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. 2026 Jan 2;40(1):628–639. doi: 10.21873/invivo.14225

Pterostilbene Attenuates High Fat Diet-induced Obesity and Hepatic Dysfunction in Rats: A Functional Evaluation Based on Taiwan’s Health Food Assessment Criteria

CHIEN-JUNG HUANG 1,2, SHIH-CHANG TSAI 3, JAI-SING YANG 4, PO-CHUEN SHIEH 2, YU-JEN CHIU 5,6, DA-TIAN BAU 7,8,9, CHIH-HSIN HUNG 1
PMCID: PMC12764253  PMID: 41482364

Abstract

Background/Aim

Obesity represents a significant global health challenge and is closely linked to the prevalence of metabolic syndromes and liver disorders. In Taiwan, the Ministry of Health and Welfare has instituted specific evaluation protocols for functional foods to mitigate body fat accumulation, underscoring mechanisms beyond caloric restriction. The present study sought to assess the anti-adipogenic and metabolic effects of pterostilbene (PTS) using a rat model of high fat diet (HFD)-induced obesity, in compliance with Taiwan's regulatory standards for health claims about "difficult-to-form body fat”.

Materials and Methods

Male Sprague-Dawley (SD) rats were fed a HFD for six months to induce obesity. Subsequently, the SD rats were administered PTS orally at dosages of 30 or 50 mg/kg/day for 45 days. This study evaluated various parameters, including body weight, food intake, feed efficiency, body fat percentage, liver weight, and serum biochemical markers.

Results

Forty-five day 30 and 50 mg/kg PTS oral treatment significantly reduced body weight gain, food intake, and feed efficiency (all p<0.05). Remarkably, over 70% of the rats exhibited reduction in body fat exceeding 0.02%, meeting the established regulatory efficacy standards. Furthermore, notable improvements were observed in the aspartate aminotransferase (AST), alanine aminotransferase (ALT), triglycerides (TG), total cholesterol (TC), and glucose (GLU) levels (all p<0.05).

Conclusion

PTS is a promising natural compound for the formulation of health foods aimed at enhancing fat metabolism and providing liver protection. The observed effects are consistent with physiological expectations and aligned with the regulatory efficacy criteria established in Taiwan.

Keywords: Pterostilbene (PTS), high fat diet (HFD), obesity, liver protection

Introduction

Obesity is a prevalent metabolic disorder worldwide (1,2), which is closely linked to an elevated risk of numerous comorbidities, including non-alcoholic fatty liver disease (3,4), hypertension (5,6), cardiovascular diseases (7,8), type 2 diabetes (9,10), pulmonary diseases (11,12), chronic kidney disorder (13,14) various forms of cancer (15-17). In social life, obese people may suffer discrimination from others and lose their self-confidence (18). Clinically, FDA-approved anti-obesity medications (AOMs) provide different pharmacological mechanisms for the treatment of obesity (19). For example, the mechanism of action (MOA) of phentermine is mainly to increase the secretion of norepinephrine, dopamine, and serotonin in the hypothalamus (20-22); Liraglutide and semaglutide are mainly glucagon-like peptide-1 (GLP-1) receptor agonists (22-24). Although many AOM have exerted significant effects on obesity, adverse reactions (ADR) have also been reported such as insomnia, dry mouth, constipation, anxiety, headache, elevated blood pressure, tachyarrhythmia, nausea, vomiting, constipation, pancreatitis (22,25,26). Therefore, the development of novel AOMs derived from phytochemicals and natural products represents a critical area of research.

Pterostilbene (trans-3,5-dimethoxy-4-hydroxystilbene; PTS) is a naturally occurring phytochemical found in the heartwood of red sandalwood and the Indian Kino tree (27), as well as in grapes and blueberries (28,29). PTS exhibits a broad spectrum of pharmacological properties, including antioxidant and anti-inflammatory effects (30,31), hepatoprotective activity (32), anti-atherosclerotic effects (33,34), anti-cancer properties (28,29,35), anti-diabetic activity (31,36), and anti-obesity effects (27,37). A growing body of evidence has demonstrated that PTS exhibits anti-obesity activity in both in vitro and in vivo models (27,38,39). In studies using 3T3-L1 adipocytes, PTS has been shown to inhibit adipogenesis by reducing lipid accumulation during adipocyte differentiation (27). In the tumor necrosis factor alpha (TNF-α)-induced 3T3-L1 adipocyte inflammation model, PTS down-regulated cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), interleukin-6 (IL-6), and interleukin-1 beta (IL-1β) mRNA expression and inflammatory cytokine secretion (38). In vivo studies have shown that chronic supplementation with PTS induces alterations in brown adipose tissue in mice fed a high-fat diet (HFD), and reduces fat accumulation in rats subjected to an obesogenic diet (39,40). The aim of this study was to investigate the anti-obesity effects of PTS in rats fed a HFD. Our findings demonstrated that PTS administration significantly reduced body weight gain, food intake, feed efficiency, and body fat accumulation. Additionally, PTS treatment led to marked improvements in key biochemical parameters, including aspartate aminotransferase (AST), alanine aminotransferase (ALT), triglycerides (TG), total cholesterol (TC), and glucose (GLU) levels.

Materials and Methods

Chemicals and materials. PTS was acquired from Sigma-Aldrich (Merck KGaA, Darmstadt, Germany). The high-fat diet (HFD, catalog number D21492) was obtained from Research Diets, Inc. (New Brunswick, NJ, USA). The HFD consists of 60% kcal% fat, 20% kcal% protein, and 20% kcal% carbohydrate according to the indications of the manufacturer.

Animals. Fifteen male Sprague-Dawley (SD) rats (250-300 g; eight weeks old) obtained from the National Laboratory Animal Center (Taipei, Taiwan, ROC) were used in the study. SD rats were housed in wire-mesh cages (26.5×42.0×15.0 cm) under controlled environmental conditions, including 60% relative humidity and a 12-h light/dark cycle (lights on from 08:00 to 20:00). The temperature was maintained at 22±2˚C. The Institutional Animal Care and Use Committee of the China Medical University approved the experimental protocol (No. CMUIACUC-2018-312). Rats fed a HFD for six months gained more than 20% of their body weight compared to those on a basic diet. Subsequently, the obese rats (N=5) were stratified into three distinct cohorts: one cohort received a corn oil (vehicle control), while the remaining two cohorts were orally administered PTS at 30 and 50 mg/kg/day, respectively, for 45 consecutive days. This experimental model aligns with the official guidelines established by the Taiwan Food and Drug Administration (TFDA) for evaluating functional foods with anti-obesity claims, specifically those targeting diet-induced obesity rather than obesity of endocrine origin (41).

Determination of body weight, food intake and feed efficiency. Animals were monitored and body weights, food intake, feed efficiency and were recorded daily. Body weight change=ending weight-starting weight. Feed efficiency=[weight gain (g)/total feed intake (g)]×100% (41).

Determination of body fat percentage and liver/body weight ratio. Following 45-day treatment, all rats were anesthetized, and blood samples were collected via cardiac puncture. The serum was collected using centrifugation at 1,500×g 4˚C for 30 min. The liver tissues, fat around the epididymis, fat around the kidneys and fat above the mesentery were resected and immediately weighed. Body fat mass (g) = fat around the epididymis (g)+fat around the kidneys (g)+fat above the mesentery (g). Body fat percentage = [Body fat mass (g)/ ending weight (g)]×100%. Liver/body weight ratio = [liver weight/ body weight]×100% (41).

Measurement of serum biochemical markers. Serum levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), triglycerides (TG), total cholesterol (TC), and glucose (GLU) were measured using a Fujifilm Dri-Chem NX-500 automated clinical chemistry analyzer (Fujifilm Corporation, Tokyo, Japan). All consumables utilized for the tests, including Fuji Dri-Chem Slide glutamic oxaloacetic transaminase (GOT)/AST-P III (#3150), glutamic pyruvic transaminase (GPT)/ALT-P III (#3250), TG-P III (#1650), TC-P III (#1450), and GLU-P III (#1050), were sourced from Fujifilm (Tokyo, Japan). Prior to use, each batch of consumables was calibrated with the original quality control (42).

Statistical analysis. Data are presented as the mean±standard error of the mean (SEM) based on five replicates (N=5). Differences between multiple experimental groups were assessed using one-way analysis of variance (ANOVA), followed by Dunnett’s test or Tukey’s post hoc test, conducted with SPSS 16.0 software (SPSS, Inc., IBM, Armonk, NY, USA). A p-Value of <0.05 was considered statistically significant (42).

Results

PTS attenuates body weight gain in obese rats. The experimental design employed in this study is illustrated in Figure 1A. Rats administered a higher dose (50 mg/kg/day) of PTS exhibited a significant reduction in body size, indicative of a substantial decrease in adipose tissue mass (Figure 1B). As shown in Figure 2A, PTS administration led to a dose-dependent reduction in body weight gain over the 45-day treatment period. In contrast, mice in the vehicle-treated control group exhibited a continuous increase in body weight throughout the study. Figure 2B illustrates the net change in body weight, revealing that rats treated with PTS at doses of 30 and 50 mg/kg/day not only stabilized their weight but also exhibited significant weight reduction. Notably, over 70% of the animals in the 50 mg/kg/day PTS treatment group experienced weight loss exceeding 0.020 kg.

Figure 1.

Figure 1

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Experimental design and effects of pterostilbene (PTS) on obese rats. (A) Schematic representation of experimental procedure. Male SD rats were fed a HFD for six months to induce obesity, which was defined as body weight exceeding 20% of those fed a basic diet. Subsequently, the rats were divided into three groups and subjected to a 45-day treatment regimen with control vehicle (corn oil), 30 mg/kg/day PTS (administered orally), or 50 mg/kg/day PTS (administered orally). After the treatment period, all rats were euthanized for subsequent analysis. (B) Representative images of rats from the control group and high-dose (50 mg/kg/day) PTS group.

Figure 2.

Figure 2

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Effects of pterostilbene (PTS) on body weight in obese rats. (A) Body weight during the 45-day treatment period in control and PTS-treated groups. SD rats in the control group (black circles) exhibit a continuous increase in body weight, whereas those treated with PTS at 30 mg/kg/day (light gray circles) and 50 mg/kg/day (dark gray circles) show significantly reduced weight gain. Statistical significance: *p<0.05, ***p<0.001 vs. control group. (B) Body weight change during the treatment period. The control group shows a steady increase in body weight, whereas the PTS 30 and 50 mg/kg/day groups exhibit weight stabilization and reduction, respectively. Statistical significance: ***p<0.001 vs. control group. Data are presented as mean±SEM.

Effects of PTS on food intake and feed efficiency. Figure 3A shows a significant reduction in food intake in the PTS-treated groups, particularly at the higher dosage. Additionally, a notable decline in feed efficiency was documented in the treated groups, especially within the 50 mg/kg/day cohort (Figure 3B). Our results suggest that less body mass was gained per unit of food consumed, consistent with the established effects of PTS on enhancing mitochondrial function and reducing nutrient storage efficiency (43).

Figure 3.

Figure 3

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Effects of pterostilbene (PTS) on food intake and feed efficiency in obese rats. (A) Food intake during the 45-day treatment period in control and PTS-treated groups. The control group (black circles) maintains a relatively stable food intake, whereas rats treated with PTS at 30 mg/kg/day (light gray circles) and 50 mg/kg/day (dark gray circles) show a significant reduction in food intake over time. Statistical significance: ***p<0.001 vs. control group. (B) Feed efficiency (%) during the treatment period. Statistical significance: ***p<0.001 vs. control group. Data are presented as mean±SEM.

Reduction of body fat percentage and liver/body weight ratio by PTS. Body fat percentage, as shown in Figure 4A, was significantly lower in both PTS-treated groups compared to the control group. Furthermore, liver/body weight ratio was also markedly decreased (Figure 4B). The results indicate that the PTS intervention reduced the HFD-induced adiposity through reduced body fat and liver weight.

Figure 4.

Figure 4

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Effects of pterostilbene (PTS) on body fat percentage and liver/body weight ratio in obese rats. (A) Body fat percentage in control and PTS-treated groups. The control group exhibits the highest body fat percentage, whereas PTS treatment at 30 and 50 mg/kg/day show significantly reduced body fat accumulation. Statistical significance: ***p<0.001 vs. control group. (B) Liver/body weight ratio (%) in control and PTS-treated groups. Statistical significance: ***p<0.001 vs. the control group. Data are presented as mean±SEM.

Serum biochemistry reveals hepatoprotective effects of PTS. The effects of PTS on key serum biomarkers were systematically assessed. Compared to the control group, both PTS-treated groups demonstrated significant reductions in serum levels of AST, ALT, TG, TC, and GLU (Figure 5). Our results suggest that PTS may have positive effects on liver enzymes and liver function in mice with HFD-induced obesity.

Figure 5.

Figure 5

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Effects of pterostilbene (PTS) on serum biochemical parameters in obese rats. Serum biochemical test values for aspartate aminotransferase (AST), alanine aminotransferase (ALT), total cholesterol (TC), triglycerides (TG), and glucose (GLU) in the control and PTS-treated groups. Statistical significance: ***p<0.001 vs. the control group. Data are presented as mean±SEM.

Discussion

Numerous studies have demonstrated that stilbene derivatives possess anti-obesity properties (44-46). Studies have confirmed that both PTS and resveratrol exhibit anti-obesity effects, which may be attributed to their structural characteristics and the regulatory pathways they influence (27,47,48). In vitro studies demonstrated that the MOA of the anti-obesity agent resveratrol and PTS are thermogenic activation in brown adipose tissue and the browning of white adipose tissue (48). PTS is a resveratrol analogue, featuring one hydroxyl group and two methoxy groups. These structural modifications enhance its lipophilicity, facilitating improved cellular and fatty acid uptake compared to resveratrol (27,47). In this study, we demonstrated that PTS attenuates HFD-induced obesity and hepatic dysfunction in SD rats. These findings are consistent with previous research highlighting the anti-obesity effects of PTS (37,40,49,50).

Given the limited number of studies investigating the effects of PTS in the high-fat diet (HFD)-induced obesity model in Sprague-Dawley (SD) rats, we aimed to establish this model in our laboratory. After six months of HFD feeding, SD rats gained more than 20% of their body weight compared to rats on a standard diet (Prolab®, RMH2500, 5P14) (data not shown). Our results demonstrated that PTS exhibited a significant reduction in body size (Figure 1B), body weight (Figure 2), body fat percentage (Figure 4A) and liver/body weight ratio (Figure 4B). Notably, the rats receiving PTS demonstrated a pronounced reduction in body size, indicating a significant decrease in fat accumulation. This finding is consistent with the well-established lipolytic activity of PTS, which is likely mediated through the activation of hormone-sensitive lipase (HSL) (51,52). Previous reports indicate that polyphenolic compounds such as PTS may enhance energy expenditure by activating AMP-activated protein kinase (AMPK) and promoting fatty acid oxidation (45,53). Figure 2 highlights the net body weight change, showing that rats treated with 50 mg/kg/day showed not only stabilized but significantly reduced weight. Remarkably, more than 70% of animals in PTS exhibited weight loss >0.02 kg, fulfilling the regulatory benchmark for 'reduced adipogenesis' in Taiwan’s health food evaluation guidelines (41). However, the potential contribution of appetite suppression to the observed weight loss cannot be entirely excluded and warrants further investigations.

Obese individuals often struggle to regulate their dietary energy intake or expend significant amounts of energy through exercise. As a result, researchers are persistently exploring effective treatments for obesity. Reduction in body fat can be achieved via reducing food intake and feed efficiency. Our results showed that PTS reduced food intake and feed efficiency (Figure 3). Although appetite suppression is not recognized as a primary mechanism under the regulatory criteria for functional foods that claim to reduce body fat this phenomenon may represent a secondary benefit associated with enhanced metabolic regulation (54,55). In Figure 4, the results demonstrate reduction of body fat percentage and liver/body weight ratio by PTS. These findings are consistent with previous reports on PTS’s ability to reduce ectopic fat accumulation via inhibition of lipogenesis and enhancement of fatty acid oxidation (45,53). However, the absence of histological quantification of hepatic lipid content limits the strength of this conclusion and requires further validation through tissue-level lipid analysis.

Our results demonstrated that PTS significantly reduced serum levels of AST, ALT, TG, TC, and GLU (Figure 5). These changes reflect improvements in hepatic function and overall metabolic health, consistent with previous reports that characterized PTS as a potent antioxidant and insulin-sensitizing compound (51,56-58). Notably, the decline in ALT and AST levels by PTS suggests a hepatoprotective effect, potentially mitigating liver stress or injury. The reduction in circulating lipid parameters indicates the suppression of lipogenesis and enhanced lipid metabolism. Collectively, these results support the potential of PTS as a functional ingredient for metabolic health promotion (32,59,60). Nevertheless, it remains to be clarified whether these biochemical improvements are primarily secondary to reductions in adiposity or driven by the direct molecular actions of PTS. Further mechanistic studies are needed to elucidate the underlying pathways. This study presents compelling evidence that PTS confers multifaceted benefits in a rat model of HFD-induced obesity. In accordance with Taiwan’s evaluation framework, which emphasizes mechanisms independent of appetite suppression, we observed that PTS significantly reduced body fat percentage, liver weight, and serum metabolic markers even under controlled caloric intake conditions. One limitation of this study is the lack of histological confirmation of liver lipid accumulation and adipose tissue morphology, which would facilitate differentiation between subcutaneous and visceral fat loss. Additionally, although rodent models provide valuable physiological insights, extrapolation to human efficacy requires validation through rigorously controlled clinical trials that adhere to similar energy balance constraints.

Conclusion

In conclusion, our results provide compelling evidence supporting the anti-obesity effects of PTS. Our findings support the potential use of PTS as a functional ingredient in health foods aimed at managing obesity and enhancing metabolic health, in accordance with scientific evidence and regulatory guidelines established by the Taiwan Ministry of Health and Welfare.

Conflicts of Interest

The Authors declare no potential conflicts of interest with respect to the research, authorship and publication of this article.

Authors’ Contributions

Research design: Huang CJ, SC Tsai, Yang JS, Bau DT and Hung CH; experimental design, organization and conduction: SC Tsai, Yang JS, Shieh PC, Bau DT and Hung CH; statistical analysis: Yang JS, Chiu YJ and Shieh PC; data clearance and validation: Huang CJ, SC Tsai, Yang JS, Bau DT and Hung CH; article writing: Bau DT, SC Tsai, Yang JS and Hung CH; correction of manuscript: SC Tsai, Yang JS, Shieh PC and Hung CH; review and revision: SC Tsai, Yang JS, Hung CH and Bau DT.

Acknowledgements

The Authors wish to acknowledge the excellent technical and equipment support work of Mr. Yung-Shuan Chang (Bio-Cando Ltd. Taiwan). The authors would like to thank the Office of Research and Development, China Medical University (Taichung, Taiwan), for providing the Medical Research Core Facilities for performing the experiments and data analysis.

Funding

This work was supported in part by a project (CMU-113-S-35) from China Medical University Hospital, and MOST 109-2320-B-039-041- from the Ministry of Science and Technology, Taiwan.

Artificial Intelligence (AI) Disclosure

No artificial intelligence (AI) tools, including large language models or machine learning software, were used in the preparation, analysis, or presentation of this manuscript.

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