Background: Naringenin, a natural resource-derived flavanone, exhibits a plethora of pharmacological properties. The present study aimed to investigate the effects of naringenin on obesity-associated hypertension and its underlying mechanism. Methods: Obesity-associated hypertension rat model was established with a high-fat diet (HFD) and was administrated with naringenin (25, 50, 100 mg/kg). Body and fat weights were recorded and blood pressure was measured. Serum lipid parameters (cholesterol, low-density lipoprotein [LDL], high-density lipoprotein [HDL], and triglycerides), oxidative stress biomarkers (malondialdehyde [MDA], superoxide dismutase [SOD], nitrite oxide [NO], and glutathione [GSH]), and adipocytokines (leptin and adiponectin) were determined. The expressions of signal transducer and activator of transcription (STAT) 3 were determined by using Western blotting. Results: Treatment with naringenin (100 mg/kg) reduced body and fat weight in HFD-induced rats. Besides, treatment with naringenin (50 and 100 mg/kg) reduced blood pressure and regulated lipid parameters by decreasing cholesterol, triglycerides, and LDL and increasing HDL. Treatment with naringenin (50 and 100 mg/kg) reduced serum MDA and NO, whereas it increased serum SOD and GSH. Furthermore, treatment with naringenin (50 and 100 mg/kg) regulated adipocytokines and decreased the phosphorylation of STAT3. Conclusion: Naringenin ameliorates obesity-associated hypertension by regulating lipid disorder and oxidative stress.

Cardiovascular diseases are the leading cause of death in the world [1, 2]. Hypertension is a cardiovascular condition in which the blood pressure is persistently raised and causes the risk of heart disease and stroke [3, 4]. Hypertension is caused by many risk factors including age, alcohol and tobacco abuse, chronic conditions (kidney disease and diabetes), and obesity [4, 5]. Among them, obesity is associated with the development of hypertension and is a significant cause of hypertension, which accounts for 65∼78% of essential hypertension [5, 6]. The relationship between obesity and hypertension is well established in children and adults [6, 7]. Obese individuals are usually accompanied by high blood pressure as compared to nonobese individuals [7]. Current studies have revealed that obesity-induced hypertension is associated with sympathetic nervous system over-activation, the stimulation of the renin-angiotensin-aldosterone system, and abnormal expressions of adipocytokines including leptin and adiponectin [8-10]. However, the mechanisms that are involved in obesity-induced hypertension are still not fully understood.

Due to its complicated mechanisms, obesity-induced hypertension is more difficult to be controlled [9]. Utilization of a single antihypertensive medication acquires poor responsiveness with adverse effects for patients with obesity-induced hypertension [9, 11]. For instance, treatment with β-blockers regulates renin activity and heart rate, thereby reducing blood pressure. However, for obese patients without kidney complications, the use of β-blockers has side effects on glucose mechanisms [12]. A combination of multiple antihypertensive drugs is recommended in the therapeutic strategies against obesity-induced hypertension [13]. However, obese individuals are more likely to develop hypertension that is resistant to antihypertension therapy [14]. Therefore, it is important to discover effective therapeutic strategies with fewer side effects for patients with obesity-induced hypertension.

Naringenin is a natural resource-derived flavanone that is predominantly distributed in citrus fruits such as grapefruit and oranges, and figs belonging to smyrna-type Ficus carica [15, 16]. Previous studies have reported that naringenin exhibits a plethora of pharmacological activities, including anti-inflammatory, antibacterial, antiviral, antitumor, and cardiovascular protective effects [15, 17, 18]. In 2014, Ahmed et al. [19] reported that the combination of naringenin with L-arginine ameliorated pulmonary hypertension induced by monocrotaline in the rat by the regulation of oxidative stress and inflammation. In 2019, Wang et al. [20] found that treatment with naringenin attenuated kidney damage in a rat model of renovascular hypertension. These results indicated that naringenin might be a good drug candidate in the treatment of hypertension. Interestingly, naringenin also exerts anti-obesity properties in a mouse model by the inhibition of neutrophil and macrophage accumulation in adipose tissue. However, it is still unknown whether naringenin has therapeutic effects against obesity-associated hypertension. Therefore, in the present study, we aimed to explore the effects of naringenin on obesity-associated hypertension and its underlying mechanisms.

Animals

Thirty 8-week-old male Wistar rats (220∼260 g) were purchased from Shanghai Model Organisms (Shanghai, China). The rats were kept in a 12 h light/12 h dark cycle with temperatures of 20∼24°C with free access to water. The animal protocol has been reviewed and approved by Animal Care and Use Committee, Tianjin Hospital.

Experimental Design

The chow diet consists of 20.25% protein, 7.25% fat, and 62% carbohydrates (Xietong Biology, Nanjing, China). High-fat diet (HFD) consists of 22% protein, 27% fat, and 41% carbohydrates (Xietong Biology). Naringenin was purchased from Selleck (Shanghai, China). In this study, the animals were divided into five groups. The rats in the control group were fed a chow diet for 16 weeks. The rats in HFD were fed HFD for 16 weeks. The rats in naringenin (25 mg/kg) group were fed with HFD for 16 weeks and administrated with 25 mg/kg naringenin in the last 4 weeks. The rats in naringenin (50 mg/kg) were fed with HFD for 16 weeks and administrated with 50 mg/kg naringenin in the last 4 weeks. The rats in naringenin (100 mg/kg) were fed with HFD for 16 weeks and administrated with 100 mg/kg naringenin in the last 4 weeks. The naringenin was dissolved in dimethyl sulfoxide. For the control and HFD groups, the rats were administrated with an equal volume of dimethyl sulfoxide in the last 4 weeks.

Bodyweight was measured and recorded every 2 weeks. At the end of the experimental period (16 weeks), the rats were utilized and the plasma was collected. Besides, the fat tissue (epididymal and perirenal fat) was removed and weighed. Hypothalamus was collected and stored in liquid nitrogen for further assays.

Measurement of Blood Pressure

To evaluate the effects of naringenin on blood pressure, heart rate, systolic blood pressure (SBP), and diastolic blood pressure (DBP) were measured by using a pressure transducer every 2 weeks during the experimental period. Measurement of heart rate, SBP, and DBP were recorded for continuous 20 mins. The data were then analyzed by using data acquisition software.

Determination of Lipid Parameters

At the end of the experimental period, the rats were utilized and the plasma was collected. Next, the serum was separated and the lipid parameters including total cholesterol, low-density lipoprotein (LDL), high-density lipoprotein (HDL), and triglycerides were determined by using the commercialized kit (Sigma-Aldrich, St. Louis, MO, USA).

Measurement of Oxidative Stress-Related Biomarkers

To evaluate the effects of naringenin on oxidative stress, oxidative stress-related biomarkers including malondialdehyde (MDA), superoxide dismutase (SOD), nitrite oxide (NO), and glutathione (GSH) were determined. MDA and SOD were determined by using MDA and SOD assay kits (Boster Biological Technology, Wuhan, China), respectively. NO was determined by using Griess reagent (Promega). The GSH was determined by using the GSH assay kit (Abcam, Abcam, Cambridge, MA, USA).

Determination of Adipocytokines

Adipocytokines including leptin and adiponectin were determined by using ELISA kits, according to the manufacturer’s document (R&D Biosystem, Minneapolis, MN, USA).

Western Blotting

The protein extraction and qualification were performed according to the previous reports [21]. The hypothalamus was collected and lysed by using a radioimmunoprecipitation assay buffer containing protease inhibitor on ice. Next, the removal of the insoluble components was performed by using centrifugation. A bicinchoninic acid protein assay kit was applied to qualify protein concentration. An equal amount of protein sample (10 μg) was loaded on the precast sodium dodecyl sulfate-polyacrylamide gel electrophoresis gel followed by transferring to 0.22 μm polyvinylidene fluoride membrane. Membrane blocking was applied by incubating the membrane with 5% bovine serum albumin at room temperature for 2 h. The primary antibodies against signal transducer and activator of transcription (STAT) 3 (1:1,000, Abcam), p-STAT3 (1:1,000, Abcam), and GADPH (1:2,000, Sigma) were added to incubate with the membrane at 4°C overnight. Next, the membrane was incubated with horseradish peroxidase conjugated-secondary antibodies at room temperature for another 2 h. The Biorad Gel Imaging System was applied and the expressions of target proteins were analyzed by comparing them with the internal control (GADPH).

Statistical Analysis

Data analysis was performed by using GraphPad Prism8 software (San Diego, CA, USA). All data were presented as the means ± SD. Two-way or one-way ANOVA was performed and a p value less than 0.05 was considered a statistical difference.

Treatment with Naringenin Reduced Body and Fat Weight in HFD-Induced Rats

To investigate the effects of naringenin on HFD-induced obesity, we first recorded body weight and fat weight in HFD-induced rats. The results demonstrated that HFD significantly increased the body weight from the 6th week as compared to the control group (Fig. 1a). No significant difference was observed in the body weight between the naringenin (25 and 50 mg/kg) and the HFD group. However, treatment with naringenin (100 mg/kg) significantly reduced the body weight as compared to the HFD group (Fig. 1a). Interestingly, we also observed that treatment with naringenin (50 and 100 mg/kg) for 4 weeks significantly reduced the epididymal and visceral fat weight as compared to the HFD group (Fig. 1b, c), indicating that treatment with naringenin may prevent rat obesity from HFD. However, treatment with naringenin at a dose of 25 mg/kg did not significantly reduce the epididymal and visceral fat weight as compared to the HFD group (Fig. 1b, c).

Fig. 1.

Effects of NAR on the body weight (a) and fat weight including epididymal (b) and visceral fat weight (c) in rats fed by HFD (n= 6). Data were represented as the means ± SD. *p< 0.05 versus control group, #p< 0.05 versus HFD group. NAR, naringenin.

Fig. 1.

Effects of NAR on the body weight (a) and fat weight including epididymal (b) and visceral fat weight (c) in rats fed by HFD (n= 6). Data were represented as the means ± SD. *p< 0.05 versus control group, #p< 0.05 versus HFD group. NAR, naringenin.

Close modal

Treatment with Naringenin Reduced Blood Pressure in HFD-Induced Rats

Next, we evaluated the effects of naringenin on blood pressure in HFD-induced rats. We noticed that blood pressure approached a plateau at week 10. The results demonstrated that heart rate was increased in the HFD group as compared to the control group, whereas treatment with naringenin (50 and 100 mg/kg) significantly decreased the heart rate (Fig. 2a). Besides, the SBP and DBP were also significantly increased in the HFD group as compared to the control group, whereas treatment with naringenin (50 and 100 mg/kg) for 4 weeks reduced the SBP and DBP (Fig. 2b, c). These results supported that treatment with naringenin (50 and 100 mg/kg) reduced blood pressure in HFD-induced rats.

Fig. 2.

Effects of NAR on heart rate (a), SBP (b), and DBP (c) in rats fed by HFD (n= 6). Data were represented as the means ± SD. *p< 0.05 versus control group, #p< 0.05 versus HFD group. NAR, naringenin.

Fig. 2.

Effects of NAR on heart rate (a), SBP (b), and DBP (c) in rats fed by HFD (n= 6). Data were represented as the means ± SD. *p< 0.05 versus control group, #p< 0.05 versus HFD group. NAR, naringenin.

Close modal

Treatment with Naringenin Regulated Lipid Parameters in HFD-Induced Rats

Moreover, we investigated the effects of naringenin on the serum lipid parameters. The results demonstrated that serum triglycerides, cholesterol, and LDL were significantly increased in the rats fed by HFD for 16 weeks (Fig. 3a–c). Treatment with naringenin (50 and 100 mg/kg) for 4 weeks significantly reduced serum triglycerides, cholesterol, and LDL as compared to the HFD group (Fig. 3a–c). Additionally, a significant reduction in HDL was observed in the HFD group, whereas treatment with naringenin (50 and 100 mg/kg) for 4 weeks significantly increased serum HDL (Fig. 3d). However, treatment with naringenin at a dose of 25 mg/kg did not significantly ameliorate these lipid parameters except for HDL as compared to the HFD group. These results suggested that treatment with naringenin at doses of 50 and 100 mg/kg regulated lipid parameters in HFD-induced rats.

Fig. 3.

Effects of NAR on serum lipid parameters in rats fed by HFD (n= 6). At the end of the experimental period, the plasma was collected and serum was separated. Lipid parameters including triglycerides (a), total cholesterol (b), LDL (c), and HDL (d) were then analyzed. Data were represented as the means ± SD. *p< 0.05 versus control group, #p< 0.05 versus HFD group. NAR, naringenin.

Fig. 3.

Effects of NAR on serum lipid parameters in rats fed by HFD (n= 6). At the end of the experimental period, the plasma was collected and serum was separated. Lipid parameters including triglycerides (a), total cholesterol (b), LDL (c), and HDL (d) were then analyzed. Data were represented as the means ± SD. *p< 0.05 versus control group, #p< 0.05 versus HFD group. NAR, naringenin.

Close modal

Treatment with Naringenin Ameliorated Oxidative Stress in HFD-Induced Rats

To evaluate the effects of naringenin on oxidative stress in HFD-induced rats, we then measured oxidative stress-related biomarkers including MDA, SOD, NO, and GSH. The results showed that serum MDA and NO were elevated in rats fed by HFD for 16 weeks. Interestingly, treatment with naringenin (50 and 100 mg/kg) for 4 weeks significantly reduced serum MDA and NO as compared to the HFD group (Fig. 4a, c). Additionally, a reduction in serum SOD and GSH was observed in the HFD group, whereas treatment with naringenin (50 and 100 mg/kg) for 4 weeks significantly increased serum SOD and GSH (Fig. 4b, d). In addition, treatment with naringenin at a dose of 25 mg/kg significantly reduced the levels of MDA but did not significantly affect the levels of SOD, NO, and GSH as compared to the HFD group (Fig. 4). These results indicated that naringenin (50 and 100 mg/kg) exerted ameliorated effects against oxidative stress in HFD-induced rats.

Fig. 4.

Effects of NAR on oxidative stress-related biomarkers in rats fed by HFD (n= 6). At the end of the experimental period, the plasma was collected and serum was separated. Serum MDA (a), SOD (b), NO (c), and GSH (d) were determined. Data were represented as the means ± SD. *p< 0.05 versus control group, #p< 0.05 versus HFD group. NAR, naringenin.

Fig. 4.

Effects of NAR on oxidative stress-related biomarkers in rats fed by HFD (n= 6). At the end of the experimental period, the plasma was collected and serum was separated. Serum MDA (a), SOD (b), NO (c), and GSH (d) were determined. Data were represented as the means ± SD. *p< 0.05 versus control group, #p< 0.05 versus HFD group. NAR, naringenin.

Close modal

Treatment with Naringenin Regulated Adipocytokines in HFD-Induced Rats

Next, we evaluated the effects of naringenin on the adipocytokines in HFD-induced rats by measuring the levels of leptin and adiponectin. The results showed that the levels of leptin were significantly increased in the rats fed by HFD, whereas treatment with naringenin (25, 50, and 100 mg/kg) for 4 weeks significantly decreased leptin in HFD-induced rats (Fig. 5a). Additionally, we found that the levels of adiponectin were significantly decreased in the HFD group, whilst treatment with naringenin (50 and 100 mg/kg) for 4 weeks significantly reduced adiponectin (Fig. 5b). Treatment with naringenin at a dose of 25 mg/kg did not significantly increase the levels of adiponectin as compared to the HFD group (Fig. 5b). These results supported that treatment with naringenin regulated adipocytokines in HFD-induced rats.

Fig. 5.

Effects of NAR on serum adipokine including leptin (a) and adiponectin (b) in rats fed by HFD (n= 6). Data were represented as the means ± SD. *p< 0.05 versus control group, #p< 0.05 versus HFD group. NAR, naringenin.

Fig. 5.

Effects of NAR on serum adipokine including leptin (a) and adiponectin (b) in rats fed by HFD (n= 6). Data were represented as the means ± SD. *p< 0.05 versus control group, #p< 0.05 versus HFD group. NAR, naringenin.

Close modal

Treatment with Naringenin Enhanced the Phosphorylation of STAT3 in the Hypothalamus

Finally, we explored the underlying mechanisms of naringenin on the regulation of obesity-associated hypertension. We found that the phosphorylation of STAT3 in the hypothalamus was reduced in the HFD group (Fig. 6a–c). Treatment with naringenin at a dose of 25 mg/kg did not significantly enhance the phosphorylation of STAT3 in the hypothalamus as compared to the HFD group. Interestingly, treatment with naringenin (50 and 100 mg/kg) for 4 weeks significantly enhanced the phosphorylation of STAT3 in the hypothalamus as compared to the HFD group (Fig. 6a–c). Therefore, we inferred that the effects of naringenin on obesity-associated hypertension were associated with its regulation on STAT3.

Fig. 6.

Effect of NAR on the expressions of STAT3 in the hypothalamus from rats fed by HFD (n= 6). a The expressions of STAT3 protein including phosphorylated- and total-STAT3 were determined by Western blot. The relative STAT3 (b) and p-STAT3/STAT3 protein expression levels (c) were quantified. Data were represented as the means ± SD. *p< 0.05 versus control group, #p< 0.05 versus HFD group. NAR, naringenin.

Fig. 6.

Effect of NAR on the expressions of STAT3 in the hypothalamus from rats fed by HFD (n= 6). a The expressions of STAT3 protein including phosphorylated- and total-STAT3 were determined by Western blot. The relative STAT3 (b) and p-STAT3/STAT3 protein expression levels (c) were quantified. Data were represented as the means ± SD. *p< 0.05 versus control group, #p< 0.05 versus HFD group. NAR, naringenin.

Close modal

This study reported that naringenin exerted therapeutic effects against obesity-associated hypertension in a rat model induced by HFD. First, we found that treatment with naringenin (100 mg/kg) reduced body weight and blood pressure in the HFD-induced rat model. Second, treatment with naringenin (50 and 100 mg/kg) regulated lipid disorders by decreasing total cholesterol, triglycerides, and LDL and increasing HDL. Third, treatment with naringenin (50 and 100 mg/kg) regulated oxidative stress and adipocytokines. Finally, we revealed that the effects of naringenin on obesity-associated hypertension are associated with regulatory effects on STAT3. In addition, our results also suggested that naringenin at a dose of 25 mg/kg did not exert strong beneficial effects on the improvement of obesity-associated hypertension.

The aim of this study is to explore the therapeutical effects of naringenin on obesity-associated hypertension. Many studies reported that naringenin exhibited anti-obesity effects in high-fat-induced mouse models [22-24]. For instance, Yoshida et al. [23] found that administration of 100 mg/kg naringenin reduced the infiltration of macrophages by suppressing monocyte chemoattractant protein-1. However, weight loss was not observed in this study because of a short administration period (3 days) [23]. Interestingly, another study initiated by Ke et al. [24] reported that feeding naringenin with HFD for 14 days reduced body weight and adipose mass as compared to mice only fed with HFD. Additionally, naringenin also exerted antihypertension properties in preclinical studies [19, 20]. The combination of naringenin with L-arginine ameliorates the rat model of pulmonary hypertension by the regulation of oxidative stress and inflammation [19]. Treatment with naringenin attenuated kidney damage in a rat model of renovascular hypertension [20]. Taken together, these results encourage us to explore the therapeutical effects of naringenin on obesity-associated hypertension.

In this study, we selected naringenin in a dosage range from 25 to 100 mg/kg, according to previously reported studies [19, 25]. Oyagbemi et al. [25] reported that naringenin at a dose of 50 mg/kg exhibits antihypertensive and neuroprotective effects in hypertensive rats. Another study initiated by Ahmed et al. [19] found that treatment with naringenin at a dose of 50 mg/kg for 3 weeks ameliorates oxidative stress, inflammation, and nitric oxide in hypertensive rats induced by monocrotaline. Therefore, we aimed to explore the effects of naringenin in a wide range from 25 to 100 mg/kg on obesity-associated hypertension.

Obesity is a major cause of hypertension, accounting for 65∼78% of essential hypertension [9]. The primary goal of obesity-associated hypertension therapy is to reduce body weight [26]. In this study, we established a rat model of obesity-associated hypertension by HFD, which is a widely-used animal model for the evaluation of drug effectiveness. Our results showed a significant increase in body weight and fat weight in rats fed with HFD for 16 weeks, indicating that the obesity model was successfully constructed. Interestingly, we observed that treatment with naringenin (50 and 100 mg/kg) for 4 weeks reduced body weight as well as blood pressure as compared to the HFD group. There is a positive correlation between body mass index and blood pressure, including SBP and DBP [27]. Obesity is accompanied by an elevation of SBP and DBP [27]. We observed that the body weight and blood pressure (SBP and DBP) were significantly increased in the HFD group, whereas treatment with naringenin (50 and 100 mg/kg) reduced the body weight and blood pressure (SBP and DBP).

Obesity aggravates lipid disorders and is associated with a decrease in TC and LDL and an increase in HDL [28, 29]. Dyslipidemia further impairs arterial structure and properties, leading to an increase in blood pressure [30, 31]. In addition, clinical studies frequently observed hyperlipidemia in patients with hypertension [32]. In this study, we observed an increase in triglycerides, cholesterol, and LDL as well as a decrease in HDL. Interestingly, we observed that treatment with naringenin (50 and 100 mg/kg) for 4 weeks reduced serum triglycerides, cholesterol, and LDL and increased HDL. These results are similar to a previous study, in which LDL-receptor knockout mice fed with naringenin and HFD exhibited a reduction in cholesterol and LDL as compared to those fed with HFD. These results suggested that administration with naringenin ameliorated lipid disorder in obesity-associated hypertension.

Oxidative stress has been implicated in the development of hypertension [33, 34]. Hypertension is associated with vascular alternation including endothelial dysfunction, leading to a reduction in NO production [33, 35]. MDA is a marker of lipid peroxidation, whereas SOD improves hypertension by modulating vascular structure and function [36]. In addition, GSH oxidation is observed in patients with hypertension [37]. In this study, we found an increase in MDA and NO and a reduction in SOD and GSH in the HFD group, indicating the alternation of redox state in hypertension rats. However, treatment with naringenin (50 and 100 mg/kg) for 4 weeks significantly reduced MDA and NO and increased SOD and GSH, indicating that naringenin ameliorated oxidative stress conditions in HFD-induced rats.

Finally, we explored the underlying mechanisms of naringenin for the treatment of obesity-associated hypertension. The leptin signal transduction pathway is a breakthrough linked with obesity and hypertension [9, 11]. Leptin is a hormone in the hypothalamus that regulates food intake and energy expenditure, thereby increasing the fat mass [11, 38]. However, when fat mass decreases, an elevation of adiponectin is observed [38]. An elevation of leptin activates the phosphorylation of STAT3, regulating the transcriptions of downstream obesity-related genes [38]. In this study, we observed a reduction in adiponectin and an increase in leptin in the HFD group, which is accompanied by the phosphorylation of STAT3. Interestingly, treatment with naringenin (50 and 100 mg/kg) regulated levels of adiponectin and leptin and phosphorylation of STAT3. These results suggested that the ameliorated effects of naringenin on obesity-associated hypertension were associated with its regulatory effects on leptin signal transduction pathways.

Naringenin ameliorated obesity-associated hypertension by reducing body weight and blood pressure. In addition, naringenin also regulated serum lipid parameters and oxidative stress-related biomarkers induced by HFD. Furthermore, naringenin regulated adipocytokines and decreased the phosphorylation of STAT3. Importantly, our results suggested that naringenin at a dose of 100 mg/kg exerts strong beneficial effects on the improvement of obesity-associated hypertension. These results suggested that the ameliorated effects of naringenin on obesity-associated hypertension were associated with its regulatory effects on STAT3. A major limitation of this study is the lack of standard control, which should be included in further investigations. Furthermore, to confirm the therapeutical effects of naringenin on obesity-associated hypertension, clinical studies are warranted.

The animal protocol has been reviewed and approved by the Animal Care and Use Committee, Tianjin Hospital (2012XSD).

The authors declared that they have no conflict of interest.

The study was supported by the Tianjin Natural Science Foundation (17jcybjc27800), Tianjin Health Commission Project Fund (16kg120), Tianjin postgraduate research and innovation project (2019yjss181), and Research Fund of Zhu Xianyi Memorial Hospital of Tianjin Medical University (zxy-yjj2020-9).

Hui Liu and Hui Zhao conceived and designed the experiments. Hui Liu, Hui Zhao, Jingjin Che, and Weijie Yao performed the experiments. Hui Liu, Hui Zhao, Jingjin Che, and Weijie Yao analyzed and interpreted the data. Hui Liu, Hui Zhao, and Jingjin Che contributed reagents, materials, analysis tools or data. Hui Liu and Hui Zhao wrote the paper.

All data generated or analyzed during this study can be obtained upon reasonable request to the corresponding author.

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