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Introduction
Over the past few decades, obesity, which results from excessive white adipose tissue expansion, has steadily increased worldwide (1-3). The World Health Organization defines overweight and obesity as a body mass index (BMI, i.e., the ratio of the body weight [kg] to height squared m2) of 25∼30 kg/m2, and >30 kg/m2, respectively. It is estimated that by 2030, approximately 60% of the world’s adult population will be obese or overweight (4, 5), which are considered risk factors for obesity-associated morbidities, including type 2 diabetes, insulin resistance, cardiovascular diseases, and metabolic dysfunction-associated steatotic liver disease (MASLD) (6-9). Recently, many research groups have focused on clinical and mechanistic studies aimed at overcoming metabolic diseases by identifying potential therapeutic targets (10-13).
Traditionally, obesity treatment is based on lifestyle changes, nutritional education, and increased physical activity, which are all necessary for long-term success (4). However, because many obesity control methods have limited success, there has been an increased focus on the use of drugs with anti-obesity effects, including those that suppress appetite, reduce food intake, and limit the absorption (14, 15). Although various chemicals have been employed for this, they can cause adverse effects, including headaches, insomnia, and increased blood pressure (16). Therefore, the development of novel, safe, and effective therapeutic interventions targeting the intricate pathophysiology of obesity is required (17, 18).
Recent evidence suggests that the flavonoids and phenolic compounds in natural products and medicinal plants with anti-obesity activities are promising therapeutic agents against obesity and obesity-associated morbidities. In vitro and in vivo studies show that these compounds can significantly reduce adipocyte growth and differentiation, and improve glucose metabolism and insulin sensitivity (11, 19-21), highlighting their promise as adjuvant treatments for obesity management and prevention.
Pears (Pyrus spp.) are rich in bioactive phenolic compounds, such as flavan-3-ols, flavonoids, and phenolic acids, which have antioxidant, antimicrobial, and anti-inflammatory roles (22-24). Previous studies have shown that pear extract affects various physiological systems. An in vitro study found that treating 3T3-L1 adipocytes with pear pomace extract inhibited adipogenesis and induced mature adipocyte apoptosis via AMPK activation (25). Additionally, in obese mice, pear extract supplementation led to significant weight loss and improved metabolic parameters, including glucose tolerance and insulin sensitivity (26). However, further studies are needed to identify the biologically active compounds causing the observed effects and to evaluate the long-term safety and efficacy of pear extract in human clinical trials. Here, we show that pear extract reduces obesity without adverse side effects or undesirable changes.
Materials and Methods
Study design and population
Participants who voluntarily signed the consent form for the human application trial were assessed for compliance with the exclusion criteria through a site visit evaluation. Those who met the criteria were randomly assigned to the experimental or control groups based on the order of registration. Participants took pear extract or the placebo designated for the human application trial for 12 weeks. The inclusion criteria were: 1) an age of ≥19 years and ≤65 years; 2) a BMI of ≥25 kg/m2 and <35 kg/m2 at visits 1 and 2; 3) waist circumferences of ≥90 cm and ≥85 cm for male and female, respectively; and 4) consent to participate in the human application trial before it began and signing of a written informed consent form. The following were excluded: 1) those undergoing treatment for severe diseases of the cardiovascular, immune, respiratory, gastrointestinal/liver and biliary, renal and urinary, nervous, and musculoskeletal systems; 2) those undergoing treatment for psychiatric diseases, infectious diseases, or malignant tumors although depending on their condition, they could be included at the investigator’s discretion; 3) those using medications that affect body weight (e.g., anti-obesity drugs like appetite suppressants, fat absorption inhibitors, and GLP-1 receptor agonists, drugs for psychiatric conditions like depression or schizophrenia, as well as beta-blockers, diuretics, contraceptives, steroids, and female hormones); 4) those on health functional foods/supplements for weight control, herbal medicine, or diet-formulated foods for weight control in the month (30 days) before visit 1; 5) those with uncontrolled hypertension (systolic blood pressure of ≥160 mmHg or diastolic blood pressure of ≥100 mmHg) based on measurements taken after a 10-minute rest; 6) those with fasting blood glucose levels ≥126 mg/dL, or were taking anti-diabetic medications (e.g., oral hypoglycemic agents and insulin); 7) those with TSH levels of ≤0.1 μIU/mL or ≥10 μIU/mL; 8) those with creatinine levels more than twice higher than the upper limit for normal levels at the trial site; 9) those with aspartate aminotransferase (glutamic oxaloacetic transaminase) (AST [GOT]) or alanine aminotransferase (glutamic pyruvic transaminase) (ALT [GPT]) levels more than thrice higher than the upper limit for normal levels at the trial site; 10) those with an alcohol use disorder or central nervous system disorders; 11) those judged to be unable to exercise because of musculoskeletal disorders; 12) those with a body weight change of >10% in the three months before visit 1; 13) those who participated in a commercial weight-loss program in the three months before visit 1; 14) those who participated in another interventional clinical trial (including human application trials) in the month (30 days) before visit 1 or planned to participate in one after the start of this trial; 15) those who were pregnant, breastfeeding, or planning to become pregnant during the trial period; 16) those with sensitivity or allergy to any ingredients in this trial’s test food; and 17) those the investigator deemed unsuitable for other reasons. The trial was approved by the Institutional Review Board (HKS 2021-06-007-008 and GIRB-22418-HM).
Treatment
UPhenonⓇ (Suheung Co., Ltd.), a coated tablet with a unique flavor, is free of off-taste or smell and has a dark gray-brown color (27). Each tablet contained 800 mg, and participants were directed to take one tablet once daily with water. Corn starch, in the form of a dark gray-brown coated tablet with a unique flavor and free of off-taste or smell, was used as the control. The consumption period was 12 weeks. The effective intake was based on a study in which six-week-old C57BL/6 mice were fed a high-fat diet for six weeks, followed by daily consumption of the test food at 100 and 200 mg/kg of bw/day for five weeks. Significant toxicity was not observed in any group, and similar body fat-reducing efficacy was observed across all groups. Therefore, it was concluded that regarding the food’s efficacy, 100 and 200 mg/kg bw/day were appropriate (26). Based on FDA conversion guidelines, the preclinical effective dose of 200 mg/kg/day in mice corresponds to a human equivalent dose of approximately 975.6 mg/day for a 60 kg adult. To ensure both safety and formulation feasibility, the daily intake was conservatively set at 800 mg/day, close to the preclinical efficacy level.
Safety evaluation
To assess UPhenonⓇ’s safety, hematology and blood chemistry parameters were tested during screening. The levels of white blood cells, red blood cells, hemoglobin, platelets, neutrophils, lymphocytes, eosinophils, basophils, AST, ALT, total protein, albumin, ALP, Ca, creatine kinase, blood urea nitrogen, creatinine, uric acid, gamma-glutamyl transferase, glucose, Na, K, and Cl were evaluated at the 0- and 12-week intervention periods.
Statistical analysis
Statistical analyses were performed using SASⓇ version 9.4 (SAS Institute). Within-group comparison of changes in body fat mass before and after intake, measured using dual-energy X-ray absorptiometry (the primary efficacy evaluation variable), was done using the paired t-test. At each time point, the statistical significance of the degree of change in the experimental vs. control group was evaluated using a two-sample t-test or Wilcoxon rank sum test, depending on whether normality assumptions were met. Additionally, a generalized linear model (GLM; equivalent to ANCOVA) was used with baseline values as covariates. If the baseline characteristics were statistically significantly different between the groups, the corresponding variables were considered covariates in the GLM. For secondary efficacy evaluation variables, such as weight, waist circumference, hip circumference, waist-to-hip ratio, BMI, lean mass, blood lipids (total cholesterol, high- and low-density lipoprotein cholesterol, and triglycerides), high-sensitivity C-reactive protein, adiponectin, and leptin, the within-group comparison of the before and after intake changes were analyzed using a paired t-test. At each time point, depending on normality assumptions, the statistical significance of the degree of changes in the experimental vs. control group was evaluated using a two-sample t-test or Wilcoxon rank sum test. Any baseline characteristics with statistically significant differences between the groups were used as covariates in the GLM. All adverse reactions that occurred after test food intake were tabulated and their incidence rates were evaluated. The proportion of participants with adverse reactions in each group was then calculated and compared between the groups using a chi-square test or Fisher’s exact test. For clinical pathology tests (hematological, biochemical, and urinalysis), the within-group comparison of changes in hematological and biochemical test values before and after intake was done using the paired t-test. The statistical significance of the degree of change in the experimental vs. control groups was evaluated using the two-sample t-test or Wilcoxon rank sum test, depending on normality assumptions. Urinalysis results were classified as normal or abnormal, and within-group differences were compared using the McNemar’s test. For the vital signs, blood pressure and pulse, the within-group comparison of changes before and after intake was analyzed using the paired t-test. The statistical significance of the degree of change in the experimental vs. control groups was evaluated using the two-sample t-test or Wilcoxon rank sum test, depending on normality assumptions.
Results
Subject characterization
This was a randomized, double-blind, placebo-controlled parallel study with four visits. Recruitment took place between October 2021 and September 2022. Upon voluntarily signing an informed consent form, the participants underwent demographic and lifestyle surveys, medical history and medication use assessments, vital sign (blood pressure and pulse) measurements, physical examinations, clinical pathology tests, pregnancy tests (for female of childbearing age), anthropometric measurements, and BMI calculations. If they met the inclusion and exclusion criteria, they were registered in the trial through random assignment. The participants assigned to the experimental and control groups (at a 1：1 ratio) consumed the test food or the placebo, for 12 weeks respectively. The flow of participants in the trial is shown in Fig. 1. A total of 100 participants volunteered for the study and of these, 14 withdrew consent because of personal reasons or were lost to follow-up without any reason being given, and they were excluded before the release of the double-blinding.
Baseline clinical characteristics
The baseline clinical characteristics of the study participants appeared to be well-matched across several parameters (Table 1). Body weight, BMI, sex, and drinking and smoking status were similar between the two groups (Table 1). Age was also similar between the two groups (mean age: approximately 43 and 42 years for the pear extract and placebo groups, respectively.
Effect of pear extract on body weight and body mass index
Table 2 shows the changes in biomarkers after 6 and 12 weeks of pear extract supplementation. No significant differences were found between the test and placebo groups and there were no apparent pear extract adverse effects. However, when compared with baseline measurements, body fat mass (−802.61±1,460.82 g, p<0.0007), body weight (−1.28±1.29 kg, p<0.0001), waist round (−1.66±2.17 cm, p<0.0001), hip round (−1.30±2.18 cm, p<0.0003), and BMI (−0.46±0.46, p<0.0001) were significantly reduced after 12 weeks of pear extract administration (Table 2). We further investigated age and sex differences in this trial; however, no significant differences were observed between the groups (Table 3, 4).
Effect of pear extract on hematological parameters
Table 5 shows hematological parameter changes after pear extract supplementation for 12 weeks. No significant differences were found in the test vs. placebo groups, indicating no adverse effects or significant changes in the supplementation and placebo groups.
Effect of pear extract on blood chemistry parameters
Table 6 shows blood chemistry parameter changes after pear extract supplementation for 12 weeks. No significant differences were found in the test vs. placebo groups, indicating no adverse effects or significant changes in the supplementation or placebo groups, except for AST (GOT) levels, which were significantly decreased (−1.28±1.29 IU/L, p<0.0314) in the pear extract group when compared with the placebo group (Table 6). Since AST levels are strongly associated with liver injury and damage, this suggests that pear extract has potential therapeutic efficacy against obesity-induced liver diseases.
Discussion
Metabolic syndrome is defined by a cluster of risk factors that increase the likelihood of developing cardiovascular diseases, type 2 diabetes, and vascular abnormalities (28, 29). It is diagnosed when a person exhibits at least three of the following medical conditions: abdominal obesity, hypertension, hyperglycemia, high serum triglycerides, and low serum high-density lipoprotein cholesterol. Abdominal obesity, which plays a pivotal role in metabolic syndrome diagnosis, is assessed using common measurements, including waist circumference, BMI, and waist-to-hip ratio, which are widely used to evaluate obesity (30-32).
Obesity treatment often begins with lifestyle changes that incorporate diet, exercise, and behavioral modifications. Nutritional education and modification play a key role, with strategies like caloric restriction through low-calorie and carbohydrate- or fat-restricted diets. Other treatment options include anorectic drugs, probiotic/prebiotic supplementation, and bariatric surgery, a digestive system-altering weight loss procedure (31, 33, 34). However, most studies show that traditional treatments have limited success. Therefore, to effectively address obesity, combining various approaches has become increasingly important in recent years.
Natural compounds are increasingly recognized as promising therapeutic agents for obesity and associated health conditions. Numerous studies have demonstrated that these compounds can significantly help prevent and manage obesity and type-2 diabetes (11, 33). These findings suggest that natural compounds can be valuable adjunctive metabolic syndrome treatments. Our trial shows that in patients with obesity, pear extract administration for 12 weeks resulted in reduced body weight and BMI when compared with baseline measurements. Importantly, there were no significant differences observed in the pear extract vs. placebo groups, indicating that neither group experienced adverse effects or significant physiological changes, which underscores pear extract’s safety profile.
Adipocytes are differentiated from mesenchymal stem cells (MSCs) derived from tissues such as bone marrow, adipose tissue, and muscle (35). Adipocyte differentiation plays a central role in regulating energy metabolism and the development of metabolic disorders (36). MSCs initially differentiate into preadipocytes, which subsequently mature into adipocytes in response to signals such as insulin, glucocorticoids, and PPARγ. Accordingly, the expression levels of key adipogenic transcription factors, such as PPARγ, C/EBPα, and FABP4, as well as lipogenic enzymes and regulatory proteins including FAS, SCD1, ACC1 and the lipogenesis-associated transcription factor SREBP-1c, are critical for adipocyte differentiation (37). Previous studies have demonstrated that pear extract suppresses the expression of key adipogenic transcription factors, lipogenic enzymes and regulatory proteins. Furthermore, pear extract improves the expression of metabolic regulators leptin and adiponectin, enhances glycemic homeostasis and insulin sensitivity, and effectively reduces body fat accumulation by modulating energy metabolism (26). Therefore, the clinical findings obtained in this study provide compelling evidence for the therapeutic potential of pear extract in the prevention and management of obesity and metabolic disorders.
Our study has several limitations. First, the supplementation and placebo groups did not differ significantly in body fat mass, body weight, BMI, hematological parameters, or blood chemistry parameters. However, when compared with baseline measurements, a significant reduction in body fat mass, body weight, and BMI was observed after 12 weeks of pear extract administration. It is noteworthy that several metabolic parameters also improved within the placebo group. This observation may be largely explained by behavioral phenomena such as the placebo effect and the Hawthorne effect, wherein individuals alter their lifestyle practices simply due to their awareness of participating in a clinical trial. Evidence from a large-scale meta-analysis involving over 20,000 subjects in weight loss interventions supports this interpretation, reporting significant decreases in BMI, body weight, and waist circumference among placebo recipients, changes likely driven by increased motivation, attention, and self-monitoring (38). Accordingly, the biomarker reductions observed in our placebo group may reflect such non-specific behavioral influences rather than any intrinsic physiological effect. By contrast, the selective and significant decrease in body fat mass observed exclusively in the pear extract-treated group indicates a potential compound-specific mechanism of action that cannot be fully explained by behavioral factors alone. Second, because human clinical trial participants are generally influenced by their expectations and willingness to experience the functional effects of the test food, changes in their daily life and behavior may occur, which can impact the results. Although efforts are made to minimize these effects by controlling and managing the participants’ daily routines, the limitation remains. For example, in trials assessing fat loss functions, participants may engage in additional diet management and exercise to enhance the effects of fat loss. Third, after pear extract supplementation, we found a slight decrease in AST (GOT) levels, suggesting a potential association with reduced MASLD, a key metabolic syndrome-related disease. Interestingly, several studies reported that pear extract exerts beneficial effects on MASLD. For example, You et al. (39), demonstrated that pear pomace water extract suppresses liver lipid peroxidation and protects against liver injury by enhancing hepatic antioxidants. Similarly, Basit et al. (40), reported that pear extract, which contains polyphenols such as Chlorogenic acid, confers hepatoprotective effects by inhibiting the TLR4/NF-κB signaling pathway and activating the Nrf2 pathway. However, in our study, although pear extract may have the potential to reduce MASLD, no participants were evaluated as having clinically significant findings by the examiner.”
In conclusion, our findings indicate that pear extract supplementation may effectively reduce obesity without side effects, making it a promising alternative to synthetic anti-obesity medications.
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