insulin resistance as demonstrated by increased of HOMA-IR and FPG were developed. Those changes confirmed the creation of fatty liver and increased of adipose tissue cell size and fat deposition. Our results also demonstrated that 6-gingerol treatment attenuated lipid accumulation in the liver and adipose tissue and decreased TC, TG, FPG, HOMA-IR, and leptin and improved HDL-C and adiponectin levels.

Leptin regulates the release of most of the adipocytokines, inhibits the production of adiponectin which is a protective hormone against the effects harmful to obesity. Leptin is released as a regulatory mechanism of general metabolism, and its production is increased in a greater quantity in MetS (Ghadge and Khaire, 2019, Margoni et al., 2011). On the other hand, adiponectin, whose expression decreased in obesity, seems to have a protector role in MetS development (von Frankenberg et al., 2017). In our present study, the levels of leptin and adiponectin showed increased and decreased, respectively in the HFHF diet-fed rats compared with the ND-fed rats. Treatment with 6-gingerol dose-dependently resulted in a significant decrease in leptin level and a tendency to increase adiponectin level. Correspondingly, previous study has demonstrated that 6-gingerol increased adiponectin levels followed by improved insulin sensitivity (Isa et al., 2008). Numerous studies have also confirmed that 6-gingerol and ginger could reduce serum leptin levels in animals treated with high-fat diet (Saravanan et al., 2014, Wadikar and Premavalli, 2011). In line with the previous study, we have also demonstrated that the administration of 6-gingerol, in a dose-dependent mode, can improve insulin sensitivity which was shown in the increase of HOMA-IR as well as in the decrease of FPG which, at least in part, by adipocytokines regulation.

In addition to regulating blood glucose levels, controlling cholesterol including its synthesis and absorption, is also regulated by proper insulin levels (Pihlajamäki et al., 2004). In the current study, we also noticed that HFHF diet, not only decreased the insulin sensitivity but also significantly increased the levels of TC and TG and decreased the levels of HDL-C as compared with those of ND-fed rats. Rats treated with 6-gingerol, in a dose-dependent mode, attenuated lipid profile, though not statistically significant as compared with those of ND-fed rats. Moreover, 6-gingerol treatment significantly reduced epididymal fat and body weight as compared to ND-diet rats. Taheri et al. (2020) have demonstrated that adipocytokines, leptin and vaspin, were positively correlated with FPG, insulin, and HOMA-IR in patients with normal weight obesity (Taheri et al., 2020). Accordingly, our results demonstrated that the hypoglycemic and hypolipidemic effects of 6-gingerol on HFHF diet-induced MetS is regulated, in part, by adipocytokines.

In this study, the administration of the HFHF diet increased the proinflammatory cytokine, including IL-6 and TNF-α significantly as compared to the ND-fed rats. After administration of 6-gingerol for 8 weeks, IL-6 level decreased significantly, mainly at a dose of 200 mg/kg/day as compared to the HFHF diet-fed rats, while the level of TNF-α also decreased significantly in the rats treated with 6-gingerol doses 50 mg, 100 mg, and 200 mg/kg/day compared to the ND-fed rats. In fact, inflammation plays an important role in the pathogenesis of MetS, in which adipose tissue contributes the inflammatory pathways via the release of pro-inflammatory adipokines such as leptin and dysregulation of anti-inflammatory adiponectin which in turn leads to insulin resistance (Reddy et al., 2019). Several studies have demonstrated that the administration of 6-gingerol to diabetic mice model or non-alcoholic steatohepatitis rat model could reduce pro-inflammatory cytokines in the kidney and liver tissues (Almatroodi et al., 2021). Previous study has also shown that in diabetic patients serum, there were reduction of adiponectin level and increase of IL-6 level (Upadhyaya et al., 2013). In the current study, we noticed that the administration of 6-gingerol could also alleviate inflammation process by reducing the pro-inflammatory cytokines, IL-6 and TNF-α, in the serum as well as in the liver and adipose tissues of HFHF diet-fed rats, through at least in part by regulating of adipocytokines.

One of the most important characteristics of MetS is fat accumulation in the liver and adipose cells, resulting in both insulin resistance, obesity, and inflammation in the liver (Chait and den Hartigh, 2020). In the present study, accumulation of fat in the liver and adipose cells were observed, confirming the production of fatty liver and deposition of fat in the adipose cells by applying high-fat, high-fructose diet. Interestingly, the administration of 6-gingerol at doses 50 mg, 100 mg, and 200 mg/kg/day could attenuate the fat deposition in the liver as well as in the adipose cells as compared to those observed in the ND diet-fed rats.

Previous studies have demonstrated that continuous administration of a HFD will lead to obesity by increasing energy intake (Saravanan et al., 2014, Ghibaudi et al., 2002, Abdul Kadir et al., 2015). Because fats are the most highest energy-dense macronutrient, which is 9 kcal/g compared to protein and carbohydrates, which are 4 kcal/g, respectively, adding fat to food will increase calories and energy density (Rolls, 2017). Accordingly, in our study, adding 29.02 % fat to the diet increases caloric intake which in turn causes obesity in our experimental animals as compared to the normal diet which only contains 4 % fat. We have also shown that 6-gingerol administration for 8 weeks resulted in decreased food intake which in turn decreased caloric intake and body weight. In line to our study, Sukalingam et al., have also demonstrated that 6-gingerol administration reduced food intake in STZ-induced diabetic rats and this could be due to 6-gingerol potentiating glucagon-like peptide-1 (GLP-1) mediated insulin secretion pathway and increased glucose uptake in skeletal muscle (Sukalingam et al., 2013, Samad et al., 2017). It has been shown that potentiation of GLP-1 can also suppress appetite in the brain (Zhao et al., 2021).

5. Conclusion

Considering all these findings, it is suggested that MetS induced by HFHF diet and low-dose STZ injection potentially damages the liver and adipose cells through the accumulation of lipid and increased inflammatory processes in these cells via increased adipokines which are eventually leads to insulin resistance. 6-gingerol administration significantly blunted the lipid accumulation in the liver and fat deposition in adipose cells as well as inflammatory processes, at least in part through the decrease of caloric intake and regulation of adipocytokines (Fig. 4). Accordingly, 6-gingerol attenuated signs of MetS, namely weight gain and insulin resistance. Moreover, 6-gingerol shows hepatoprotective effects in MetS rat model through the inhibitions of inflammatory markers such as TNF-α and IL-6 and improves serum lipid profiles. We are aware that our study also has several limitations, namely related to the duration of 6-gingerol administration which is still quite short-term when compared to previous studies which provided 6-gingerol in the long-term.

Fig. 4.

Fig. 4

Open in a new tab

Schematic representation describing the possible pathway modulation by 6-gingerol on weight gain and insulin resistance in HFHF-induced metabolic syndrome rats.

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgments

Acknowledgements

This study was supported by a research grant from Ministry of Education, Culture, Research and Technology of the Republic of Indonesia with a grant number NKB-915/UN2.RST/HKP.05.00/2022. We thank members in our laboratory for helpful advice.

Author contributions

S.G., V.S., F.F., and E.H.P. designed the experiment. S.G. and V.S. wrote the manuscript. S.G., E.M., E.T.W., and V.S. performed the experiments and analysis data. P.E.W. and M.L. provided scientific advice. All authors reviewed the manuscript.

Footnotes

Peer review under responsibility of King Saud University.

References

  1. Abdul Kadir N.A., Rahmat A., Jaafar H.Z. Protective effects of tamarillo (cyphomandra betacea) extract against high fat diet induced obesity in sprague-dawley rats. J. Obes. 2015;2015 doi: 10.1155/2015/846041. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Albaraccin M.L.G., Torres A.Y.F. Adiponectin and leptin adipocytokines in metabolic syndrome: what is its importance? Dubai Diabetes Endocrinol. J. 2020;26:93–102. [Google Scholar]
  3. Alberti K.G., Eckel R.H., Grundy S.M., Zimmet P.Z., Cleeman J.I., Donato K.A., et al. International Diabetes Federation Task Force on Epidemiology and Prevention; Hational Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; International Association for the Study of Obesity. Harmonizing the metabolic syndrome: a joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity. Circulation. 2009;120:1640–1645. doi: 10.1161/CIRCULATIONAHA.109.192644. [DOI] [PubMed] [Google Scholar]
  4. Almatroodi, S.A., Abdullah, M., Alnuqaydan, Babiker, A.Y., Almogbel, M.A., Khan, A.A., et al., 2021. 6-Gingerol, a Bioactive Compound of Ginger Attenuates Renal Damage in Streptozotocin-Induced Diabetic Rats by Regulating the Oxidative Stress and Inflammation. Pharmaceutics. 13, 317. [DOI] [PMC free article] [PubMed]
  5. Benny M., Shylaja M.R., Antony B., Gupta N.K., Mary R., Anto A., et al. Acute and sub-acute toxicity studies with ginger extract in rats. IJPSR. 2021;33:2799–2809. doi: 10.13040/ijpsr.0975-8232.12(5).2799-09. [DOI] [Google Scholar]
  6. Chait A., den Hartigh L.J. Adipose tissue distribution, inflammation and its metabolic consequences, including diabetes and cardiovascular disease. Front. Cardiovasc. Med. 2020;7:22. doi: 10.3389/fcvm.2020.00022. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Cheng J.X., Yu K. New discovered adipokines associated with the pathogenesis of obesity and type 2 diabetes. Diabetes Metab. Syndr. Obes. 2022;15:2381–2389. doi: 10.2147/DMSO.S376163. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Choy K.W., Murugan D., Mustafa M.R. Natural products targeting er stress pathway for the treatment of cardiovascular diseases. Pharmacol. Res. 2018;132:119–129. doi: 10.1016/j.phrs.2018.04.013. [DOI] [PubMed] [Google Scholar]
  9. Ghadge A.A., Khaire A.A. Leptin as a predictive marker for metabolic syndrome. Cytokine. 2019:154735. doi: 10.1016/j.cyto.2019.154735. [DOI] [PubMed] [Google Scholar]
  10. Ghibaudi L., Cook J., Farley C., van Heek M., Hwa J.J. Fat intake affects adiposity, comorbidity factors, and energy metabolism of sprague-dawley rats. Obes Res. 2002;10:956–963. doi: 10.1038/oby.2002.130. [DOI] [PubMed] [Google Scholar]
  11. Grundy S.M., Hansen B., Smith S.C., Jr, et al. American Heart Association, National Heart, Lung, and Blood Institute, American Diabetes Association. Clinical management of metabolic syndrome: report of the American Heart Association/National Heart, Lung, and Blood Institute/American Diabetes Association conference on scientific issues related to management. Arterioscler. Thromb. Vasc. Biol. 2004;24:e19–e24. doi: 10.1161/01.ATV.0000112379.88385.67. [DOI] [PubMed] [Google Scholar]
  12. Isa Y., Miyakawa Y., Yanagisawa M., Goto T., Kang M.S., Kawada T., et al. 6-Shogaol and 6-gingerol, the pungent of ginger, inhibit TNF-α mediated downregulation of adiponectin expression via different mechanisms in 3T3-L1 adipocytes. Biochem. Biophys. Res. Commun. 2008;373:429–434. doi: 10.1016/j.bbrc.2008.06.046. [DOI] [PubMed] [Google Scholar]
  13. Jung U.J., Choi M.S. Obesity and its metabolic complications: The role of adipokines and the relationship between obesity, inflammation, insulin Resistance, dyslipidemia and nonalcoholic Fatty Liver Disease. Int. J. Mol. Sci. 2014;15:6184–6223. doi: 10.3390/ijms15046184. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Kim J.E., Kim J.S., Jo M.J., Cho E., Ahn S.Y., Kwon Y.J., et al. The roles and associated mechanisms of adipokines in development of metabolic syndrome. Molecules. 2022;27:334. doi: 10.3390/molecules27020334. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Lopez-Jaramillo P., Gomez-Arbelaez D., Lopez-Lopez J., Lopez-Lopez C., Martinez-Ortega J., Gomez Rodriguez A., et al. The role of leptin/adiponectin ratio in metabolic syndrome and diabetes. Horm. Mol. Biol. Clin. Invest. 2014;18:37–45. doi: 10.1515/hmbci-2013-0053. [DOI] [PubMed] [Google Scholar]
  16. Mao Q.Q., Xu X.Y., Chao S.Y., Gan R.Y., Corke H., Beta T., et al. Bioactive compounds and bioactivities of ginger (zingiber officinale roscoe) Foods. 2019;185:1–21. doi: 10.3390/foods8060185. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Margoni A., Perrea D.N., Vlachos I., Prokopaki G., Pantopoulou A., Fotis L., et al. Serum leptin, adiponectin and tumor necrosis factor-α in hyperlipidemic rats with/without concomitant diabetes mellitus. Mol. Med. 2011;17:36–40. doi: 10.2119/molmed.2010.00167. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Pihlajamäki J., Gylling H., Miettinen T.A., Laakso M. Insulin resistance is associated with increased cholesterol synthesis and decreased cholesterol absorption in normoglycemic men. J. Lipid Res. 2004;45:507–512. doi: 10.1194/jlr.M300368-JLR200. [DOI] [PubMed] [Google Scholar]
  19. Rahimlou M., Yari Z., Rayyani E., Keshavarz S.A., Hosseini S., Morshedzadeh N. Effects of ginger supplementation on anthropometric, glycemic and metabolic parameters in subjects with metabolic syndrome: A randomized, double-blind, placebo-controlled study. J. DiabetesMetab. Disord. 2019;18:119–125. doi: 10.1007/s40200-019-00397-z. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Reddy P., Lent-Schochet D., Ramakrishnan N., McLaughlin M., Jialal I. Metabolic syndrome is an inflammatory disorder: A conspiracy between adipose tissue and phagocytes. Clin. Chim. Acta. 2019;496:35–44. doi: 10.1016/j.cca.2019.06.019. [DOI] [PubMed] [Google Scholar]
  21. Rolls B.J. Dietary energy density: Applying behavioural science to weight management. Nutr Bull. 2017;42:246–253. doi: 10.1111/nbu.12280. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Samad M.B., Mohsin M.N.A.B., Razu B.A., Hossain M.T., Mahzabeen S., Unnoor N., Muna I.A., et al. [6]-Gingerol, from Zingiber officinale, potentiates GLP-1 mediated glucose-stimulated insulin secretion pathway in pancreatic β-cells and increases RAB8/RAB10-regulated membrane presentation of GLUT4 transporters in skeletal muscle to improve hyperglycemia in Leprdb/db type 2 diabetic mice. BMC Complement Altern. Med. 2017;17:395. doi: 10.1186/s12906-017-1903-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Saravanan, G., Ponmurugan, P., Deepa, M.A., Senthilkumar, B., 2014. Anti-obesity action of gingerol: effect on lipid profile, insulin, leptin, amylase and lipase in male obese rats induced by a high-fat diet. J. Sci. Food Agric. 94, 2972-7. [DOI] [PubMed]
  24. Song S., Dang M., Kumar M. Anti-inflammatory and renal protective effect of gingerol in high-fat diet/streptozotocin-induced diabetic rats via inflammatory mechanism. Inflammopharmacology. 2019;27:1243–1254. doi: 10.1007/s10787-019-00569-6. [DOI] [PubMed] [Google Scholar]
  25. Sarrafan A., Ghobeh M., Yaghmaei P. The effect of 6-gingerol on biochemical and histological parameters in cholesterol-induced nonalcoholic fatty liver disease in NMRI mice. Braz. J. Pharm. Sci. 2021;57 doi: 10.1590/s2175-979020200003181020. [DOI] [Google Scholar]
  26. Sukalingam, K., Ganesan, K., Gani, S.B., 2013. Hypoglycemic effect of 6-gingerol, an active principle of ginger in streptozotocin induced diabetic rats. Research and Reviews: Journal of Pharmacology and Toxicological Studies. e-ISSN: 2322-0139 p-ISSN: 2322-0120.
  27. Taheri E., Hosseini S., Qorbani M., Mirmiran P. Association of adipocytokines with lipid and glycemic profiles in women with normal weight obesity. BMC Endocr. Disord. 2020;20:171. doi: 10.1186/s12902-020-00648-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Tzeng T.F., Liou S.S., Chang C.J., Liu I.M. 6-gingerol protects against nutritional steatohepatitis by regulating key genes related to inflammation and lipid metabolism. Nutrients. 2015;7:999–1020. doi: 10.3390/nu7020999. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Tzeng T.F., Liou S.S., Chang C.J., Liu I.M. 6-Gingerol dampens hepatic steatosis and inflammation in experimental nonalcoholic steatohepatitis. Phytomedicine. 2015;22:452–461. doi: 10.1016/j.phymed.2015.01.015. [DOI] [PubMed] [Google Scholar]
  30. Upadhyaya S., Kadamkode V., Mahammed R., Doraiswami C., Banerjee G. Adiponectin and IL-6: Mediators of inflammation in progression of healthy to type 2 diabetes in Indian population. Adipocyte. 2013;3:39–45. doi: 10.4161/adip.26553. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. von Frankenberg A.D., Reis A.F., Gerchman F. Relationships between adiponectin levels, the metabolic syndrome, and type 2 diabetes: a literature review. Arch. Endocrinol. Metab. 2017;61:614–622. doi: 10.1590/2359-3997000000316. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Wadikar D., Premavalli K. Appetizer administration stimulates food consumption, weight gain and leptin levels in male Wistar rats. Appetite. 2011;57:131–133. doi: 10.1016/j.appet.2011.04.001. [DOI] [PubMed] [Google Scholar]
  33. Wallace T.M., Levy J.C., Matthews D.R. Use and abuse of HOMA modeling. Diabetes Care. 2004;27:1487–1495. doi: 10.2337/diacare.27.6.1487. [DOI] [PubMed] [Google Scholar]
  34. Zhao X., Wang M., Wen Z., Lu Z., Cui L., Fu C., et al. GLP-1 receptor agonists: beyond their pancreatic effects. Front. Endocrinol. (Lausanne). 2021;12 doi: 10.3389/fendo.2021.721135. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Saudi Pharmaceutical Journal : SPJ are provided here courtesy of Springer

RESOURCES