Research Article

Role of Vitamin E in Wound Healing of Rats Fed High-Fat Diet

Devita Anggraeni*, Artina Prastiwi, Mungky Ema Ramadhani

Department of Surgery and Radiology, Faculty of Veterinary Medicine, Universitas Gadjah Mada, Jl. Fauna 2, Yogyakarta 55281, Indonesia.

Received | October 02, 2025; Accepted | October 31, 2025; Published | November 20, 2025

*Correspondence | Devita Anggraeni, Department of Surgery and Radiology, Faculty of Veterinary Medicine, Universitas Gadjah Mada, Jl. Fauna 2, Yogyakarta 55281, Indonesia; Email: [email protected]

Citation | Anggraeni D, Prastiwi A, Ramadhani ME (2025). Role of vitamin E in wound healing of rats fed high-fat diet. Adv. Anim. Vet. Sci., 13(11):2545-2553.

DOI | https://dx.doi.org/10.17582/journal.aavs/2025/13.11.2545.2553

ISSN (Online) | 2307-8316

Copyright: 2025 by the authors. Licensee ResearchersLinks Ltd, England, UK.

This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).

INTRODUCTION

Globally, while the prevalence of obese adolescents has increased fourfold since 1990, the number of obese adults has more than doubled. In 2022, over 890 million of the nearly 2.5 billion people who were deemed overweight were obese (WHO, 2024). Modern high-calorie diets and sedentary lifestyles are contributing to the global rise in obesity by causing an energy imbalance that eventually results in weight gain (Ahmed and Mohammed, 2025). Obesity, defined as the excessive accumulation of visceral and subcutaneous fat, leads to increased body weight and health problems (Dias et al., 2021). Epidemiological estimations indicate that over 5 million deaths globally in 2019 were caused by high body mass index, suggesting the significant mortality burden associated with obesity-related illnesses (WHO, 2024). Diets high in fat are known to cause obesity and a number of metabolic diseases in both people and animals, including diabetes and heart disease (Eastep and Chen, 2015). Alma et al. (2023) state that these health issues also significantly inhibit the wound healing.

A wound is characterized as damage with disruption of the normal structure and tissue function (Liu et al., 2022). The damage can vary from a simple rupture of the epithelium to more severe lesions that extend into the subcutaneous tissue and might impact the muscles, organs, nerves, arteries, and bones (Okur et al., 2020). Inflammation, proliferation, and maturation are the three phases of wound healing that preserve tissue structure and function. Many cell types, cytokines, and growth factors interact during each phase (Shin et al., 2017; Kopcewicz et al., 2020).

The process of wound healing is influenced by numerous factors, frequently classified as local or systemic. Local factors, such as oxygen availability and infection, directly impact the wound site, while systemic factors relate to an individual’s overall health and illness condition, including age, hormonal status, stress, diabetes, obesity, and drugs (Rosyid, 2022). Obesity has been associated with a higher risk of wound infection, dehiscence, and death in surgical patients; therefore, the detrimental impact of obesity on wound healing is an important aspect (Arnke et al., 2023). According to Yudhistira et al. (2022), obesity constitutes a risk factor for an impaired skin barrier. In obesity, hypertrophic adipocytes release pro-inflammatory cytokines that damage the stratum corneum, disrupting its lipid composition and leading to impaired skin barrier function, as evidenced by increased TEWL. A study demonstrated that obesity due to a high-fat diet prolongs the inflammatory phase, thereby impairing wound healing in a rat model (Pierpont et al., 2014). A high-fat diet inhibits wound contraction and reepithelialization, increases inflammatory cell migration, and delays myofibroblastic differentiation, collagen deposition, epithelial and connective cell proliferation, and angiogenesis. Short-term high-fat diet consumption can impede wound healing by delaying extracellular matrix deposition and wound closure due to inflammatory phase disruptions (Schaunel et al., 2020).

Vitamin E enhances wound healing through its vital antioxidant properties, with α-tocopherol considered the most effective form (Thompson et al., 2022). This vitamin also provides protection against metabolic disorders, such as diabetes, cancer, cardiovascular disease, and obesity (Shin et al., 2017). The function of vitamin E as the body’s primary defense is protecting cell membranes from free radical damage by inhibiting lipid peroxidation (Joshi et al., 2023). According to Fatima et al. (2025), vitamin E affects skin health by providing antioxidant protection and improving skin structure. It accomplishes this by stabilizing phenoxyl radicals, neutralizing free radicals, facilitating enzymatic regeneration processes, and enhancing collagen synthesis, which collectively diminish oxidative stress and improve skin resilience (Figure 1). Thus, this study evaluated the therapeutic potential of vitamin E for wound healing in high-fat diet-fed rats, specifically assessing its effects on lipid profile, wound surface area, histopathologic figures, and polymorphonuclear cell count.

 

MATERIALS AND METHODS

Experimental design

This present study was carried out at the Center for Food and Nutrition Studies, Universitas Gadjah Mada, Yogyakarta, Indonesia. As in a study conducted by Chinko and Precious-Abraham (2024), this study utilized twenty male Wistar rats at twelve weeks old and weighing 200 g on average. They were exposed to a 12-hour light/dark cycle and kept at a steady temperature of 26 °C. The rats were randomly allocated to four groups (I, II, III, and IV) of five animals each. Each rat was housed individually and provided with unrestricted standard diet and water for a week. Upon completion of the adaptation period, the rats were assigned to the following treatment groups: Group I received a standard diet, Group II a high-fat diet, Group III a standard diet plus vitamin E supplementation (Ever E, Konimex, Indonesia) at 300 IU/kg, and Group IV a high-fat diet plus vitamin E supplementation (300 IU/kg). Vitamin E in oil-based form was administered orally using a feeding syringe. The treatment period was 8 weeks, following the previous study by Lasker et al. (2019). Table 1 lists the composition of standard and high-fat diets, modified from the AIN-93 diet formulation (Shirai et al., 2016).

Excisional wound

After completing the 8-week treatment, all rats were weighed, and samples of blood were taken. Before drawing the blood, the rats were anesthetized by injecting ketamine 50 mg/kg (Ilium Ketamil, Troy Laboratories PTY LTD, Australia) and xylazine 5 mg/kg (Xyla-Z 2%, BSHM Co., China) intramuscularly. Blood was drawn for triglyceride, cholesterol, LDL, and HDL analysis. Following the blood collection, the hair on the back area was clipped, and the skin was then rubbed with iodine before being excised. Skin excisions were made on the back using a biopsy punch with a diameter of 0.8 cm. Topical chloramphenicol (Ikamicetine, Ikapharmindo, Indonesia) was then applied to the wounds twice daily for 7 days. Seven days after wound excision, all rats were anesthetized, followed by wound surface area measurement.

 

Table 1: Composition of standard and high-fat diets

Diet	Standard (g/100g)	High-fat (g/100g)
Vitamins	5	5
Cellulose	5	5
Animal fat	4	20
Sucrose	10	10
Corn flour	62	46
Casein	14	14
Total	100	100

 

Hematoxylin-eosin (HE) staining procedure

The wounded skin was excised and preserved in 10% neutral buffered formalin (Leica Biosystems Richmond, US). Histopathologic examination was performed using hematoxylin and eosin staining. The staining procedure commenced with deparaffinization using three changes of xylene, each for 2 minutes. Subsequent rehydration was performed using a declining ethanol series (100%, 95%, 90%, 80%, and 70%) with 5-minute incubations at each concentration, after which the slides were rinsed in running tap water for 10 minutes. The tissues were subsequently stained with hematoxylin for 5 minutes, rinsed for another 10 minutes, and then stained with eosin for 2 minutes. The slides were then dehydrated in a graded alcohol series, cleared in xylene, and permanently mounted with mounted medium (Yudhika et al., 2021).

Wound surface area measurement

A millimeter-grid paper with a central hole was placed over the wound for scale calibration (Supplementary Figure 2). A digital image was captured, and the wound surface area was measured using Digimizer Image Analysis Software.

Polymorphonuclear cell counts

The counting of tissue polymorphonuclear cells was performed by capturing images of the skin histopathological section in four random fields directly beneath the scab, using a microscope equipped with a digital camera (Optilab, Miconos, Indonesia) at a magnification of 400x, as described by Lopez et al. (2012).

Statistical analysis

Cholesterol, triglyceride, LDL, HDL, body weight, wound surface area, and polymorphonuclear cell counts were statistically evaluated with two-way ANOVA, followed by Tukey’s post hoc test to identify specific group differences, as described by Rosanto et al. (2021). A P-value less than 0.05 was considered to be statistically significant. Histopathological figures of the wounded skin were assessed descriptively.

RESULTS

Body weight

Body weight is one of the critical parameters related to the high-fat diet and vitamin E supplementation. The results indicate a significant effect of vitamin E and a high-fat diet on the body weight of rats. Rats maintained on a standard diet exhibited a significantly lower body weight (243.20 ± 7.28 g) than those subjected to a high-fat diet (284.40 ± 28.22 g; P<0.05). Additionally, the body weight of rats administered vitamin E (247.30 ± 11.51) was significantly lower than that of rats not receiving vitamin E (280.30 ± 32.48; P<0.05) (Table 2). This study demonstrated that vitamin E supplementation effectively reduced body weight in both rats on a standard diet and those on a high-fat diet.

 

Table 2: Mean body weight (in grams) of rats fed standard or high-fat diets, with or without vitamin E supplementation (300 IU/kg), after eight weeks of treatment.

	w/o vit E	w/vit E	Total mean
Standard diet	249.6±2.70	236.80±3.11	243.20±7.28b
High-fat diet	311.00±3.16	257.80±3.56	284.40±28.22a
Total mean	280.30±32.48x	247.30±11.51y

 

Different superscripts (a,b) within a column denote significant differences (P<0.05). Different superscripts (x,y) within a row denote significant differences (P<0.05).

 

Lipid profile

Excessive fat consumption may contribute to an increase in body weight, which can affect blood triglyceride, HDL, LDL, and cholesterol levels. The current study demonstrated that a high-fat diet and the presence of vitamin E affected blood cholesterol levels. Higher cholesterol level (188.26 ± 45.93) was exhibited in rats on a high-fat diet compared to those on a standard diet (87.68 ± 4.38; P<0.05). However, vitamin E supplementation in rats effectively decreased cholesterol levels (114.38 ± 32.55) compared to those that did not receive it (161.57 ± 73.83; P<0.05) (Table 3).

This study demonstrated that both a high-fat diet and vitamin E influenced blood triglyceride levels. Rats subjected to a high-fat diet had markedly higher triglyceride levels (124.57 ± 12.62) compared to those on a standard diet (70.56 ± 7.05; P<0.05). In contrast, rats administered vitamin E exhibited significantly reduced triglyceride levels (88.91 ± 26.40) compared to those not receiving vitamin E (106.22 ± 31.09; P<0.05) (Table 4).

 

Table 3: Mean blood cholesterol levels (mg/dL) of rats fed standard or high-fat diets, with or without vitamin E supplementation (300 IU/kg), after eight weeks of treatment.

	w/o vit E	w/vit E	Total mean
Standard diet	91.57±1.59	83.80±1.71	87.68 ± 4.38b
High-fat diet	231.57±3.71	144.96±6.63	188.26±45.93a
Total mean	161.57±73.83x	114.38±32.55y

 

Different superscripts (a,b) within a column denote significant differences (P<0.05).Different superscripts (x,y) within a row denote significant differences (P<0.05).

 

Table 4: Mean blood triglyceride levels (mg/dL) of rats fed standard or high-fat diets, with or without vitamin E supplementation (300 IU/kg), after eight weeks of treatment.

	w/o vit E	w/vit E	Total mean
Standard diet	76.85 ± 2.88	64.27 ± 2.15	70.56 ± 7.05b
High-fat diet	135.57±3.31	113.56±6.67	124.57±12.62a
Total mean	106.22±31.09x	88.91±26.4y

 

Different superscripts (a,b) within a column denote significant differences (P<0.05). Different superscripts (x,y) within a row denote significant differences (P<0.05).

 

Table 5: Mean Low-Density Lipoprotein (LDL) levels (mg/dL) of rats fed standard or high-fat diets, with or without vitamin E supplementation (300 IU/kg), after eight weeks of treatment.

	w/o vit E	w/vit E	Total mean
Standard diet	29.34±1.43	26.16±1.33	27.75±2.12b
High-fat diet	75.98±1.50	52.18±2.57	64.08±12.70a
Total mean	52.66±24.62x	39.17±13.85y

 

Different superscripts (a,b) within a column denote significant differences (P<0.05). Different superscripts (x,y) within a row denote significant differences (P<0.05).

 

Table 6: Mean High-Density Lipoprotein (HDL) levels (mg/dL) of rats fed standard or high-fat diets, with or without vitamin E supplementation (300 IU/kg), after eight weeks of treatment.

	w/o vit E	w/vit E	Total mean
Standard diet	77.94 ± 2.49	84.71 ± 2.57	81.32 ± 4.29a
High-fat diet	28.09±1.21	44.26 ± 1.41	36.18 ± 8.61b
Total mean	53.02±26.33y	64.49±21.4x

 

Different superscripts (a,b) within a column denote significant differences (P<0.05). Different superscripts (x,y) within a row denote significant differences (P<0.05).

 

The means of LDL and HDL levels are shown in Tables 5 and 6. Rats consuming a high-fat diet had the levels of LDL (64.08 ± 12.70) and HDL (36.18 ± 8.61) that were markedly different from those in rats on a standard diet (P<0.05). In this study, the high-fat diet increased LDL levels while decreasing HDL levels (P<0.05). Moreover, vitamin E supplementation affected LDL (39.17 ± 13.82) and HDL (64.49 ± 21.40) levels, whereas vitamin E decreased LDL levels and increased HDL levels significantly (P<0.05).

Wound surface area

On the seventh day following excision, wound surface areas were assessed. As indicated in Table 7, the wound surface areas in rats fed a high-fat diet were significantly larger (57.42 ± 11.02) than those in rats fed a standard diet (36.96 ± 9.31; P<0.05). Meanwhile, vitamin E treatment did not significantly affect wound surface area.

 

Table 7: Mean wound surface area (mm2) after seven days of excision in rats fed standard or high-fat diets, with or without vitamin E supplementation (300 IU/kg), following eight weeks of treatment

	w/o vit E	w/vit E	Total mean
Standard diet	40.96 ± 9.93	32.96 ± 7.50	36.96 ± 9.31b
High-fat diet	58.92 ± 11.04	55.92 ± 12.07	57.42 ± 11.02a
Total mean	49.94 ± 13.69	44.44 ± 15.37

 

Different superscripts (a,b) within a column denote significant differences (P<0.05)

 

Polymorphonuclear cell counts

According to the results, a high-fat diet had no effect on polymorphonuclear cell counts, while vitamin E supplementation significantly reduced them. Rats supplemented with vitamin E had significantly lower polymorphonuclear cell counts (53.17 ± 17.87) compared to those not supplemented with vitamin E (86.15 ± 18.60; P<0.05) (Table 8).

 

Table 8: Mean polymorphonuclear cell counts after seven days of excision in rats fed standard or high-fat diets, with or without vitamin E supplementation (300 IU/kg), following eight weeks of treatment.

	w/o vit E	w/vit E	Total mean
Standard diet	78.50 ± 21.53	47.55 ± 18.45	63.03 ± 24.97
High-fat diet	93.80 ± 12.93	58.80 ± 17.30	76.30 ± 23.41
Total mean	86.15± 18.6x	53.17± 17.87y

 

Different superscripts (x,y) within a row denote significant differences (P<0.05).

 

Histopathologic figure of wound

Histopathological analysis of excision wounds (Figure 2) revealed incomplete wound closure beneath scabs in all groups. However, the vitamin E-supplemented group exhibited more extensive re-epithelialization, despite the persistent presence of inflammatory cells in the dermis (Supplementary Figure 1)

DISCUSSION

This present study indicated a substantial rise in rat body weight following consumption of a high-fat diet, suggesting a disruption in fat metabolism. This aligns with established studies, as high-fat diets promote body fat mass accumulation and body weight in both humans and animals due to their high energy density (Eastep and Chen, 2015; Yang et al., 2018; Diaz et al., 2021; Nasution et al., 2022). The crucial regulator in this process is adiponectin, a hormone that stimulates fatty acid oxidation and glucose utilization to reduce body weight (Ma et al., 2016). Obesity is characterized by decreased adiponectin levels, resulting from adiponectin resistance and reduced receptor expression (Shen et al., 2010; Soliman et al., 2014). The reduction in body weight following vitamin E supplementation observed in this study suggests that α-tocopherol upregulates adiponectin, leading to weight reduction (Hendarto et al., 2019; Emami et al., 2021).

 

Consistent with established findings that a high-fat diet causes dyslipidemia (Du et al., 2021), this study confirmed that a high-fat diet elevated blood cholesterol, triglycerides, and LDL while lowering HDL. Vitamin E supplementation effectively counteracted these effects. The liver enzyme responsible for cholesterol production, HMG-CoA reductase, is inhibited by vitamin E, thereby preventing the accumulation of cholesterol and lowering cholesterol levels (Emami et al., 2021). According to Kim et al. (2013), a high-fat diet induces oxidative stress, leading to insulin resistance and elevated triglycerides. This occurs as insulin resistance fails to suppress free fatty acid release, boosting VLDL synthesis, which subsequently raises triglyceride levels. However, vitamin E improves this condition by upregulating PPAR, a receptor that enhances hepatic fat metabolism and reduces serum triglycerides (Megawati et al., 2021).

In order to evaluate the effects of a high-fat diet and vitamin E supplementation on the wound healing process, this study conducted an excisional wound model that healed by second intention. On the seventh day following the injury, the wound surface area was measured. The findings revealed that rats on a high-fat diet had significantly larger wound surface area. According to Pierpont et al. (2014), fat tissue becomes hypoxic in response to an inadequate blood supply, which is caused by disturbed angiogenesis and chronic inflammation due to excess body fat. Despite fibroblast survival in low oxygen, their function is compromised, leading to inadequate collagen synthesis. This limits collagen production, preventing the regeneration of a robust collagen matrix, reducing its mechanical strength, and impairing wound healing. Although the current study found no statistically significant effect of vitamin E on the wound surface area, a tendency toward reduction was observed. This aligns with established mechanisms whereby vitamin E facilitates wound healing by neutralizing free radicals, reducing proinflammatory cytokines (Emami et al., 2021), and enhancing immune function such as phagocytosis (Hobson, 2014; Lewis et al., 2019).

In this study, vitamin E significantly reduced tissue polymorphonuclear cell counts, likely due to its anti-inflammatory and antioxidant properties. This is consistent with findings that vitamin E suppresses proinflammatory cytokines like TNF-α, IL-1β, and IL-6 (Salinthone et al., 2013), countering the inflammatory state induced by a high-fat diet (Bae et al., 2023).

Histopathological examination of excision wounds demonstrated incomplete wound closure beneath scabs among all groups. Nevertheless, the group receiving vitamin E supplementation showed enhanced re-epithelialization, despite the ongoing presence of inflammatory cells in the dermis. Schaunel et al. (2020) have demonstrated that an obesity-induced high-fat diet adversely impacts wound healing by extending the inflammatory phase. A high-fat diet not only facilitates the migration of inflammatory cells and disrupts wound contraction but also inhibits myofibroblast differentiation, diminishes collagen deposition, impairs the proliferation of epithelial and connective cells, and compromises angiogenesis. The degree and duration of obesity contribute to the levels of proinflammatory cytokines, mononuclear and polymorphonuclear cells, and macrophages, which lead to pathological alteration in inflammation (Pierpont et al., 2014; Cotterell et al., 2024).

The role of antioxidants is to protect cells from ROS-induced oxidative damage (Fatima et al., 2025). Vitamin E is a major fat-soluble antioxidant that protects cell membranes by scavenging free radicals and inhibiting lipid peroxidation. Additionally, it promotes skin health by maintaining the integrity of the skin barrier through regulated TEWL and enhanced lipid synthesis, as well as by modifying inflammatory pathways to lower pro-inflammatory cytokines (Fatima et al., 2025; Joshi et al., 2023). Even though all groups showed incomplete wound closure, the re-epithelialization was improved by vitamin E administration. This improvement is probably the result of vitamin E’s dual function as an antioxidant that reduces oxidative stress caused by ROS and its anti-inflammatory properties that influence healing processes even when dermal inflammation is ongoing.

CONCLUSION

This study demonstrated that vitamin E supplementation decreased the body weight of rats on both standard and high-fat diets. In addition to its effects on weight, vitamin E positively improved the lipid profile, as shown by reduced cholesterol, triglycerides, and LDL levels, and increased HDL levels. At the wound site, the healing process showed marked improvement, as indicated by a reduced number of polymorphonuclear cells, highlighting the beneficial anti-inflammatory and antioxidant properties of vitamin E. Although complete wound closure was not achieved during the observation period, the anti-inflammatory properties of vitamin E indicate a potential mechanism to alleviate obesity-related healing problems. Accordingly, further research is needed to investigate its clinical potential.

ACKNOWLEDGEMENTS

The authors are grateful to the Faculty of Veterinary Medicine and the Center for Food and Nutrition Studies, Universitas Gadjah Mada, for supporting this study.

Novelty Statement

The efficacy of vitamin E in the context of obesity-impaired healing remains unexplored, presenting a clear gap in knowledge that this study aims to address by testing this established agent under compromised conditions

AUTHOR’S CONTRIBUTION

DA conceptualized the study, drafted the manuscript, and performed data analysis. AP contributed to the investigation, data interpretation, and reviewed the manuscript. MER participated in validation and editing the manuscript. All authors reviewed and approved the final manuscript.

Ethical approval

The Ethical Clearance Commission of Universitas Gadjah Mada’s Integrated Research and Testing Laboratory approved this study (No. 00019/04/LPPT/VII/2022), and all activities were performed in compliance with relevant regulations and recommendations.

Abbreviations

ANOVA, Analysis of variance; HDL, High-density lipoprotein; HMG-CoA, 3-hydroxy-3-methylglutaryl coenzyme A; IL-1β, Interleukin-1β; IL-6, Interleukin-6; LDL, Low-density lipoprotein; PPAR, Peroxisome proliferator-activated receptors; ROS, Reactive oxygen species; TEWL, Transepidermal Water Loss; TNF-α, Tumor necrosis factor-α.

Generative AI and AI-assisted technology statement

Generative AI and AI-assisted technologies were utilized for grammar and style checking, as well as to refine author-written paragraphs for improved clarity. The authors thoroughly reviewed, verified, and edited all AI-generated output to ensure the accuracy and integrity of the scientific content.

Conflict of interest

The authors have declared no conflict of interest.

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