Beneficial effect of Zingiber officinale on olanzapine-induced weight gain and metabolic changes

Abstract

Aim

The present study aimed to investigate the effect of Zingiber officinale (ZO) extract on weight gain, food intake, locomotor activity, and lipid and glucose metabolism in olanzapine-treated rats.

Methods

The hydroalcoholic extract of ZO was prepared by macerating the coarse dry powder in 70% v/v ethanol for 7 days, filtered, and concentrated under reduced pressure. Animals were divided into six groups containing six animals in each. Three doses of extract (100, 200, and 400 mg/kg, p.o.) were co-administered with olanzapine 2 mg/kg i.p for 21 days. Bodyweight and food intake were recorded at the interval of three days and locomotor activity once a week. At the end of the study oral glucose tolerance test was performed followed by the estimation of lipid profile.

Results

Co-administration of hydroalcoholic extract of ZO with olanzapine ameliorated olanzapine-induced weight gain and hyperphagia. Similarly, ZO extract also improved pancreatic β-cell function and glucose and lipid metabolism.

Conclusions

ZO extract ameliorated olanzapine-induced weight gain and hyperphagia by improving pancreatic β-cell functions and lipid metabolism.

Introduction

Previously, typical anti-psychotic molecules were in a great trend for the management of psychiatric illness. However, they are restricted in their clinical utilization except for urgency due to their extrapyramidal syndrome side effects including symptoms of tardive dyskinesia and neurological toxicity which lead to the utilization of atypical anti-psychotic molecules that are also called second-generation antipsychotic drugs [1, 2]. However, atypical antipsychotics like olanzapine linked prescriptions are reported to cause weight gain and metabolic changes in psychiatric illness; identified via clinical and preclinical studies [3–5]. Further, weight gain and dyslipidemia are well-known risk factors for metabolic disorders via insulin resistance and diabetes [6, 7]. Presently, for the management of olanzapine-induced weight gain, few approaches have been made like co-administration of metformin and weight-reducing agents like orlistat with olanzapine or switching the olanzapine with other antipsychotics [8–10]. However, weight gain is the outcome of the polygenic condition in which multiple-proteins are involved in its progression leading to obesity. Hence, it is important to identify a new therapeutic agent that can be supplemented along with olanzapine which should overcome the olanzapine side effects without affecting its clinical benefits.

Ayurveda and other complementary medicines record the multiple herbal medicines which are composed of multiple secondary metabolites and are effective in the management of etiological-, drug-induced weight gain. Among them, Zingiber officinale (ZO) belonging to the family Zingiberaceae, commonly known as Ginger is an enduring herbaceous plant which is commonly available in every kitchen garden of Asian countries including India, Nepal, Pakistan, China and also grown throughout the world; rhizome of the ginger is crushed, turned to powder and stored for its utilization with vegetables to enhance the taste in each dinner/lunch throughout the year. Ayurveda records ZO as “Sunthi” to be utilized for digestive impairment, flatulence with a gurgling sound, rheumatism, abdominal lump, anemia, chronic rhinitis, filariasis, and dyspnoea [11]. Additionally, extracts of ginger rhizome have been investigated to evaluate their efficacy to reduce weight gain and energy expenditure in high-fat diet-fed rodent models [12–16]. Additionally, the ZO has been reported for its anti-depressant activity [17]. Human trials have reported reduced appetite in overweight subjects after supplementation with a ginger powder [18]. However, no studies have been reported to understand its effect on olanzapine-induced weight gain along with glucose and lipid metabolism.

Hence, the present study aimed to investigate the effects of hydroalcoholic extract of ZO on body weight, food intake, and locomotor activity in an established female rat model of olanzapine-induced weight gain. Besides these, the effects of the extract on lipid and glucose metabolism were also examined in olanzapine-treated rats.

Materials and methods

Collection and extract preparation of ZO rhizomes

Rhizomes of ZO were collected from local areas of Belagavi India and rhizomes were washed to remove foreign matter. The rhizomes were then shade dried and turned into a coarse powder. The coarse powder was then macerated with 70% v/v ethanol for seven days, filtered, and concentrated using a rotator evaporator (IKA RV 10) under reduced pressure.

Animals and ethical clearance

Healthy Sprague-Dawley female rats weighing 180 ± 10 grams were purchased from the committee for the purpose of control and supervision of experiments on animals registered vendor and housed in pathogen-free conditions after ethical approval from Institutional animal ethical clearance at KLE College of Pharmacy Belagavi; resolution no. KLECOP/CPCSEA-Reg.No.221/Po/Re/S/2000/CPCSEA,Res.28 − 12/10/2019. Animals were acclimatized under a 12 light/dark cycle for 7 days before the study.

Study design and grouping of animals

Animals were randomized into 5 different groups containing six animals in each using computer-generated random numbers namely (a) control (CON): receives vehicle; (b) OLZ: receives olanzapine 2 mg/kg, i.p., b.i.d. [19]; (c) OLZ + ZO100: receives olanzapine 2 mg/kg, i.p., b.i.d.+ZO extract 100 mg/kg, p.o., OD; (d) OLZ + ZO200: olanzapine 2 mg/kg, i.p., b.i.d.+ ZO extract 200 mg/kg, p.o., OD; (e) OLZ + ZO400: olanzapine 2 mg/kg, i.p., b.i.d.+ZO extract 400 mg/kg. Each group contained three cages with two animals in each and animals of all 5 groups were fed with normal pellet diet. The detailed study design of the present study is presented in Fig. 1.

Fig. 1.

Representation of the experimentation to evaluate the hydroalcoholic extract of ZO in olanzapine-induced weight gain and metabolic changes

Measurement of body weight and food intake

The body weight and food intake were recorded from 1^st to 21^st day. The percentage gain in body weight for the corresponding day was calculated using the following formula

$$\%gaininbodyweight=\frac{(weightof{n}^{th}day-weightof{\left(n-1\right)}^{th}day)}{weightof{\left(n-1\right)}^{th}day}$$

Similarly, mean food intake in each group in a week was calculated using the following formula

$$averagefoodintake\left(grams\right)=\frac{totalfoodintakeinaweek}{7}$$

Locomotor activity

The animal locomotor behavior was examined using Actophotometer as explained by Dews [20]. Briefly, individual animals were placed in an actophotometer for 5 min to record the basal locomotor of animals followed by administration of the drug; after 30 min locomotor activity was recorded as digital counts. The increased counts reflected the increased locomotor activity.

Oral Glucose Tolerance Test (OGTT)

OGTT was performed after 21 days of treatment as explained by Kumar et al. [21] The XY plot of glucose level vs. time (min) was used to calculate the total area under the curve (AUC).

Plasma biochemical estimations

Fasting blood glucose level was measured using a glucometer (Janaushadi, India). Similarly, triglyceride (TG), total cholesterol (TC), and high-density lipid (HDL) were measured using commercially available kits (ERBA diagnostics). The LDL and VLDL levels were measured using the following formula

$$\text{VLDL}(\text{mg}/\text{dl})=\frac{\text{TG}}{5}$$

$$\text{LDL}(\text{mg}/\text{dl})=\text{TC}-(\text{HDL}+\text{VLDL})$$

Statistical analysis

All the data are expressed in mean ± SD. Bodyweight, food intake, locomotor activity, blood glucose during OGTT were analyzed using two-way ANOVA followed by Bonferroni test whereas total area under the curve of glucose during OGTT, TG, TC, HDL, LDL, and VLDL were analyzed using one-way followed by Tukey’s Test for Post-Hoc Analysis using GraphPad Prism 5. Differences among the means of groups were considered statistically significant at p < 0.05.

Results

Effect on body weight

At the end of the study, the gain in body weight (%) was significantly higher (p < 0.001, F = 57.25, R² 0.9016) in olanzapine treated rats compared to the control. This increase in body weight gain was significantly higher (p < 0.001) from the 12^th day until the 21^st day. Co-administration of ZO at the dose of 200 and 400 mg/kg with olanzapine significantly decreased (p < 0.001) olanzapine-induced body weight gain from the 12^th day to 21^st day (Fig. 2a).

Fig. 2.

Effect of ZO extract on body weight and food intake of rats treated with olanzapine. a ^*p <0.01, ^**p <0.001 compared to CON, ^#p <0.05, ^##p <0.01, ^###p <0.001 compared to OLZ; b *p <0.001 compared to normal, ^#p <0.05, ^##p <0.001 compared to OLZ

Effect on food intake

There was a significant difference (p < 0.0001 in food intake week wise, F = 242.3 vs. 86.47 as weeks vs. food intake) in food intake which was duration dependent and was affected by the co-administration of ZO extract with olanzapine. The average food intake during 2^nd week (8^th -15^th day) and 3^rd week (16^th -21^st day) were significantly higher (p < 0.001) in olanzapine treated rats compared to the control. Co-administration of ZO (100, 200, and 400 mg/kg) of olanzapine significantly decreased hyperphagia induced by olanzapine at both 2^nd and 3^rd week period (p < 0.05, 0.001) (Fig. 2b).

Effect on locomotor activity

We observed a significant difference (p < 0.0001 time-dependent locomotor counts, F = 31.92 vs. 11.72 as count vs. days) in locomotor activity after the co-administration of ZO extract with olanzapine. There was a significant decrease (p < 0.001) in locomotor activity in the olanzapine group compared to normal on the 14^th and 21^st days. Co-administration of ZO extract (400 mg/kg) with olanzapine showed a significantly increased (p < 0.05) in the decrease of locomotor activity induced by olanzapine (Fig. 3).

Fig. 3.

Effect of ZO extract on locomotor activity of rats treated with olanzapine. *p < 0.001 compared to normal, #p < 0.05 compared to olanzapine

Effect on ZO on oral glucose tolerance test

At the end of 3^rd week of the study, there was a significant difference in blood glucose level during OGTT which was time-dependent and group dependent (p < 0.0001 for both time-dependent glucose level, F = 26.46 vs. 45.80 as glucose level vs. time). Likewise, there was a significant difference (P = 0.0022, F = 5.737, R² 0.4888) in the total area under the curve of glucose of the groups. Similarly, fasting blood glucose level and area under the curve for OGTT of olanzapine treated rats were significantly higher (p < 0.05) than control. Co-administration of ZO extract had a non-significant decrease in fasting blood glucose levels. However, co-administration of ZO (200 and 400 mg/kg) with olanzapine significantly decreased (p < 0.05, 0.01) the total area under the curve and glucose levels at all three intervals (30, 60, and 120 min) of measurement to olanzapine treated rats (Fig. 4).

Fig. 4.

Effect of ZO on OGTT of rats treated with olanzapine. a*p < 0.05, **p < 0.001 compared to CON, #p < 0.05, ##p < 0.001 compared to OLZ b *p < 0.05 compared to CON, #p < 0.05, ##p < 0.01 compared to OLZ

Effect of ZO on lipid profile

There was significant difference in TG (p < 0.0001, F = 18.02, R² 0.7662), TC (p = 0.0096, F = 4.219, R² 0.4030), HDL (p < 0.0001, F = 20.24, R² 0.7714), LDL (p < 0.0001, F = 38.75, R² 0.8611), VLDL (p < 0.0001, F = 18.05, R² 0.7665) among the groups. There was a significant increase in triglycerides (p < 0.001), total cholesterol (p < 0.01), LDL (p < 0.001), and VLDL (p < 0.001) level and a decrease in HDL (p < 0.001) in the olanzapine group compared to normal. Co-administration of ZO at the dose of 400 mg/kg showed a significant increase (p < 0.001)in HDL level and decreased TG (p < 0.01) and VLDL (p < 0.01)compared to olanzapine. Similarly, co-administration of ZO extract with olanzapine significantly decreased (p < 0.001) the LDL level at 100, 200, and 400 mg/kg compared to olanzapine. However, co-administration of ZO extract with olanzapine had no influence on total cholesterol at the dose of 100, 200, and 400 mg/kg (Table 1).

Table 1.

Effect of ZO on lipid profile in rats treated with olanzapine

Groups	TG (mg/dl)	TC (mg/dl)	HDL (mg/dl)	LDL (mg/dl)	VLDL (mg/dl)
Normal	92.59 ± 1.16	76.70 ± 1.04	42.33 ± 1.99	14.82 ± 3.56	18.51 ± 0.23
Olanzapine	133.30 ± 11.37**	98.59 ± 8.68*	21.74 ± 5.24**	51.07 ± 7.03**	26.66 ± 2.28**
ZO 100 mg/kg	125.70 ± 6.76	89.33 ± 13.80	25.40 ± 3.65	37.40 ± 4.23##	25.14 ± 1.35
ZO 200 mg/kg	120.20 ± 8.04	88.48 ± 10.85	28.57 ± 3.74	35.73 ± 6.24##	24.04 ± 1.61
ZO 400 mg/kg	111.00 ± 12.47#	82.19 ± 9.86	34.34 ± 5.94##	29.63 ± 3.88##	22.20 ± 2.50#

All data are represented in Mean ± SD (n = 6), *p < 0.01, **p < 0.001 compared to normal, #p < 0.01, ##p < 0.001 compared to olanzapine

Discussion

Consistent with the previous report, rats after treatment with olanzapine (2 mg/kg) for 21 days developed increased weight gain associated with hyperphagia [19]. Treatment of a high-fat diet with ZO extract or its active contents reported reducing body weight gain, obesity, and serum leptin content [22]. Similarly, a randomized clinical trial study reported that the supplementation of 2 grams/day dry ZO powder caused a reduction of BMI and appetite score in obese women [18]. Our data suggest that ZO has a significant effect on preventing olanzapine-induced weight gain in this rat model. Rats receiving combined treatment showed a trend for less weight gain during all intervals of body weight measurement till the end of the study. Further, the food intake of these rats was less than olanzapine-treated rats. These data suggest that the ability of ZO to decrease olanzapine-induced body weight gain; may be due to reducing effect on olanzapine-induced hyperphagia.

Previous studies have reported decreased locomotors activity in rat’s model of olanzapine-induced weight gain and suggested that reduced energy expenditure may be partially responsible for olanzapine-induced weight gain [23, 24]. Consistent with these reports, in the present study, olanzapine treated rats showed reduced locomotor activity during the second and third weeks of study. Under the conditions of our study, ZO treatment did not improve olanzapine-induced hyper locomotor activity except partial movement in the third week with the highest dose (400 mg/kg) of ZO. These observations suggest that ZO may not ameliorate olanzapine-induced weight gain by modulating energy expenditure through increased physical activity. Probably this could be one of the possible explanations for partial prevention of weight gain in olanzapine and ZO co-treated rats.

Increased expression of pck1, a gene controlling hepatic gluconeogenesis, and decreased expression of GLUT4 in adipose tissue and skeletal muscle are suggested to cause insulin resistance leading to hyperglycemia in a rat model of olanzapine-induced weight gain [25]. Consistent with these reports in the present study, olanzapine treated rats showed fasting hyperglycemia and impaired glucose tolerance. Treatment of rats with ginger water reported increasing hepatic glucose uptake and its oxidation through GLUT-2 and PK mRNA expression [26]. Further, gingerol from ZO reported enhancing glycogen synthesis through increasing translocation of GLUT-4 in skeletal muscle [27] of diabetic mice. These effects of ZO may explain improved glucose metabolism in rats co-treated with olanzapine and ZO in the present study.

In the present study, rats treated with olanzapine for 3 weeks showed increased plasma level of total cholesterol, triglycerides, and decreased HDL levels which are consistent with previous reports [24]. Olanzapine is reported to upregulate the expression of the hepatic SREBP-1 gene involved in lipogenesis and down-regulate the expression of CPT1A involved in lipolysis through fatty acid β-oxidation in a rat model of weight gain [28, 29]. In our study, ZO co-treatment prevented the olanzapine-induced elevation of total cholesterol, triglycerides, and low-density lipoprotein levels. ZO is reported to prevent high-fat diet-induced dyslipidemia by decreasing the expression of SREP1-C and increasing the expression of CPT-1 in rats and such effects of ZO could be responsible for the results of the present study. The schematic representation for the probable mechanism of action of the present study is presented in Fig. 5.

Fig. 5.

Schematic representation for the probable mechanism of action of ZO in olanzapine-induced weight gain and metabolic changes. Solid and dotted lines represent the effect of olanzapine and ZO respectively. “ ” represents the probable checkpoint affected by ZO extract and “?” represents the effect of ZO extract yet to be investigated on a particular pathway

Further, it is to be understood that a plant extract composes multiple secondary metabolites and a broad biological spectrum reflecting the probability to interact with multiple proteins/pathways [30–32]. Similarly, for the present study, it is a necessity to identify the probable interaction of multiple secondary metabolites from ZO extract with numerous targets related to an olanzapine-induced weight gain which is the future scope of the present study.

Conclusions

The present study evaluated the effect of hydroalcoholic extract of ZO on olanzapine-induced weight gain and associated metabolic changes. The study revealed the potency of ZO extract to manage weight gain and food intake if co-administered with olanzapine. Additionally, it demonstrated the potency of ZO to ameliorate glucose intolerance and dyslipidemia.

Data availability

Data will be made available from the corresponding author in case of a request.

Compliance with ethical standards

Conflict of interest

There are no conflicts of interest to declare.

Consent for publication

Not Applicable.