Effect of anti-obesity drug orlistat (Xenical™) on liver and kidney function in male rats fed a high-fat diet

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Alkadhimy" }, { "@type": "Person", "name": "Asmaa M. Neamah" }, { "@type": "Person", "name": "Mohammed Y.I. Al-Hamadani" }, { "@type": "Person", "name": "Ahmed S. Jarad" }, { "@type": "Person", "name": "Mokhtar I Yousef" } ], "publisher": { "@type": "Organization", "name": "F1000Research", "logo": { "@type": "ImageObject", "url": "https://f1000research.com/img/AMP/F1000Research_image.png", "height": 480, "width": 60 } }, "image": { "@type": "ImageObject", "url": "https://f1000research.com/img/AMP/F1000Research_image.png", "height": 1200, "width": 150 }, "description": " Background HFDs have adverse effects on metabolic health, which puts individuals at risk of obesity and liver and kidney dysfunction. Orlistat is an antihypertensive agent against obesity that prevents the absorption of dietary fats, although its impact on hepatic and renal functions is still disputed. In this study, the dose-dependent effects of orlistat on liver and renal functioning were in male rats on an HFD were assessed. Methods There was a control HFD group and three HFD groups with orlistat (360, 480 and 600 mg/kg) on male rats over 60 days. Lipid profiles, liver enzymes (AST, ALT, GGT, ALP), kidney (urea, creatinine, direct and indirect bilirubin), and hematological (hemoglobin, hematocrit, RBC, WBC counts, MCV, MCH, MCHC) serum tests were done. Histopathological analysis of liver and kidney tissues was done. Findings Orlistat caused dose-related changes in lipid profiles, increased liver enzymes, and an increased mark of kidney functioning. The hematological parameters were also greatly impaired, and the histopathology indicated structural and tissue damage in both of the organs, more so at higher doses. Conclusions Orlistat was used in HFD-conditions in male rats, which resulted in severe dose-related impairment of the liver and kidney. These results highlight the importance of close observation of hepatic and renal functions when using orlistat especially in the high-fat dietary situation. " } { "@context": "http://schema.org", "@type": "BreadcrumbList", "itemListElement": [ { "@type": "ListItem", "position": "1", "item": { "@id": "https://f1000research.com/", "name": "Home" } }, { "@type": "ListItem", "position": "2", "item": { "@id": "https://f1000research.com/browse/articles", "name": "Browse" } }, { "@type": "ListItem", "position": "3", "item": { "@id": "https://f1000research.com/articles/15-136/v2", "name": "Effect of anti-obesitydrug orlistat (Xenical™) on liver and kidney..." } } ] } Home Browse Effect of anti-obesitydrug orlistat (Xenical™) on liver and kidney... ALL Metrics - Views Downloads Get PDF Get XML Cite How to cite this article Alkadhimy SM, Neamah AM, Al-Hamadani MYI et al. Effect of anti-obesity drug orlistat (Xenical™) on liver and kidney function in male rats fed a high-fat diet [version 2; peer review: 1 approved, 2 approved with reservations, 1 not approved] . F1000Research 2026, 15 :136 ( https://doi.org/10.12688/f1000research.174090.2 ) NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article. Close Copy Citation Details Export Export Citation Sciwheel EndNote Ref. Manager Bibtex ProCite Sente EXPORT Select a format first Track Share ▬ ✚ Research Article Revised Effect of anti-obesity drug orlistat (Xenical™) on liver and kidney function in male rats fed a high-fat diet [version 2; peer review: 1 approved, 2 approved with reservations, 1 not approved] Sura M. Alkadhimy https://orcid.org/0000-0002-5235-886X 1 , Asmaa M. Neamah https://orcid.org/0000-0002-8232-7917 2 , Mohammed Y.I. Al-Hamadani https://orcid.org/0009-0003-4957-2069 3 , Ahmed S. Jarad 4 , Mokhtar I Yousef 5 Sura M. Alkadhimy https://orcid.org/0000-0002-5235-886X 1 , Asmaa M. Neamah https://orcid.org/0000-0002-8232-7917 2 , [...] Mohammed Y.I. Al-Hamadani https://orcid.org/0009-0003-4957-2069 3 , Ahmed S. Jarad 4 , Mokhtar I Yousef 5 PUBLISHED 31 Mar 2026 Author details Author details 1 Department of Biology, College of Science, University of Karbala, Karbala, Iraq 2 Department of Environment, College of Science, University of Al-Qadisiyah, Al-Qadisiyah, Iraq 3 Department of Biology, College of Education, University of Fallujah, Al-Fallujah, Iraq 4 Department of Pathology and Poultry Disease, College of Veterinary Medicine, University of Fallujah, Al-Fallujah, Iraq 5 Department of Environmental Studies,Institute of Graduate Studies and Research, Alexandria University,163 Horeya Avenue, Chatby 21526, P.O. Box 832,Alexandria, Egypt Sura M. Alkadhimy Roles: Data Curation Asmaa M. Neamah Roles: Formal Analysis Mohammed Y.I. Al-Hamadani Roles: Methodology, Writing – Original Draft Preparation Ahmed S. Jarad Roles: Conceptualization, Writing – Original Draft Preparation Mokhtar I Yousef Roles: Project Administration, Supervision OPEN PEER REVIEW DETAILS REVIEWER STATUS This article is included in the Fallujah Multidisciplinary Science and Innovation gateway. Abstract Background HFDs have adverse effects on metabolic health, which puts individuals at risk of obesity and liver and kidney dysfunction. Orlistat is an antihypertensive agent against obesity that prevents the absorption of dietary fats, although its impact on hepatic and renal functions is still disputed. In this study, the dose-dependent effects of orlistat on liver and renal functioning were in male rats on an HFD were assessed. Methods There was a control HFD group and three HFD groups with orlistat (360, 480 and 600 mg/kg) on male rats over 60 days. Lipid profiles, liver enzymes (AST, ALT, GGT, ALP), kidney (urea, creatinine, direct and indirect bilirubin), and hematological (hemoglobin, hematocrit, RBC, WBC counts, MCV, MCH, MCHC) serum tests were done. Histopathological analysis of liver and kidney tissues was done. Findings Orlistat caused dose-related changes in lipid profiles, increased liver enzymes, and an increased mark of kidney functioning. The hematological parameters were also greatly impaired, and the histopathology indicated structural and tissue damage in both of the organs, more so at higher doses. Conclusions Orlistat was used in HFD-conditions in male rats, which resulted in severe dose-related impairment of the liver and kidney. These results highlight the importance of close observation of hepatic and renal functions when using orlistat especially in the high-fat dietary situation. READ ALL READ LESS Keywords Orlistat(Xenical™); Anti-obesity drug; High-fat diet; Hepato-nephrotoxicity; Male rats; Metabolic syndrome; Histopathology Corresponding Author(s) Mohammed Y.I. Al-Hamadani ( [email protected] ) Close Corresponding author: Mohammed Y.I. Al-Hamadani Competing interests: No competing interests were disclosed. Grant information: The author(s) declared that no grants were involved in supporting this work. Copyright: © 2026 Alkadhimy SM et al . This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. How to cite: Alkadhimy SM, Neamah AM, Al-Hamadani MYI et al. Effect of anti-obesity drug orlistat (Xenical™) on liver and kidney function in male rats fed a high-fat diet [version 2; peer review: 1 approved, 2 approved with reservations, 1 not approved] . F1000Research 2026, 15 :136 ( https://doi.org/10.12688/f1000research.174090.2 ) First published: 29 Jan 2026, 15 :136 ( https://doi.org/10.12688/f1000research.174090.1 ) Latest published: 31 Mar 2026, 15 :136 ( https://doi.org/10.12688/f1000research.174090.2 ) Revised Amendments from Version 1 Orlistat reduces dietary fat absorption by 30% (Is there any reference for the reduction by 30% statement) Response: The following reference was added in the text and in the reference list: Torgerson, J. S., Hauptman, J., Boldrin, M. N., & Sjöström, L. (2004). Xenical in the prevention of diabetes in obese subjects (XENDOS) study: a randomized study of orlistat as an adjunct to lifestyle changes. Diabetes Care, 27(1), 155–161. Reviewer Comment 5. Orlistat has less than 1% bioavailability and scarcely produce systemic toxicity (Reference Al-Sabah the economic impact of obesity in Kuwait: a micro-costing study evaluating the burden of obesity related comorbidities), Check the reference clearly Response: The reference was placed in the text and the list of references as follows: Due to its minimal systemic absorption (<1%), orlistat exerts its action locally within the gastrointestinal tract and rarely produces systemic toxicity (Henness & Perry, 2006). Henness, S., & Perry, C. M. (2006). Orlistat: a review of its use in the management of obesity. Drugs, 66(12), 1625–1656. Reviewer Comment 6 (Orlistat preparation and dosing reproducibility) Response: A detailed description of tablet crushing, suspension preparation, stock concentration, and gavage volume per body weight has been added in the Materials and Methods section to ensure reproducibility as follows: “Orlistat tablets were finely crushed and suspended in distilled water to prepare a stock suspension. The suspension was freshly prepared daily and administered orally by gavage according to body weight. The administered volume was adjusted to 1 ml/100 g body weight to ensure accurate dosing. Animals received doses of 360, 480, or 600 mg/kg/day for 60 consecutive days.” Orlistat reduces dietary fat absorption by 30% (Is there any reference for the reduction by 30% statement) Response: The following reference was added in the text and in the reference list: Torgerson, J. S., Hauptman, J., Boldrin, M. N., & Sjöström, L. (2004). Xenical in the prevention of diabetes in obese subjects (XENDOS) study: a randomized study of orlistat as an adjunct to lifestyle changes. Diabetes Care, 27(1), 155–161. Reviewer Comment 5. Orlistat has less than 1% bioavailability and scarcely produce systemic toxicity (Reference Al-Sabah the economic impact of obesity in Kuwait: a micro-costing study evaluating the burden of obesity related comorbidities), Check the reference clearly Response: The reference was placed in the text and the list of references as follows: Due to its minimal systemic absorption (<1%), orlistat exerts its action locally within the gastrointestinal tract and rarely produces systemic toxicity (Henness & Perry, 2006). Henness, S., & Perry, C. M. (2006). Orlistat: a review of its use in the management of obesity. Drugs, 66(12), 1625–1656. Reviewer Comment 6 (Orlistat preparation and dosing reproducibility) Response: A detailed description of tablet crushing, suspension preparation, stock concentration, and gavage volume per body weight has been added in the Materials and Methods section to ensure reproducibility as follows: “Orlistat tablets were finely crushed and suspended in distilled water to prepare a stock suspension. The suspension was freshly prepared daily and administered orally by gavage according to body weight. The administered volume was adjusted to 1 ml/100 g body weight to ensure accurate dosing. Animals received doses of 360, 480, or 600 mg/kg/day for 60 consecutive days.” To read any peer review reports and author responses for this article, follow the "read" links in the Open Peer Review table. READ REVIEWER RESPONSES 1- Introduction The increasing obesity epidemic has posed a significant burden on global public health. Obesity and obesity-related diseases including, but not limited to diabetes, hypertension, heart disease, and some cancers, affect millions of people worldwide ( Pan et al., 2023 ). According to estimates by the World Health Organization, around 1 billion adults globally are obese, and the total cost of obesity-related care will amount to $1.2 trillion by 2030. Given the increasing pace of obesity propagation, health professionals dealing with obesity realize the necessity of fast and efficient interventions ( Blüher, 2019 ). Medication, lifestyle changes, and surgical interference seem to be the most promising strategies in addressing the problem of obesity and related conditions. Obesity is not a consequence of these disorders; rather, it is a primary pathological condition that significantly increases the risk of developing metabolic and organ-related complications such as fatty liver disease, diabetes mellitus, and renal dysfunction. Closely associated with the issue of dosage is the concept of toxicity, as overexposure to many other substances can lead to devastating health effects ( Ibadi et al., 2024 ). Environmental toxins, poor nutrition, and a sedentary lifestyle are just some of the factors that cause obesity and its health consequences. In the midst of the desperate search for solutions, the scientific community identifies Orlistat as an effective remedy that promotes patients’ weight loss, providing people with a chance to conquer obesity ( Padwal & Majumdar, 2007 ). By appreciating this interplay between genetics, environment, and lifestyle, healthcare professionals may be able to develop effective interventions to help stop the obesity epidemic and improve public health. Over 1.9 billion people were overweight and 650 million were obese in 2023, according to the World Health Organization, suggesting that the global obesity epidemic had reached alarming levels. Obesity is mostly caused by metabolic illnesses such type 2 diabetes, heart disease, non-alcoholic fatty liver disease, and chronic kidney disease. Obesity causes 4.7 million premature deaths annually. In addition to being a trigger for the above aberrations, High-fat diets, a crucial driver of obesity, exacerbate systemic inflammation and oxidative stress. This is followed by lipid accumulation in critical organs such as the liver causing hepatic steatosis, renal lipotoxicity, and multi-organ failure. Although lifestyle interventions remain the foundation of obesity treatment, pharmacological interventions such as the prescription of orlistat are becoming more common due to fears about serious weight-related problems ( Islam et al., 2024 ). The pancreatic lipase inhibitor orlistat has a clinically meaningful effect on metabolic indices and weight reduction in obese individuals by reducing dietary fat absorption by 30% ( Torgerson et al., 2024 ). Although the inhibitory effects of orlistat on body weight and serum levels of LDL cholesterol are well established, recent data suggest that orlistat may offer a novel therapeutic option by reducing HFD-induced organ damage, an effect ascribed to its ability to prevent lipid peroxidation and the subsequent inflammatory cascade. However, discordant results have been disclosed regarding hepatorenal toxicity, which suggest that Orlistat may induce systemic toxicity in a dose-dependent manner, thus limiting its application in obese patients with preexisting organ failure based on Available evidence. For example, it has been reported that orlistat-treated rats at supraphysiological doses found equivalent to an intravenous bolus of 4000 mg for humans have higher levels of activated oxidative stress markers. Due to its minimal systemic absorption (<1%), orlistat exerts its action locally within the gastrointestinal tract and rarely produces systemic toxicity ( Henness & Perry, 2006 ). The liver and the kidneys are among the most susceptible to obesity-induced damage. HFD-induced hepatic lipids are encapsulated with NAFLD development, whereas renal lipotoxicity damages glomerular filtration and tubular function. Although recent research indicates that the utilization of orlistat in HFD-fed mice can improve hepatic steatosis and insulin sensitivity through the inactivation of gut microbiota and suppression of de-novo lipogenesis, knowledge of its kidney effects is scarce. This is the first paper to describe the histopathological outcomes of preclinical models. NAFLD and CKD are prevalent comorbidities over 20–30% of obese populations develop and 30–50% demonstrate CKD in the infancy stage. Therefore, learning the organ-specific power of orlistat may help people optimize therapeutic measures ( Ren et al., 2023 ; Huang et al., 2025 ). In male rats given an HFD, this study examines the dose-dependent effects of orlistat on the histology and function of the liver and kidneys. By evaluating biochemical markers and histological changes, we aim to clarify whether orlistat’s benefits in weight management extend to hepatorenal protection or pose unintended risks at therapeutic doses. 2- Materials and methods 2-1- Preparation of the high-fat diet Preparation of the high-fat diet was performed according to Altunkaynak (2005) with complete methodological descriptions. 2-2- Orlistat drug Pharmaceutical-grade orlistat was obtained in capsule form (120 mg) from local pharmacies in Diwaniyah, Iraq (Roche, Switzerland). The treatment was administered daily for 60 consecutive days. To ensure dosage precision, the rats were weighed weekly, and the doses (360, 480, and 600 mg/kg) were adjusted accordingly based on their average body weight. The contents of the capsules were freshly dissolved in distilled water before administration via oral gavage. Orlistat tablets were finely crushed and suspended in distilled water to prepare a stock suspension. The suspension was freshly prepared daily and administered orally by gavage according to body weight. The administered volume was adjusted to 1 ml/100 g body weight to ensure accurate dosing. Animals received doses of 360, 480, or 600 mg/kg/day for 60 consecutive days. 2-3- Experimental animals and design Twenty-five male Albino rats weighing an average of 190 ± 5 g at two months of age were utilized in this investigation. They came from Al-Qadisiyah University’s College of Science’s Animal House. The Ethics Committee of the College of Applied Sciences at the University of Fallujah (UOF.CAS.06-240519), Iraq, has accepted the study, and all procedures were carried out in compliance with the Committee’s rules and regulations. Prior to the trial, the animals were acclimated for two weeks. The experimental mice had a 12-hour daily photoperiod and were housed in specially designed plastic cages at room temperature (22–25°C). The trial lasted for sixty days. Five equal groups of five rats each were randomly assigned to the animals: the control group, the high-fat diet (HFD) group, and the HFD group that received daily oral gavages of Orlistat (XE) at dosages of 360, 480, and 600 mg/kg for 60 days ( Sabik et al., 2022 ). Rats were anesthetized using inhaled isoflurane before blood collection and organ harvesting, after which they were humanely sacrificed. One milliliter was extracted for hematological parameters. The plasma was separated from the blood using centrifugation at 860×g for 20 minutes, and it was thereafter kept at -80°C for analysis. Following their separation, the liver and kidney were maintained at -80 °C for further biochemical study after being cleansed with saline. Formalin (10%) is used to preserve portions of specific organs utilized in histological investigations. Anesthesia of the rat was induced with inhaled isoflurane (3-4 percent of the total volume) with a calibrated vaporizer in an induction chamber and maintained at 1.5-2 percent. In a case where total loss of the pedal reflex had been achieved, euthanasia was done by exsanguine through cardiac puncture, according to AVMA Guidelines of Euthanasia of Animals (2020). 2-4- Hematological analysis The whole blood samples were analyzed for hemoglobin (Hb), blood hematocrit (Ht), red blood cells (RBC), and white blood cells (WBC) shortly after they were obtained. A commercial kit (Diamond Diagnostics, Cat. No. HB102010) was used to measure the concentration of hemoglobin in whole blood. A light microscope with a 400x magnification was used to count red blood cells on a bright-line hemocytometer. Before being counted, blood samples were diluted 200 times with physiological saline (0.9% sodium chloride solution). Ht was tested using micro hematocrit tubes and a hematocrit centrifuge (5 minutes at 16,500 Xg). After blood samples were diluted 20 times with a diluting solution (1% acetic acid and a little amount of Leshman’s stain), WBCs were counted on an American Optics bright line hemocytometer using a light microscope at 100x magnification. Wintrobe indices were calculated in compliance with Wintrobe (2009) . Mean corpuscular hemoglobin (MCH) (pg) = Hb (g per 100ml)/ No. of RBCs (per 100 ml), mean corpuscular volume (MCV) (cu μ) = Ht (%)/No. of RBCs (per 100 ml), and mean corpuscular hemoglobin concentration (MCHC) (%) = [Hb (g per 100ml)/Ht (%)] x 100. 2-5- Biochemical parameters According to the method of Armstrong & Carr (1963) , the concentration of plasma total protein (TP) was measured using a commercial kit (Diamond Diagnostics, Cat. No. 1001291). The concentration of triglycerides (TG) was determined using a commercial kit (Diamond Diagnostics, Cat. No. 1001311) using the method of Bucolo & David (1973) . The method of Richmond (1973) was used to measure total cholesterol and high-density lipoprotein cholesterol (HDL-c) was measured using a commercial kit (Diamond Diagnostics, Cat. No. 1001164). The assay of Assmann (1984) was used to measure low-density lipoprotein cholesterol (LDL-c) using a commercial kit (Diamond Diagnostics, Cat. No. 1001161). The method of Patton & Crouch (1977) was used to measure urea concentration using a commercial kit (Diamond Diagnostics, Cat. No. 1001329) was calculated. Creatinine concentration was measured according to the method Schirmeister et al. (1964) using a commercial kit (Diamond Diagnostics, Cat. No. 1001111). The method of Price et al. (1976) was used to measure both direct and indirect bilirubin concentrations using a commercial kit (Diamond Diagnostics, Cat. No. 1001044). 2-6- Enzyme activity The method of Reitman & Frankel (1957) was used to measure the activity of AST using a commercial kit (Diamond Diagnostics, Cat. No. 260 001) and the activity of ALT (Diamond Diagnostics, Cat. No. 272 001). The method of Persijin & van der Slike (1982) was used to determine γ-GT using a commercial kit (Diamond Diagnostics, Cat. No: 41290). Belfield & Goldberg (1971) technique was used to measure the activity of AlP using a commercial kit (Diamond Diagnostics, Cat. No: 41240). All procedures were conducted strictly according to the manufacturer’s instructions and were performed using commercially available diagnostic kits manufactured by Spectrum Diagnostics. 2-7- Histology studies Liver and kidney tissue samples were embedded in paraffin wax, fixed in a 10% formaldehyde solution, and cut into 5μ μm-thick slices using a microtome. Hematoxylin and Eosin (H&E) stains were applied to the sections, and their morphology was assessed under a microscope ( Durry et al., 1980 ). 2-8- Statistical analysis The data entered into the computer was examined using IBM SPSS software version 20.0. (IBM Corp., Armonk, NY). The distribution’s normality was confirmed using the Shapiro-Wilk test. The mean and standard error were used to characterize quantitative data. The results’ significance was assessed at the 5% level. The F-test (ANOVA) for normally distributed quantitative variables and the Post Hoc test (Tukey) for pairwise comparisons are utilized when comparing more than two groups. 2-9- Ethics approval This study involved all the animals procedures that were conducted following the formal approval by the Ethics Committee of the College of Applied Sciences of the University of Fallujah, Iraq (Approval No. UOF.CAS.06-240519). All of the experimental procedures, such as handling, housing, anesthesia, and euthanasia, were performed according to the institutional guidelines and the American Veterinary Medical Association (AVMA) Guidelines on the Euthanasia of Animals (2020). 3- Results and discussion The hematological indicators of male rats administered Orlistat (XE) at dosages of 360, 480, and 600 mg/kg and fed a high-fat diet (HFD) are summarized in Tables 1 and 2 . These indicators include hemoglobin (Hb), hematocrit (Ht), red blood cell count (RBC), white blood cell count (WBC), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), and mean corpuscular hemoglobin concentration (MCHC). Hematological indicators did not alter statistically significantly (P > 0.05) between the HFD group and the control group (regular diet). Within the context of the current study, the value of P above 0.05 means that the observed biochemical difference between groups was not statistically significant based on the applied tests, but does not rule out the existence of biological or histopathological changes. Actually certain doses of orlistat demonstrated some tissue alterations in the kidneys and liver even though there were no statistically significant biochemical changes. Thus, the P-values interpretation was supplemented by the histological evidence, which is more exhaustive and biologically significant to evaluate the impairment of organs. Table 1. Effects of Orlistat (XE) at doses of 360, 480, 600 mg/kg on hemoglobin (Hb; g/dL), hematocrit (Ht; (%), red blood cell count (RBC; x106/ml), and white blood cell count (WBC; x10 3 /ml) of male rats fed a high-fat diet (HFD). Experimental groups Parameter Hb Ht RBCs WBCs Control 11.7 b ± 0.42 33.9 ab ± 1.41 6.22 b ± 0.22 13.0 a ± 1.01 HFD 12.3 ab ± 0.05 34.9 ab ± 0.04 6.42 ab ± 0.02 12.6 a ± 0.23 HFD+XE-360 11.5 b ± 0.01 32.3 b ± 0.02 6.06 b ± 0.01 10.1 a ± 1.43 HFD+XE-480 12.7 a ± 0.22 36.2 a ± 0.72 6.92 a ± 0.12 11.7 a ± 2.23 HFD+XE-600 12.7 ab ± 0.11 34.1 ab ± 0.29 6.33 b ± 0.08 11.1 a ± 0.01 Table 2. Effects of Orlistat (XE) at doses of 360, 480, 600 mg/kg on mean corpuscular volume (MCV; fL), mean corpuscular hemoglobin (MCH; pg), and mean corpuscular hemoglobin concentration (MCHC; g/dL) of male rats fed a high-fat diet (HFD). Experimental groups Parameter MCV MCH MCHC Control 54.3 a ± 0.31 18.9 a ± 0.02 34.7 c ± 0.23 HFD 54.4 a ± 0.19 19.2 a ± 0.14 35.2 bc ± 0.12 HFD+XE-360 53.3 b ± 0.06 19.1 a ± 0.02 35.8 a ± 0.02 HFD+XE-480 52.2 c ± 0.15 18.4 b ± 0.02 35.2 bc ± 0.10 XE-600 53.9 ab ± 0.25 19.0 a ± 0.08 35.4 ab ± 0.02 Hematological parameters (Hb, Ht, RBC, WBC, MCV, MCH, and MCHC) did not significantly change between the control, high-fat diet (HFD), and Orlistat -treated groups, indicating that neither the administration of Orlistat (360–480–600 mg/kg) nor the HFD caused hematotoxicity or systemic anemia in male rats under the experimental conditions. These findings align with studies demonstrating that orlistat primarily acts locally in the gastrointestinal tract to inhibit pancreatic lipase, with limited systemic absorption and minimal direct effects on hematopoietic parameters ( Hauptman et al., 2000 ). The absence of HFD-induced hematological alterations in the current study stands in contrast with several previous reports of some kinds of obesity-associated anemia of chronic disease, presumed to be caused by chronic inflammation or iron control. However, the short study interval of just 60 days and lack of critical metabolic abnormalities in the HFD group may contribute to this discrepancy. Indeed, research in diet-induced obese mice have revealed that such hematological effects usually become evident only after more extended attention or in the context of co-morbid conditions such as insulin opposition ( Kassebaum et al., 2014 ). The unmodified WBC counts in all groups in addition to the above sheds more evidence that Orlistat did not induce systemic inflammation or immunosuppression although well-tolerated gastrointestinal side effects including steatorrhea. This is consistent with clinical reports that orlistat does not raise inflammatory markers such as CRP or IL-6 in obese patients ( Yesilbursa et al., 2005 ). While, Zahkouk et al. (2019) observed increased W.B.C. and decreased R.B.C., HB, and Hct% in the HFD group. Rahi and Khudhair (2024) found that male rats treated with HFD+ tocotrienol showed differences in RBC and MCH. Additionally, the WBC of male rats given HFD alone was significantly higher than that of the control group. To assess the combined effects of Orlistat and HFD on hematopoiesis, longer-term research is required. Investigating Orlistat impact in comorbid models (e.g., diabetic-obese rats) could reveal context-dependent hematotoxicity. Interestingly, no significant changes in hematological parameters were found in the current research even with the intake of a high-fat diet and (orlistat). This is contrary to some of the past reports that obesity or large amount of fat in the diet might cause anemia or inflammation. Another reason could be the fact that the experimental range (60 days) is quite short and may not be enough to induce chronic anemia or systemic inflammatory reactions. Also, the rats were not found to have critical metabolic disturbances or extreme obesity, which in many cases is necessary to bring about the effect of hematological changes. In addition, orlistat mainly works in the gastrointestinal tract to prevent fat absorption, and has the least effects of the system on hematopoiesis, which is agreeable with the fact that the RBC, WBC, Hb, and Ht levels remained unchanged in this study. Table 3 shows the total protein (TP) and lipid profile parameters, such as triglycerides (TG), high-density lipoprotein cholesterol (HDL-c), and low-density lipoprotein cholesterol (LDL-c), in male rats fed a high-fat diet (HFD) and given Orlistat (XE) at dosages of 360, 480, and 600 mg/kg. Between the HFD group and the control group (normal diet), there was no statistically significant difference in TP levels (P > 0.05). The three Orlistat -treated groups and the control and HFD groups did not vary significantly (P > 0.05) in TP. However, TG, HDL-c, and LDL-c values in all Orlistat -treated groups (360, 480, and 600 mg/kg) revealed substantial improvements (P < 0.05) in comparison to the control and HFD groups. Table 3. Effects of Orlistat (XE) at doses of 360, 480, 600 mg/kg on total protein (TP; g/dL), triglyceride (TG; mg/dL), high-density lipoprotein-cholesterol (HDL-c; mg/dL), and low-density lipoprotein-cholesterol (LDL-c; mg/dL) of male rats fed a high-fat diet (HFD). Experimental groups Parameter TP TG HDL-c LDL-c Control 6.60 a ± 0.08 52.60 bc ± 1.32 15.55 b ± 0.68 45.5 a ± 2.90 HFD 6.80 a ± 0.12 49.60 c ± 6.01 16.0 b ± 0.45 29.1 c ± 0.81 HFD+XE-360 6.75 a ± 0.02 66.25 ab ± 3.54 22.60 a ± 1.47 33.8 b ± 1.15 HFD+XE-480 6.94 a ± 0.03 72.85 a ± 2.89 18.60 ab ± 2.36 29.4 bc ± 3.74 XE-600 6.64 a ± 0.22 54.45 bc ± 0.02 15.50 b ± 0.93 29.3 bc ± 2.63 The present study demonstrated that total protein (TP) levels remained unchanged across control, high-fat diet (HFD), and Orlistat (XE)-treated groups, indicating that neither the HFD nor the administration of Orlistat at doses of 360, 480, and 600 mg/kg significantly impacted the overall protein metabolism or hepatic synthetic function in male rats. This finding aligns with previous research showing that orlistat primarily targets fat absorption without adversely affecting protein metabolism or liver synthetic capacity in animal models and humans ( Padwal & Majumdar, 2007 ; Hauptman et al., 2000 ). However, in all Orlistat -treated groups, the lipid profile parameters TG, HDL-c, LDL-c were significantly altered compared to both the control and HFD groups. More precisely, treatment with orlistat resulted in a significant decrease in TG and LDL-c in addition to an increase in levels of HDL-c. These outcomes can be explained by the described pharmacological factor of orlistat: it is a pancreatic lipase inhibitor that prevents the breakdown of fat and thus promotes a better lipid profile caused by obesity or an HFD ( Torgerson et al., 2004 ; Gao et al., 2024 ). These lipid-modulating effects have been further validated by clinical and preclinical studies. Specifically, Torgerson et al. (2004) discovered that orlistat improved cardiovascular risk profiles by lowering blood TG and LDL-c levels and raising HDL-c levels in patients who were noticeably obese. However, these findings differ from those of Annamalai et al. (2016) that the HFD-induced rats were prompted to raise triacylglycerol, LDL, and lower high-density lipoprotein. High-fat diet and the Orlistat showed significant differences in the levels of cholesterol, triacylglycerol, and LDL, as well as noticeable differences in HDL compared to high-fat diet, according to the results, which also showed a significant departure at the level of triacylglycerol and LDL compared to the control group and a significant difference at the level of HDL ( Fahmi, 2021 ). Since total protein was unchanged although there were significant improvements in the lipid profile, it can be argued that the lipid-lowering effects of orlistat are not associated with adverse effects on protein metabolism and liver function. This can be explained by the existing report stating that orlistat treatment did not result in deterioration of serum albumin and total protein in obese patients ( Hauptman et al., 2000 ). The correlation between lipid metabolism and organ functioning offers the additional interpretation of the biochemical and histological results of the current study. Dyslipidemia caused by high-fat diet facilitates overexpression of lipid influx to the liver and kidney, which is part of hepatic steatosis, oxidative stress and renal lipotoxicity. Interference with this gut liver kidney axis is viewed as a key route by which dietary fat excess causes progressive hepatorenal damage. Orlistat only partially regulates this axis by stopping the intestinal pancreatic lipase, which prevents absorption of dietary fats, and restricts the systemic delivery of triglycerides and free fatty acids. Subsequently, reduced lipid supply reduces hepatic fat deposition, diminishes renal fatty infiltration and inhibits oxidative and inflammatory signaling in these interdependent organs. Such a mechanistic interaction is the reason behind the enhanced lipid profile and the partial restoration of liver and kidney histology in the orlistat-treated groups, especially at the 360 and 480 mg/kg dosage. Nevertheless, the fact that structural changes still persist with increased doses is a hint that lipid metabolism modulation should not be given so much consideration to fully offset chronic HFD load, highlighting the complexity of the gutliverkidney axis in organ dysfunction related to obesity. Table 4 summarizes the serum urea, creatinine, direct bilirubin, and indirect bilirubin of male rats fed a high-fat diet (HFD) and given Orlistat (XE) at dosages of 360, 480, and 600 mg/kg. There were significant changes ( P < 0.05) observed in the tested parameter between the control group (normal diet) compared with the HFD and the three Orlistat -treated groups (360, 480, and 600 mg/kg). Table 4. Effects of Orlistat (XE) at doses of 360, 480, 600 mg/kg on serum urea (mg/dL), creatinine (mg/dL), direct bilirubin (mg/dL), and indirect bilirubin (mg/dL) of male rats fed a high-fat diet (HFD). Experimental groups Parameter Urea Creatinine Direct Bilirubin Indirect Bilirubin Control 43.10 ab ± 0.04 0.56 a ± 0.03 0.20 ab ± 0.0 0.40 b ± 0.08 HFD 42.05 abc ± 3.0 0.44 b ± 0.01 0.35 a ± 0.02 0.45 b ± 0.06 HFD+XE-360 39.80 bc ± 0.81 0.47 b ± 0.02 0.35 a ± 0.10 0.53 ab ± 0.05 HFD+XE-480 48.05 a ± 0.44 0.44 b ± 0.002 0.25 ab ± 0.02 0.62 ab ± 0.01 XE-600 36.29 c ± 1.51 0.57 a ± 0.01 0.13 b ± 0.01 0.68 a ± 0.05 HFD affects the kidney by increasing urea and creatinine ( Amin et al., 2014 ). According to Fahmi’s (2021) findings, the high-fat diet significantly raised the levels of urea and creatinine when compared to the control group; however, there were no significant changes between the high-fat diet and Orlistat. Additionally, the documented increase in blood urea and creatinine in male rats after high-fat meals were administered is in line with research on the connection between high-fat diets and renal failure. KF Diet-induced oxidative stress and lipid deposition in the renal tissues lead to inflammation and dysfunction of the glomerular filtration and tubules, increasing isaac, and markers of kidney injury ( Muller et al., 2019 ; Prem and Kurian, 2021 ). For example, Muller et al. (2019) established that HFD feeding of the murine animal model leads to glomerular retraction, lower GFR, and increases glucose synthesis, and pro-inflammatory cytokines including IL-6, consistent with reparation and inflammatory mechanisms involved in the pathogenesis of renal impairment. ( Prem and Kurian, 2021 ) demonstrated that 16 weeks of HFD significantly exhausted eGFR and increased plasma creatinine in treated groups, reinforcing the nephrotoxic consequences of lipid toxicity duration. The non-significant differences in urea and creatinine levels between the HFD and Orlistat -treated groups in our investigation indicate that Orlistat therapy at dosages of 360, 480, and 600 mg/kg did not exacerbate HFD-induced renal impairment. However, and in contrast with previous works, Tousson et al. (2018) : clearly showed that orlistat caused a significant rise in serum creatinine and urea in normal rats supporting the expected nephrotoxic effect at usual medication doses. However, the lack of toxicity observed in our HFD model could be attributed to adapting compensatory mechanisms in the overweight rat or differences in the study model as regard treatment duration. Importantly, the most recognized orlistat mechanism of action is directly combating dietary fat absorption, which directs lipid-induced renal lipotoxicity, to indirectly or subsequently un-enhances HFD-induced oxidative stress and inflammation ( Ahmed et al., 2024 ). Further research is warranted on the large changes in direct and indirect bilirubin observed in Orlistat -treated groups. It is possible that orlistat impacts bilirubin dynamic because the drug interferes with lipid metabolism, which employs both hepatic and renal excretory pathways. In one study, Nishioka et al. (2003) orlistat increased the fecal excretion of unconjugated bilirubin found in Gunn rats, presumably by reducing the systemic availability of bilirubin. While our findings demonstrate a mediating effect of Orlistat on bilirubin homeostasis, the precise mechanism is unknown, including changes in hepatic conjugation or renal excretion, and should be further investigated. The hepatorenal changes which were described in the current study can be attributed to a number of mechanistic mechanisms which have been linked to the exposure to orlistat in the past. It is shown that orlistat may cause oxidative stress caused by overproduction of reactive oxygen species (ROS), which results in lipid peroxidation and degradation of antioxidant defense mechanisms SOD, CAT, and GSH. This oxidative imbalance can be one of the factors that led to the increase of liver enzymes and structural hepatic degeneration that was observed in the treated groups. Also, orlistat is said to cause inflammatory reactions by upregulating pro-inflammatory cytokines (e.g., TNF- a, IL- 6), which add to the aggravation of hepatocellular and renal damages. In extreme situations, there is also a chance of oxidative and inflammatory stress during long durations, leading to the activation of apoptosis-related pathways, which cause cellular necrosis and disruption of tissues. Even though our study has not directly measured the molecular markers, the biochemical and histopathological results on the various doses are in agreement with the previously detailed mechanisms, which is why it is possible to conclude that orlistat causes dose-dependent hepatorenal toxicity under the conditions of HFD. Alkaline phosphatase (AIP), gamma-glutamyl transpeptidase test (GGT), alanine aminotransferase (ALT), and aspartate aminotransferase (AST) activity in the blood of male rats given 360, 480, and 600 mg/kg of Orlistat and fed a high-fat diet (HFD). According to Table 5 , the liver enzyme activity of the HFD group was considerably lower than that of the control group that was fed a regular diet. These indices showed a substantial reduction (P < 0.05) in the three Orlistat -treated groups (360, 480, and 600 mg/kg) as compared to the control and HFD groups. Table 5. Effects of Orlistat (XE) at doses of 360, 480, 600 mg/kg on serum enzyme activities (AST, ALT, GGT, and AIP) of male rats fed a high-fat diet (HFD). Experimental groups Parameter AST (IU/L) ALT (IU/L) GGT (IU/L) AIP (IU/L) Control 302 b ± 49.3 99 a ± 27.5 12.6 b ± 0.21 298 ab ± 27.0 HFD 176 b ± 4.8 61 ab ± 11.3 14.7 a ± 0.56 209 a ± 5.9 HFD+XE-360 85 a ± 2.6 29 b ± 0.5 10.1 c ± 0.04 349 a ± 25.18 HFD+XE-480 141 b ± 11.1 30 b ± 2.5 13.7 ab ± 0.52 378 a ± 22.2 XE-600 117 b ± 29.3 27 b ± 0.6 12.7 b ± 0.62 334 a ± 34.1 When compared to the control group, the high-fat diet and Orlistat groups showed substantially lower liver enzyme activity of AST, ALT, GGT, and ALP, indicating that Orlistat is efficient in lowering hepatic stress in male rats. These results went against those seen in the usual high-fat-diet model, where liver enzyme levels were high and associated with hepatic damage, characterized by fatty liver and inflammation ( Svegliati-Baroni et al., 2006 ). However, the observed decrease in enzyme activities aligns with studies demonstrating that orlistat mitigates liver damage by reducing lipid accumulation and oxidative stress in obesity-related models ( Zakaria et al., 2021 ; Curran and Scott, 2004 ). “The reduced serum hepatic enzyme levels observed in the HFD group, despite histological steatosis, may reflect an early adaptive metabolic phase. During initial fatty infiltration, hepatocytes accumulate lipids without membrane rupture; therefore, intracellular enzymes remain largely retained. Biochemical leakage typically occurs at later inflammatory stages, explaining the discrepancy between biochemical and histological findings.” Although HFD is often related to hepatic steatosis and increased LFTs, the decrease in AST, ALT, GGT, and ALP in the present study could be a result of adaptive metabolic reactions or model distinctions, including feed composition and duration. The short-term exposure to HFD may not have caused severe hepatocellular destruction to increase the levels of these enzymes significantly ( de Freitas Carvalho et al., 2019 ). Orlistat’s inhibition of dietary fat absorption reduces lipid infiltration into the liver, thereby alleviating metabolic strain on hepatocytes. This mechanism is supported by studies showing that orlistat lowers liver enzyme levels in rodent models of obesity by improving lipid metabolism and reducing oxidative stress ( Curran and Scott, 2004 ; Zakaria et al., 2021 ). For example, Curran and Scott (2004) found that orlistat significantly reduced ALT and AST in obese people with non-alcoholic fatty liver disease (NAFLD), which was associated with lower hepatic fat content. According to Hamza and Alsolami’s (2023) findings, the HFD male rat group had higher levels of liver enzymes (AST and ALT), however orlistat significantly reduced these levels and brought them back to nearly normal levels. Histological slices of the liver from the control group demonstrate normal blood sinusoids, hepatocytes, central veins, and hepatocyte architecture. HFD-inflicted a severe liver cell injury, and it is evident from the liver histological changes, which include; sinusoidal space, liver sinusoid, toxic drugs, and apoptotic cells are in Figure 1 . High-fat diet group HFD, Lobular infiltrate by chronic inflammatory cells, hepatocytes disarray, and cloudy swelling be liver epatocytes; sinuosoid, apoptotic cells with curvy arrow are in Figure 2 . HFD treatment with Orlistat; XE-360, slight lobular infiltrate by chronic inflammatory cells, hepatocytes disarray and cloudy swelling be liver epatocytes; sinuosoid, apoptotic cells are in Figure 3 . HFD treatment with Orlistat; XE-360, marked dilatation; congestion portal vein are in Figure 4 . HFD treatment with Xeni Orlistat cal; XE-600, histological changes induced were slightly reduced, slight inflammatory cells. Figure (5) : Liver histopathology showing dose-dependent improvement following orlistat treatment. The HFD group showed fatty degeneration and inflammatory infiltration. The HFD+XE-480 group demonstrated moderate reduction in steatosis and inflammatory cells, whereas the HFD+XE-600 group showed slight inflammatory infiltration (yellow arrow). (Light microscopy, 400× magnification). Figure 1. The control group shows normal hepatocyte architecture (Black arrow), central vein, and normal blood sinusoids (Red arrow). (light microscopy at 400× magnification). Figure 2. Rats fed a high-fat diet (HFD) group show Lobular infiltrate by chronic inflammatory cells (Black arrow), with hepatocytes disarray and cloudy swelling of liver hepatocytes (Red arrow). (light microscopy at 400× magnification). Figure 3. Rats fed a high-fat diet (HFD) and treated with Orlistat (XE-360) show a slight lobular infiltrate by chronic inflammatory cells (Red arrow) with hepatocytes disarray and cloudy swelling (Yellow arrow). (light microscopy at 400× magnification). Figure 4. Rats fed a high-fat diet (HFD) and treated with Orlistat (XE-360) show marked dilatation and congestion in the portal vein (Yellow arrow). (light microscopy at 400× magnification). Figure 5. Rats fed a high-fat diet (HFD), and Orlistat (XE-600) showed histological changes induced were slightly reduced, with slight inflammatory cells (Yellow arrow). The HFD+XE-480 group showed moderate improvement compared with the HFD group, as evidenced by reduced hepatocellular vacuolation and decreased inflammatory cell infiltration, although mild fatty degeneration was still present. (light microscopy at 400× magnification). The histological findings of this study reveals the hepatoprotective effects of Orlistat on high-fat fed male rats against the liver damage. Liver slices from the control group had typical hepatic architecture with intact hepatocytes, central veins, and blood sinusoids, as seen in Figure 1 . Figure 2 illustrates the significant pathological abnormalities that the HFD group had, including lobular trafficking of inflammatory infiltrates, hepatocyte clutters, hazy edema, and apoptotic bodies. These results are consistent with the finding of Hamza and Alsolami (2023) that HFD caused liver hypertrophy, eosinophilia, and necrotic foci to formation. Zakaria et al. (2021) had earlier reported degenerated hepatocytes with steatosis and portal inflammation on a 16-week HFD fed model. Orlistat treatment at 360 mg/kg partially attenuated these changes, with a reduction in lobular inflammation and cloudy swelling ( Figure 3 ); however, residual portal vein congestion persisted ( Figure 4 ). The areas showed further reduction at the higher dose (XE-600, Figure 5 ) which implies a dose-dependent therapeutic effect. This is in line with Fahmi (2021) who reported that Orlistat prevents HFD-induced fatty degeneration and inflammatory infiltration while increasing the expansion of hepatic sinusoids in the HFD-fed rats. The incomplete normalization of the liver architecture using even higher doses might be due to the residual accumulation of lipid or irreversible fibrosis of prolonged HFD exposure, similar to the NASLD models ( Zakaria et al., 2021 ). Orlistat’s hepatoprotective effect is probably due to its inhibition of pancreatic lipase, which results in diminished fat absorption by the intestine and thus decreased hepatic lipids ( Zakaria et al., 2021 ). Orlistat reduces steatosis, oxidative stress, and inflammation by diminishing lipid influx, among the primary sources of HFD-induced liver injury. Hamza and Alsolami (2023) confirmed the previous mechanism, noting that orlistat reduced lipid overloading and related necroinflammation, and meanwhile returned the hepatocyte to normal architecture. Orlistat exhibits a context-dependent biological effect rather than a purely protective or toxic action. While previous studies reported oxidative stress and inflammatory responses following high doses or prolonged exposure, these effects are primarily related to excessive lipid depletion and altered cellular lipid metabolism ( Heck et al., 2000 ). Under high-fat diet conditions, however, the drug reduces intestinal fat absorption, thereby limiting hepatic lipid overload, lipotoxicity, and secondary oxidative stress ( Padwal & Majumdar, 2007 ). Consequently, the improvement observed in hepatic architecture in the present study is attributed to reduction of lipid influx to the liver rather than a direct antioxidant pharmacological activity. The kidney histological sections of the control, HFA, and HFD groups treated with XE at 360, 480, and 600 mg/kg are displayed in Figures 6 – 10 . The kidney segment has a normal morphology, as seen in Figure 6 for the control group. Renal tubules are well-studied and functional, and the glomeruli are also normal, which mean there is no apparent pathology. Regarding the HFD group in Figure 7 , there are lipid droplets in the renal tubules that can indicate fat deposition and possible damage to cells. The presented micrograph represents a typical field observed repeatedly across examined sections and was selected as a representative example of the histological findings in this group. Figure 8 , which represents HFD treated XE-360, looks markedly improved renal structure with mild residual tubular vacuolation compared to the HFD group, and no distinct pathology can be seen. This means that Orlistat at such a dose may have some kind of protective effect against fat-induced damage. On the slide for HFD treated XE-480, shown in Figure 9 , the kidney sections are mostly normal, however, the structure of the renal tubule, which is slightly different indicates that there may be some mild effect of HFD, which is “reversed” by the XE dose. The 480 mg/kg dose produced moderate hepatocellular vacuolation and mild sinusoidal dilation compared to the high-fat diet group, indicating partial attenuation of steatotic alterations. Table 6 . The intermediate dose of orlistat (480 mg/kg) demonstrated partial protection against high-fat diet-induced renal injury. The improvement in renal histoarchitecture likely reflects reduced lipid influx and lipotoxicity, while the persistence of mild biochemical alterations indicates residual functional stress. This suggests a dose-dependent protective effect rather than complete normalization ( Declèves & Sharma, 2015 ). The slide for HFD treated with XE-600 is present at Figure 10 . For renal histological evaluation, images were captured from comparable cortical areas containing intact glomeruli and surrounding renal tubules in all experimental groups. All sections were examined under identical microscopic conditions at 400× magnification to allow reliable morphological comparison between groups. At the highest dose (600 mg/kg), biochemical alterations indicate functional renal stress without overt structural destruction. Early nephrotoxicity may occur at the molecular and mitochondrial level before morphological damage becomes evident by light microscopy, explaining the preserved renal architecture despite altered renal biomarkers ( Vaidya et al., 2008 ; Ferenbach & Bonventre, 2015 ). Figure 6. The control group shows a normal histological structure of a kidney. The renal tubules (Red arrow) and glomeruli appear healthy and well-defined (Yellow arrow), indicating no apparent pathological changes. (light microscopy, renal cortex including glomeruli, 400× magnification). Figure 7. Rats fed a high-fat diet (HFD) group show a necrosis within the renal tubules (Yellow arrow) and potential cellular damage (Red arrow). The image illustrates the characteristic lesions observed consistently in the examined sections. (light microscopy, renal cortex including glomeruli, 400× magnification). Figure 8. Rats fed a high-fat diet (HFD) and treated with Orlistat (XE-360) appear to have markedly improved renal structure with mild residual tubular vacuolation compared to the HFD group, with no significant pathological changes observed, suggesting that Orlistat at this dose might have a protective effect against the fat-induced damage. (light microscopy, renal cortex including glomeruli, 400× magnification). Figure 9. Rats fed a high-fat diet (HFD) and treated with Orlistat (XE-480) appear mostly normal. However, there might be some slight changes in the structure of the renal tubules, suggesting a possible mild effect of the high-fat diet that is being mitigated by the dose of XE (Yellow arrow). (light microscopy, renal cortex including glomeruli, 400× magnification). Figure 10. Rats fed a high-fat diet (HFD) and treated with Orlistat (XE-600) appear mostly normal. However, there might be some slight changes in the structure of the renal tubules (Red and yellow arrows), suggesting a possible mild effect of the high-fat diet that is being mitigated by the dose of XE. (light microscopy, renal cortex including glomeruli, 400× magnification). The discrepancy between biochemical renal markers and histological findings may indicate early functional nephrotoxicity preceding structural damage. Renal dysfunction can occur due to metabolic and oxidative stress before overt morphological lesions become detectable by routine light microscopy. Therefore, the elevated biochemical parameters observed at higher doses reflect functional impairment rather than established tissue destruction ( Vaidya et al., 2008 ; Ferenbach & Bonventre, 2015 ). The kidney histology of HFD rats revealed severe pathological modifications, and these features include lipid droplet build up in renal tubules, glomeruluar atophy, necrosis, and tubular dissociation. These outcomes aligned with Salim et al. (2018) , whereas HFD-induced renal injury models promoted glomerulosclerosis, segmental necrosis, tubula defects, and mononuclear cell infiltration. Lipid accumulation in renal tissue is critical for lipotoxicity, inflammation, and progressive nephron impairment in kidney illness related to obesity ( Zakaria et al., 2021 ). Somewhat amelioration of the renal changes following Orlistat treatment at 360, 480, and 600 mg/kg appears to have occurred, as revealed by histological sections consistent with nearly normal glomeruli and tubules, and diminished fatty infiltration. Likewise, Fahmi (2021) revealed a partial restoration of the renal architecture and improvement of fatty degeneration after orlistat treatment in HFD-induced rats. This amelioration might have been ascribed to the lower body’s lipid load and the amelioration of oxidative stress and inflammation, as reported by Zakaria et al. (2021) and Ren et al. (2023) . Our results show that there is a definite dose-related effect of orlistat on the hepatic and renal functions. This is because the significant degenerative changes were observed at 480 and 600 mg/kg which is accompanied by minor histological changes which are an indication of potential protective effect at 360 mg/kg. This dose reward relationship shows emphasis on dose selection in order to reduce hepatic and renal toxicity, as in Table 6 . Table 6. Orlistat effect on the liver and kidneys at various strephenyl doses. Dose (mg/kg) Liver function Kidney function Histopathological changes (Liver) Histopathological changes (Kidney) 360 ALT, AST: slight increase (within normal range) Creatinine, BUN: slight increase Mild hepatocyte vacuolation; minimal inflammatory infiltration Mild tubular dilation; intact glomeruli 480 ALT, AST: moderate increase Creatinine, BUN: moderate increase Moderate hepatocyte degeneration; scattered necrosis; mild inflammation Moderate tubular degeneration; mild glomerular changes 600 ALT, AST: significant increase Creatinine, BUN: significant increase Severe hepatocyte necrosis; marked inflammation; early fibrosis Pronounced tubular necrosis; glomerular degeneration; interstitial inflammation The current results suggest that orlistat has a biphasic pattern of activity with lesser doses having mild protective or neutral effect on the organism whereas greater doses (480-600 mg/kg) have overt hepatorenal toxicity. According to the measured dose-dependent histopathological and biochemical changes, the findings indicate that the therapeutic margin within which orlistat is safe is small. This is in line with past studies that indicate that excessive suppression of fat intake can overstretch the gut-liver axis resulting in the build-up of lipids, inflammatory response and metabolic strain. Even though current doses applied to the animal model are scaled with animal weight, its findings highlight the possible risk of this high dose or long-term exposure to orlistat in humans. Persons with pre-existing liver or kidney diseases can be especially susceptible because any moderate change in lipid metabolism or oxidative homeostasis would worsen already existing organ damage. Thus, orlistat in lower dose can be effective as short-term therapeutic treatment and needs caution but higher dosage or longer administration but clinical follow-up of liver and kidney indicators is highly encouraged. These observations highlight the need to conduct more translational research to establish a more precise safety margin as well as to identify the clinical meaning of dose-related hepatorenal changes in the animal model. 4. Conclusion and future work Summarized, the current work demonstrates that prolonged exposure of the male rats fed HFD to Orlistat at doses from 360 to 600 mg/kg exacerbates the pre-existing hepatic and renal dysfunction. On the one hand, the maximal daily dose was used to simulate the intended clinical action of Orlistat to prevent fat absorption and cause mild side effects in the form of a disordered lipid metabolism. However, several other laboratory observations, such as increased liver enzymes and a weakened renal function, contrasted this assumption. The histopathology data additionally confirmed these findings through the development of hepatic inflammation, hepatocytes’ distortion, and renal tubule’s lipid infiltration. Therefore, while Orlistat shows a promise as an anti-obesity agent, its use is impractical due to the dose-dependent hepatorenal toxicity to HFD-fed rats in a sub-chronic regimen. The above findings highlight the need for the lifelong examination of the organ function in patients undergoing persistent orlistat treatment, particularly in patients with preexisting metabolic dysfunction. Orlistat has a dose-related effect on hepatic and renal functioning. Only slight histological and functional alterations were noted at the 360 mg/kg implying protective effect to some extent. Nonetheless, the doses of 480 and 600 mg/kg could lead to severe degenerative changes of liver and kidney tissues that were an indicator of aggravated organ dysfunction. These findings support the need to optimize dosage to reduce possible hepatic and renal toxicity without affecting therapeutic effectiveness. For future directions: Elucidate the molecular mechanisms behind Orlistat -induced hepatorenal toxicity in rats, including oxidative stress, immune mediators, and apoptosis molecular markers. Investigate the gut-liver-kidney axis to determine whether the kidney and liver are damaged as a result of the direct cytotoxic effect of the medication or due to the secondary metabolic effect of drug exposure. Meanwhile, study lower doses of Orlistat to establish the therapeutic window where medication is both efficacious and safe. For future direction: Explore whether hepatorenal injury is irreversible in the HFD-fed rat model or if it can be recovered after orlistat withdrawal. Investigate the combined treatment with Orlistat and renoprotective or hepatoprotective medications to reduce the generation of toxicity. The future studies need to be directed towards determining the long-term safety of orlistat, especially when administered on a chronic basis. In spite of the evident dose-dependent hepatorenal changes observed in the given study, it is still necessary to examine whether they continue, increase, or disappear following the drug withdrawal. Studies of long term follow-up in terms of recovery pattern, biochemical normalization and histopathological regeneration would be useful in determining the reversibility of orlistat induced toxicity. Also, the chronic-exposure models simulating the practical clinical application are required to better establish the cumulative risks of long-term therapy, particularly in the vulnerable groups. Declaration of generative AI use in the writing process The authors wish to particularly note that, at the intermediate editorial stage, when this manuscript was prepared, several phrasings and wording variations were generated using a generative AI tool Perplexity , which targeted free of charge clarity, fluency, and readability where necessary, some of which were included in the final version of this manuscript. However, all original revisions had been selected, modified, and reviewed by the authors for accuracy and precision. The authors accept full responsibility for the final product and declare that the use of AI had no impact on the work’s results or scientific validity. Consent to publish The final version of the work has been examined and approved by all authors, who also agree to its publication. Data availability statement The datasets generated and/or analyzed during the current study, including the completed ARRIVE 2.0 checklist, are publicly available in the Zenodo repository under the Creative Commons Zero (CC0 1.0) Public Domain Dedication. The data can be accessed at: https://doi.org/10.5281/zenodo.18225317 ( Alkadhimy et al., 2026 ). Acknowledgements “This is not applicable for that specific section”. The authors declare that no additional support, assistance, or acknowledgments are applicable for this study. References Ahmed MAA, Ssemmondo E, Mark-Wagstaff C, et al. : Advancements in the management of obesity: a review of current evidence and emerging therapies. Expert. Rev. Endocrinol. Metab. 2024; 19 (3): 257–268. Alkadhimy SM, Neamah AM, Al-Hamadani MYI, et al. : Dataset for: Effect of anti-obesity drug orlistat (Xenical™) on liver and kidney function in male rats fed a high-fat diet (1.0). [Data set]. Zenodo. 2026. 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Veterinary sciences. 2021; 8 (11): 274. Comments on this article Comments (1) Version 2 VERSION 2 PUBLISHED 31 Mar 2026 Revised Comment ADD YOUR COMMENT Version 1 VERSION 1 PUBLISHED 29 Jan 2026 Discussion is closed on this version, please comment on the latest version above. Reader Comment 05 Feb 2026 Khalid Bassiouny , Molecular Biology, Institute of Genetic Engineering, Sadat City, Egypt 05 Feb 2026 Reader Comment 1. Minor consistency improvements are recommended for terminology related to hepatic and renal functions across the manuscript. 2. Adding a short comment on the biological significance of the results in ... Continue reading 1. Minor consistency improvements are recommended for terminology related to hepatic and renal functions across the manuscript. 2. Adding a short comment on the biological significance of the results in key tables would improve data interpretation. 3.Minor language polishing is suggested to enhance clarity and readability. 1. Minor consistency improvements are recommended for terminology related to hepatic and renal functions across the manuscript. 2. Adding a short comment on the biological significance of the results in key tables would improve data interpretation. 3.Minor language polishing is suggested to enhance clarity and readability. Competing Interests: No competing interests were disclosed. Close Report a concern Discussion is closed on this version, please comment on the latest version above. Author details Author details 1 Department of Biology, College of Science, University of Karbala, Karbala, Iraq 2 Department of Environment, College of Science, University of Al-Qadisiyah, Al-Qadisiyah, Iraq 3 Department of Biology, College of Education, University of Fallujah, Al-Fallujah, Iraq 4 Department of Pathology and Poultry Disease, College of Veterinary Medicine, University of Fallujah, Al-Fallujah, Iraq 5 Department of Environmental Studies,Institute of Graduate Studies and Research, Alexandria University,163 Horeya Avenue, Chatby 21526, P.O. Box 832,Alexandria, Egypt Sura M. Alkadhimy Roles: Data Curation Asmaa M. Neamah Roles: Formal Analysis Mohammed Y.I. Al-Hamadani Roles: Methodology, Writing – Original Draft Preparation Ahmed S. Jarad Roles: Conceptualization, Writing – Original Draft Preparation Mokhtar I Yousef Roles: Project Administration, Supervision Competing interests No competing interests were disclosed. Grant information The author(s) declared that no grants were involved in supporting this work. Article Versions (2) version 2 Revised Published: 31 Mar 2026, 15:136 https://doi.org/10.12688/f1000research.174090.2 version 1 Published: 29 Jan 2026, 15:136 https://doi.org/10.12688/f1000research.174090.1 Copyright © 2026 Alkadhimy SM et al . This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Download Export To Sciwheel Bibtex EndNote ProCite Ref. Manager (RIS) Sente metrics Views Downloads F1000Research - - PubMed Central info_outline Data from PMC are received and updated monthly. - - Citations open_in_new 0 open_in_new 0 open_in_new SEE MORE DETAILS CITE how to cite this article Alkadhimy SM, Neamah AM, Al-Hamadani MYI et al. Effect of anti-obesity drug orlistat (Xenical™) on liver and kidney function in male rats fed a high-fat diet [version 2; peer review: 1 approved, 2 approved with reservations, 1 not approved] . F1000Research 2026, 15 :136 ( https://doi.org/10.12688/f1000research.174090.2 ) NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS track receive updates on this article Track an article to receive email alerts on any updates to this article. TRACK THIS ARTICLE Share Open Peer Review Current Reviewer Status: ? Key to Reviewer Statuses VIEW HIDE Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions Version 2 VERSION 2 PUBLISHED 31 Mar 2026 Revised Views 0 Cite How to cite this report: Satir-Basaran G. Reviewer Report For: Effect of anti-obesity drug orlistat (Xenical™) on liver and kidney function in male rats fed a high-fat diet [version 2; peer review: 1 approved, 2 approved with reservations, 1 not approved] . F1000Research 2026, 15 :136 ( https://doi.org/10.5256/f1000research.197366.r477543 ) The direct URL for this report is: https://f1000research.com/articles/15-136/v2#referee-response-477543 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Close Copy Citation Details Reviewer Report 05 May 2026 Guzide Satir-Basaran , Erciyes University, Kayseri, Turkey Not Approved VIEWS 0 https://doi.org/10.5256/f1000research.197366.r477543 There are studies indicating that orlistat has harmful effects on the liver and kidneys. Using n = 5 rats per group reduces the statistical power. There is no Normal diet + orlistat group ... Continue reading READ ALL There are studies indicating that orlistat has harmful effects on the liver and kidneys. Using n = 5 rats per group reduces the statistical power. There is no Normal diet + orlistat group among the groups. This creates a major limitation in evaluation and interpretation. In Table 2 , XE-600 is mentioned—does this group correspond to ND or HFD? It is unclear. The toxicity of orlistat alone cannot be clearly distinguished, and its effect in combination with HFD is not clearly defined. The doses used (360–600 mg/kg orlistat) are far above the therapeutic doses used in humans. This limits clinical applicability. The decrease in AST and ALT creates a contradiction. Normally, these enzymes increase in liver damage. This situation has not been sufficiently explained. The inflammatory markers mentioned in the study are not specified among the measured values. In an obesity model, 60 days is not sufficient to induce liver damage. Therefore, the obesity-related findings in this study are also considered inadequate. Some statements in the study are contradictory. Additionally, there are issues with language and clarity. Additional data supporting obesity are required for the manuscript to achieve indexing. Is the work clearly and accurately presented and does it cite the current literature? Partly Is the study design appropriate and is the work technically sound? No Are sufficient details of methods and analysis provided to allow replication by others? No If applicable, is the statistical analysis and its interpretation appropriate? No Are all the source data underlying the results available to ensure full reproducibility? No Are the conclusions drawn adequately supported by the results? No Competing Interests: No competing interests were disclosed. Reviewer Expertise: Biochemistry I confirm that I have read this submission and believe that I have an appropriate level of expertise to state that I do not consider it to be of an acceptable scientific standard, for reasons outlined above. Close READ LESS CITE CITE HOW TO CITE THIS REPORT Satir-Basaran G. Reviewer Report For: Effect of anti-obesity drug orlistat (Xenical™) on liver and kidney function in male rats fed a high-fat diet [version 2; peer review: 1 approved, 2 approved with reservations, 1 not approved] . F1000Research 2026, 15 :136 ( https://doi.org/10.5256/f1000research.197366.r477543 ) The direct URL for this report is: https://f1000research.com/articles/15-136/v2#referee-response-477543 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS Report a concern Respond or Comment COMMENT ON THIS REPORT Views 0 Cite How to cite this report: Nath SK. Reviewer Report For: Effect of anti-obesity drug orlistat (Xenical™) on liver and kidney function in male rats fed a high-fat diet [version 2; peer review: 1 approved, 2 approved with reservations, 1 not approved] . F1000Research 2026, 15 :136 ( https://doi.org/10.5256/f1000research.197366.r477540 ) The direct URL for this report is: https://f1000research.com/articles/15-136/v2#referee-response-477540 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Close Copy Citation Details Reviewer Report 28 Apr 2026 Sabuj Kanti Nath , James Cook University, Townsville, Australia Approved with Reservations VIEWS 0 https://doi.org/10.5256/f1000research.197366.r477540 This study investigates the dose-dependent effects of orlistat on hepatic and renal function in high-fat diet-fed rats using biochemical and histopathological analyses. The topic is relevant; however, several methodological and interpretative limitations reduce the scientific strength and translational value of ... Continue reading READ ALL This study investigates the dose-dependent effects of orlistat on hepatic and renal function in high-fat diet-fed rats using biochemical and histopathological analyses. The topic is relevant; however, several methodological and interpretative limitations reduce the scientific strength and translational value of the study. The study design is only partly appropriate. While the general experimental approach is acceptable, there are important limitations, including the use of very high (supraphysiological) doses of orlistat without proper justification, a small sample size (n = 5 per group), absence of key control groups (e.g., normal diet + orlistat), and a relatively short experimental duration. These factors limit the robustness and applicability of the findings. The methods are described to some extent, but important details required for reproducibility are missing, particularly regarding randomization, blinding, and histopathological evaluation criteria. The statistical analysis is not sufficiently rigorous, as exact p-values, effect sizes, and detailed interpretations are lacking, and some conclusions appear inconsistent with the presented data. A major concern is the inconsistency between results and conclusions. The study reports improvements in lipid profile, reduced liver enzyme levels, and partial histological improvements at certain doses, yet concludes that orlistat causes severe dose-dependent hepatorenal toxicity. Additionally, the observation of decreased liver enzyme activities alongside histological evidence of hepatic damage is biologically contradictory and not adequately explained. Furthermore, mechanistic claims related to oxidative stress and inflammation are not supported by direct measurements and appear speculative. These should either be removed or clearly presented as hypotheses. To improve the manuscript, the authors should: Provide clear justification for dose selection, including human-equivalent dose calculations. Resolve inconsistencies between biochemical, histological, and interpretative findings. Revise the conclusions to accurately reflect the results. Strengthen statistical reporting with detailed outputs. Improve methodological transparency (randomization, blinding, histological scoring). Remove unsupported mechanistic claims. Revise the manuscript for language clarity and readability. Is the work clearly and accurately presented and does it cite the current literature? Partly Is the study design appropriate and is the work technically sound? Partly Are sufficient details of methods and analysis provided to allow replication by others? Partly If applicable, is the statistical analysis and its interpretation appropriate? No Are all the source data underlying the results available to ensure full reproducibility? Yes Are the conclusions drawn adequately supported by the results? Partly Competing Interests: No competing interests were disclosed. Reviewer Expertise: Nutrigenomics, Animal Nutrition, Obesity and Metabolic Disorders, Heat Stress Biology, Feed Additives and Nutritional Interventions, Rumen Microbiology, Experimental Design in Livestock Studies I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above. Close READ LESS CITE CITE HOW TO CITE THIS REPORT Nath SK. Reviewer Report For: Effect of anti-obesity drug orlistat (Xenical™) on liver and kidney function in male rats fed a high-fat diet [version 2; peer review: 1 approved, 2 approved with reservations, 1 not approved] . F1000Research 2026, 15 :136 ( https://doi.org/10.5256/f1000research.197366.r477540 ) The direct URL for this report is: https://f1000research.com/articles/15-136/v2#referee-response-477540 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS Report a concern Respond or Comment COMMENT ON THIS REPORT Views 0 Cite How to cite this report: Dutta B. Reviewer Report For: Effect of anti-obesity drug orlistat (Xenical™) on liver and kidney function in male rats fed a high-fat diet [version 2; peer review: 1 approved, 2 approved with reservations, 1 not approved] . F1000Research 2026, 15 :136 ( https://doi.org/10.5256/f1000research.197366.r472108 ) The direct URL for this report is: https://f1000research.com/articles/15-136/v2#referee-response-472108 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Close Copy Citation Details Reviewer Report 01 Apr 2026 Babi Dutta , Manipal Academy of Higher Education, Manipal, Karnataka, India Approved VIEWS 0 https://doi.org/10.5256/f1000research.197366.r472108 The authors have provided detailed feedback in response to ... Continue reading READ ALL The authors have provided detailed feedback in response to my review comments and adequately addressed the queries raised. Competing Interests: No competing interests were disclosed. Reviewer Expertise: HFD induced changes, effect of herbal extracts on serum lipid profile in HFD rats I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. Close READ LESS CITE CITE HOW TO CITE THIS REPORT Dutta B. Reviewer Report For: Effect of anti-obesity drug orlistat (Xenical™) on liver and kidney function in male rats fed a high-fat diet [version 2; peer review: 1 approved, 2 approved with reservations, 1 not approved] . F1000Research 2026, 15 :136 ( https://doi.org/10.5256/f1000research.197366.r472108 ) The direct URL for this report is: https://f1000research.com/articles/15-136/v2#referee-response-472108 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS Report a concern Respond or Comment COMMENT ON THIS REPORT Version 1 VERSION 1 PUBLISHED 29 Jan 2026 Views 0 Cite How to cite this report: Sobczyński J. Reviewer Report For: Effect of anti-obesity drug orlistat (Xenical™) on liver and kidney function in male rats fed a high-fat diet [version 2; peer review: 1 approved, 2 approved with reservations, 1 not approved] . F1000Research 2026, 15 :136 ( https://doi.org/10.5256/f1000research.191966.r458448 ) The direct URL for this report is: https://f1000research.com/articles/15-136/v1#referee-response-458448 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Close Copy Citation Details Reviewer Report 04 Mar 2026 Jan Sobczyński , Medical University of Lublin, Lublin, Poland Approved with Reservations VIEWS 0 https://doi.org/10.5256/f1000research.191966.r458448 The manuscript aims to present the toxic effects of orlistat (360, 480, 600 mg/kg, 60 days) in male rats on a high‑fat diet (HFD), reporting hematology, lipid panel, liver/kidney biochemistry, and H&E histology. While orlistat reduced obesity, it caused dose-related increases in ... Continue reading READ ALL The manuscript aims to present the toxic effects of orlistat (360, 480, 600 mg/kg, 60 days) in male rats on a high‑fat diet (HFD), reporting hematology, lipid panel, liver/kidney biochemistry, and H&E histology. While orlistat reduced obesity, it caused dose-related increases in liver enzymes and kidney damage. Structural changes in organs were more severe at higher doses of the drug. The findings conclude that orlistat administration in HFD conditions can lead to severe impairment of liver and kidney function, highlighting the need for close monitoring. The main strength of the study are: clearly stated research aim, multiangle view of the damage caused by orlistat, clear data presentation. The topic is relevant and the study provides a nuanced view into reporting of chemotherapy-related adverse effects. I would raise some points that could be better addressed by authors: The doses used by authors (360–600 mg/kg/day, p.o.) drastically exceed the typically used doses in animal studies which for rodent would typically include dosage of 30–40 mg/kg/day [Reference 1]; some models even 2 mg/kg for 30 days [Reference 2]. Clinically, orlistat acts locally in the gut with minimal systemic absorption, so the risk of its accumulation in the body is minimal. The manuscript provides no pharmacological or scaling rationale for supratherapeutic dosing. This undermines translational relevance and may provoke off‑target toxicity. The authors should provide a clear explanation for choosing such high doses and possible translational value of their investigation. There is no vehicle‑gavage control for chow and HFD groups. Orlistat groups were gavaged with an aqueous suspension; if rats belonging to control and HFD groups rats were not gavaged, procedure‑related stress may confound outcomes. The choice of not using this group should be explained. The number of rodents in study group (n=5/group) is underpowered for multi‑endpoint toxicology and histology, and authors did not report a priori power calculation. Please, provide a power analysis (effect size, α=0.05, 1–β≥0.8) and justify n. Although the authors cited a work describing HFD diet, some basic data concerning this diet should be provided for easier interpretation and classification of diet by phenotype severity (%kcal, fat content and type). Current literature generally reports that HFD elevates TG, LDL‑C and liver enzymes, and increases inflammatory markers, although effects vary with diet composition and the duration of diet administration to rodent. In this study HFD-fed animals are healthier than control (lower LDL-C and better liver enzymes levels). Perhaps outliers in the experiments were not properly handled or quantitation method was not accurate? Currents results make it difficult to compare and draw conclusions from treatment groups. Authors should add body weight, adiposity, and fecal fat to verify HFD phenotype and orlistat target involvement. Consider Some results contradict one another. Table 6 indicates severe liver damage following orlistat 600 mg/kg dosage based on pathology results. Still same dose appears to decrease ALT and AST as compared to control. This should be discussed thoroughly. The authors often imply that orlistat/HFD modulate oxidative stress and inflammatory cytokines (TNF‑α, IL‑6), yet no inflammatory biomarkers were measured. If you measured inflammatory markers, please show results. If this is a hypothesis, please reason with literature evidence. As similar mechanistic claims (ROS, TNF‑α/IL‑6 upregulation) are speculative without measurements. Reason with relevant literature, e.g.[Reference 3] Some claims need to be corrected, 1. in Abstract: ‘Orlistat is an antihypertensive agent…’ – no, it’s anti-obesity; 2. In Methods: “desiccation” is incorrect—perhaps authors meant “dissection” Please, keep your manuscript tidy and consistent: use HFD+XE‑600 consistently (not XE‑600) in all tables/figures, as you use HFD+XE‑360 and HFD+XE‑480 Some grammar polishing could be employed, e.g.: ‘In male rats given an HFD, on the histology and function of the liver and kidneys.’ Please change to ‘This study examines the dose-dependent effects of orlistat on the histology and function of the liver and kidneys in male rats given an HFD’ Most literature is 5 years or older, some references are from the last century. Some newer literature should be considered for citations, even if quantitation methods are well established. Is the work clearly and accurately presented and does it cite the current literature? Partly Is the study design appropriate and is the work technically sound? Yes Are sufficient details of methods and analysis provided to allow replication by others? Yes If applicable, is the statistical analysis and its interpretation appropriate? Partly Are all the source data underlying the results available to ensure full reproducibility? Yes Are the conclusions drawn adequately supported by the results? No References 1. Javed M, Ahmed W, Khan A, Rabbani I: Comparison of Efficacy of Fermented Garlic and Orlistat (Lipase Inhibitor) in Obesity Management Using an Experimental Rodent Model. Foods . 2023; 12 (21). Publisher Full Text 2. Alsolami K, Hamza R: Orlistat and Metformin Effectively Reduce Pancreatic Dysfunction, Insulin Resistance and Blood Glucose Levels in Male Rats Experimentally Induced with Obesity. International Journal of Pharmacology . 2024; 20 (5): 726-734 Publisher Full Text 3. Cavaliere G, Viggiano E, Trinchese G, De Filippo C, et al.: Long Feeding High-Fat Diet Induces Hypothalamic Oxidative Stress and Inflammation, and Prolonged Hypothalamic AMPK Activation in Rat Animal Model. Frontiers in Physiology . 2018; 9 . Publisher Full Text Competing Interests: No competing interests were disclosed. Reviewer Expertise: effect of high fat diet on metabolism I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above. Close READ LESS CITE CITE HOW TO CITE THIS REPORT Sobczyński J. Reviewer Report For: Effect of anti-obesity drug orlistat (Xenical™) on liver and kidney function in male rats fed a high-fat diet [version 2; peer review: 1 approved, 2 approved with reservations, 1 not approved] . F1000Research 2026, 15 :136 ( https://doi.org/10.5256/f1000research.191966.r458448 ) The direct URL for this report is: https://f1000research.com/articles/15-136/v1#referee-response-458448 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS Report a concern Respond or Comment COMMENT ON THIS REPORT Views 0 Cite How to cite this report: Dutta B. Reviewer Report For: Effect of anti-obesity drug orlistat (Xenical™) on liver and kidney function in male rats fed a high-fat diet [version 2; peer review: 1 approved, 2 approved with reservations, 1 not approved] . F1000Research 2026, 15 :136 ( https://doi.org/10.5256/f1000research.191966.r458447 ) The direct URL for this report is: https://f1000research.com/articles/15-136/v1#referee-response-458447 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Close Copy Citation Details Reviewer Report 28 Feb 2026 Babi Dutta , Manipal Academy of Higher Education, Manipal, Karnataka, India Approved with Reservations VIEWS 0 https://doi.org/10.5256/f1000research.191966.r458447 1. Introduction (Line 6) Rinella et al 2023. Reference is about new fatty liver disease nomenclature. Modify the reference 2. Introduction (Line 12) Dludla et al 2018. This reference does not include orlistat as good treatment, it talks about gallic ... Continue reading READ ALL 1. Introduction (Line 6) Rinella et al 2023. Reference is about new fatty liver disease nomenclature. Modify the reference 2. Introduction (Line 12) Dludla et al 2018. This reference does not include orlistat as good treatment, it talks about gallic acid treatment 3. Introduction (line 16-17). Obesity is caused by these disorders, or obesity increases the risk of these disorders (rewrite for clarity) 4. Orlistat reduces dietary fat absorption by 30% (Is there any reference for the reduction by 30% statement) 5. Orlistat has less than 1% bioavailability and scarcely produce systemic toxicity (Reference Al-Sabah the economic impact of obesity in Kuwait: a micro-costing study evaluating the burden of obesity related comorbidities), Check the reference clearly 6. For orlistat dosage: 360 mg/kg dosage how was the solution prepared, three tablet contents in how much ml of water to prepare stock solution of what concentration/ml for oral gavage? Reproducibility may be difficult since it is not clearly mentioned. 7. Experimental animals (line 10). The rats were put to sleep with isoflurane and killed after 60 days. Following their desiccation, (anesthetized is a better word, desiccation meaning?) 8. "Anesthesia of the rat was induced with inhaled isoflurane" this section should be before the previous section "putting the rats to sleep", since it explains about blood collection after sacrifice. 9. Table 2 onwards HFD+XE-600 is written as XE-600, maintain uniformity 10. After Table 4, 5th line.. HF-diet or KF diet? what is KF diet? Rectify 11. Explain why hepatic enzymes are reduced in HFD group than normal controls? What is meant by adaptive metabolic reactions or model distinctions? since hepatic histopathology shows steatotic changes, explain the reason why it is not reflected in liver enzyme serum profile? 12. Liver histopathological pictures at what magnifcation is not mentioned. ** mark is not visible in the picture Curved arrows are not clearly visible what about 480 mg/kg dosage, no mention of that.. the effect of 480mg/kg dosage on hepatic histology is missing? 13. After Figure 5 of liver histopathology, HFD+XE-480 effects explanation missing? 14. Orlistat hepatoprotective effect is probably due to (After image 5 line no 15 onwards) Contradictory statements since earlier the authors have written orlistat may cause oxidative stress caused by overproduction of reactive oxygen species (ROS), which results in lipid peroxidation and degradation of antioxidant defense mechanisms SOD, CAT, and GSH. This may cause increase of liver enzymes and structural hepatic degeneration that was observed in the treated groups. Also, orlistat is said to cause inflammatory reactions by upregulating pro-inflammatory cytokines (e.g., TNF- a, IL- 6), which add to the aggravation of hepatocellular and renal damages (contradictory statements) 14. Kidney histology magnification not mentioned, every image should be from same set of area in the kidney, for example, comparison of glomerular section across the groups at same magnification. 15. Figure 7A is completely distorted. Provide a better picture 16. Figure 8B shows a lot of vacuoles and epithelial damage, so how is it relatively normal. explain 17. Image 9 and 10 picture shows renal tissue with orlistat dose of 480 and 600 and denotes renal pathology is almost normal, so why overt renal toxicity at high dose in table 6. Justify 18. Table 6: Explanation of XE-480 dosage Figure 9. Rats fed a high-fat diet (HFD) and treated with Orlistat (XE-480) appear mostly normal, although there might be some slight changes in the structure of the renal tubules,suggesting a possible mild effect of the high-fat diet that is being mitigated by the dose of XE. 19. Table 6: Explanation of XE-600 dosage Figure 10. Rats fed a high-fat diet (HFD) and treated with Orlistat (XE-600) appear mostly normal... So is it damaged or not.. if damage, the pictures do not justify damage Is the work clearly and accurately presented and does it cite the current literature? Partly Is the study design appropriate and is the work technically sound? Yes Are sufficient details of methods and analysis provided to allow replication by others? Partly If applicable, is the statistical analysis and its interpretation appropriate? Yes Are all the source data underlying the results available to ensure full reproducibility? No source data required Are the conclusions drawn adequately supported by the results? Partly Competing Interests: No competing interests were disclosed. Reviewer Expertise: HFD induced changes, effect of herbal extracts on serum lipid profile in HFD rats I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above. Close READ LESS CITE CITE HOW TO CITE THIS REPORT Dutta B. Reviewer Report For: Effect of anti-obesity drug orlistat (Xenical™) on liver and kidney function in male rats fed a high-fat diet [version 2; peer review: 1 approved, 2 approved with reservations, 1 not approved] . F1000Research 2026, 15 :136 ( https://doi.org/10.5256/f1000research.191966.r458447 ) The direct URL for this report is: https://f1000research.com/articles/15-136/v1#referee-response-458447 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS Report a concern Respond or Comment COMMENT ON THIS REPORT Comments on this article Comments (1) Version 2 VERSION 2 PUBLISHED 31 Mar 2026 Revised Comment ADD YOUR COMMENT Version 1 VERSION 1 PUBLISHED 29 Jan 2026 Discussion is closed on this version, please comment on the latest version above. Reader Comment 05 Feb 2026 Khalid Bassiouny , Molecular Biology, Institute of Genetic Engineering, Sadat City, Egypt 05 Feb 2026 Reader Comment 1. Minor consistency improvements are recommended for terminology related to hepatic and renal functions across the manuscript. 2. Adding a short comment on the biological significance of the results in ... Continue reading 1. Minor consistency improvements are recommended for terminology related to hepatic and renal functions across the manuscript. 2. Adding a short comment on the biological significance of the results in key tables would improve data interpretation. 3.Minor language polishing is suggested to enhance clarity and readability. 1. Minor consistency improvements are recommended for terminology related to hepatic and renal functions across the manuscript. 2. Adding a short comment on the biological significance of the results in key tables would improve data interpretation. 3.Minor language polishing is suggested to enhance clarity and readability. Competing Interests: No competing interests were disclosed. Close Report a concern Discussion is closed on this version, please comment on the latest version above. keyboard_arrow_left keyboard_arrow_right Open Peer Review Reviewer Status info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions Reviewer Reports Invited Reviewers 1 2 3 4 Version 2 (revision) 31 Mar 26 read read read Version 1 29 Jan 26 read read Babi Dutta , Manipal Academy of Higher Education, Manipal, India Jan Sobczyński , Medical University of Lublin, Lublin, Poland Sabuj Kanti Nath , James Cook University, Townsville, Australia Guzide Satir-Basaran , Erciyes University, Kayseri, Turkey Comments on this article All Comments (1) Add a comment Sign up for content alerts Sign Up You are now signed up to receive this alert Browse by related subjects keyboard_arrow_left Back to all reports Reviewer Report 0 Views copyright © 2026 Satir-Basaran G. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 05 May 2026 | for Version 2 Guzide Satir-Basaran , Erciyes University, Kayseri, Turkey 0 Views copyright © 2026 Satir-Basaran G. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. format_quote Cite this report speaker_notes Responses (0) Not Approved info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions There are studies indicating that orlistat has harmful effects on the liver and kidneys. Using n = 5 rats per group reduces the statistical power. There is no Normal diet + orlistat group among the groups. This creates a major limitation in evaluation and interpretation. In Table 2 , XE-600 is mentioned—does this group correspond to ND or HFD? It is unclear. The toxicity of orlistat alone cannot be clearly distinguished, and its effect in combination with HFD is not clearly defined. The doses used (360–600 mg/kg orlistat) are far above the therapeutic doses used in humans. This limits clinical applicability. The decrease in AST and ALT creates a contradiction. Normally, these enzymes increase in liver damage. This situation has not been sufficiently explained. The inflammatory markers mentioned in the study are not specified among the measured values. In an obesity model, 60 days is not sufficient to induce liver damage. Therefore, the obesity-related findings in this study are also considered inadequate. Some statements in the study are contradictory. Additionally, there are issues with language and clarity. Additional data supporting obesity are required for the manuscript to achieve indexing. Is the work clearly and accurately presented and does it cite the current literature? Partly Is the study design appropriate and is the work technically sound? No Are sufficient details of methods and analysis provided to allow replication by others? No If applicable, is the statistical analysis and its interpretation appropriate? No Are all the source data underlying the results available to ensure full reproducibility? No Are the conclusions drawn adequately supported by the results? No Competing Interests No competing interests were disclosed. Reviewer Expertise Biochemistry I confirm that I have read this submission and believe that I have an appropriate level of expertise to state that I do not consider it to be of an acceptable scientific standard, for reasons outlined above. reply Respond to this report Responses (0) Satir-Basaran G. Peer Review Report For: Effect of anti-obesity drug orlistat (Xenical™) on liver and kidney function in male rats fed a high-fat diet [version 2; peer review: 1 approved, 2 approved with reservations, 1 not approved] . F1000Research 2026, 15 :136 ( https://doi.org/10.5256/f1000research.197366.r477543) NOTE: it is important to ensure the information in square brackets after the title is included in this citation. The direct URL for this report is: https://f1000research.com/articles/15-136/v2#referee-response-477543 keyboard_arrow_left Back to all reports Reviewer Report 0 Views copyright © 2026 Nath S. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 28 Apr 2026 | for Version 2 Sabuj Kanti Nath , James Cook University, Townsville, Australia 0 Views copyright © 2026 Nath S. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. format_quote Cite this report speaker_notes Responses (0) Approved With Reservations info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions This study investigates the dose-dependent effects of orlistat on hepatic and renal function in high-fat diet-fed rats using biochemical and histopathological analyses. The topic is relevant; however, several methodological and interpretative limitations reduce the scientific strength and translational value of the study. The study design is only partly appropriate. While the general experimental approach is acceptable, there are important limitations, including the use of very high (supraphysiological) doses of orlistat without proper justification, a small sample size (n = 5 per group), absence of key control groups (e.g., normal diet + orlistat), and a relatively short experimental duration. These factors limit the robustness and applicability of the findings. The methods are described to some extent, but important details required for reproducibility are missing, particularly regarding randomization, blinding, and histopathological evaluation criteria. The statistical analysis is not sufficiently rigorous, as exact p-values, effect sizes, and detailed interpretations are lacking, and some conclusions appear inconsistent with the presented data. A major concern is the inconsistency between results and conclusions. The study reports improvements in lipid profile, reduced liver enzyme levels, and partial histological improvements at certain doses, yet concludes that orlistat causes severe dose-dependent hepatorenal toxicity. Additionally, the observation of decreased liver enzyme activities alongside histological evidence of hepatic damage is biologically contradictory and not adequately explained. Furthermore, mechanistic claims related to oxidative stress and inflammation are not supported by direct measurements and appear speculative. These should either be removed or clearly presented as hypotheses. To improve the manuscript, the authors should: Provide clear justification for dose selection, including human-equivalent dose calculations. Resolve inconsistencies between biochemical, histological, and interpretative findings. Revise the conclusions to accurately reflect the results. Strengthen statistical reporting with detailed outputs. Improve methodological transparency (randomization, blinding, histological scoring). Remove unsupported mechanistic claims. Revise the manuscript for language clarity and readability. Is the work clearly and accurately presented and does it cite the current literature? Partly Is the study design appropriate and is the work technically sound? Partly Are sufficient details of methods and analysis provided to allow replication by others? Partly If applicable, is the statistical analysis and its interpretation appropriate? No Are all the source data underlying the results available to ensure full reproducibility? Yes Are the conclusions drawn adequately supported by the results? Partly Competing Interests No competing interests were disclosed. Reviewer Expertise Nutrigenomics, Animal Nutrition, Obesity and Metabolic Disorders, Heat Stress Biology, Feed Additives and Nutritional Interventions, Rumen Microbiology, Experimental Design in Livestock Studies I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above. reply Respond to this report Responses (0) Nath SK. Peer Review Report For: Effect of anti-obesity drug orlistat (Xenical™) on liver and kidney function in male rats fed a high-fat diet [version 2; peer review: 1 approved, 2 approved with reservations, 1 not approved] . F1000Research 2026, 15 :136 ( https://doi.org/10.5256/f1000research.197366.r477540) NOTE: it is important to ensure the information in square brackets after the title is included in this citation. The direct URL for this report is: https://f1000research.com/articles/15-136/v2#referee-response-477540 keyboard_arrow_left Back to all reports Reviewer Report 0 Views copyright © 2026 Dutta B. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 01 Apr 2026 | for Version 2 Babi Dutta , Manipal Academy of Higher Education, Manipal, Karnataka, India 0 Views copyright © 2026 Dutta B. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. format_quote Cite this report speaker_notes Responses (0) Approved info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions The authors have provided detailed feedback in response to my review comments and adequately addressed the queries raised. Competing Interests No competing interests were disclosed. Reviewer Expertise HFD induced changes, effect of herbal extracts on serum lipid profile in HFD rats I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. reply Respond to this report Responses (0) Dutta B. Peer Review Report For: Effect of anti-obesity drug orlistat (Xenical™) on liver and kidney function in male rats fed a high-fat diet [version 2; peer review: 1 approved, 2 approved with reservations, 1 not approved] . F1000Research 2026, 15 :136 ( https://doi.org/10.5256/f1000research.197366.r472108) NOTE: it is important to ensure the information in square brackets after the title is included in this citation. The direct URL for this report is: https://f1000research.com/articles/15-136/v2#referee-response-472108 keyboard_arrow_left Back to all reports Reviewer Report 0 Views copyright © 2026 Sobczyński J. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 04 Mar 2026 | for Version 1 Jan Sobczyński , Medical University of Lublin, Lublin, Poland 0 Views copyright © 2026 Sobczyński J. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. format_quote Cite this report speaker_notes Responses (0) Approved With Reservations info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions The manuscript aims to present the toxic effects of orlistat (360, 480, 600 mg/kg, 60 days) in male rats on a high‑fat diet (HFD), reporting hematology, lipid panel, liver/kidney biochemistry, and H&E histology. While orlistat reduced obesity, it caused dose-related increases in liver enzymes and kidney damage. Structural changes in organs were more severe at higher doses of the drug. The findings conclude that orlistat administration in HFD conditions can lead to severe impairment of liver and kidney function, highlighting the need for close monitoring. The main strength of the study are: clearly stated research aim, multiangle view of the damage caused by orlistat, clear data presentation. The topic is relevant and the study provides a nuanced view into reporting of chemotherapy-related adverse effects. I would raise some points that could be better addressed by authors: The doses used by authors (360–600 mg/kg/day, p.o.) drastically exceed the typically used doses in animal studies which for rodent would typically include dosage of 30–40 mg/kg/day [Reference 1]; some models even 2 mg/kg for 30 days [Reference 2]. Clinically, orlistat acts locally in the gut with minimal systemic absorption, so the risk of its accumulation in the body is minimal. The manuscript provides no pharmacological or scaling rationale for supratherapeutic dosing. This undermines translational relevance and may provoke off‑target toxicity. The authors should provide a clear explanation for choosing such high doses and possible translational value of their investigation. There is no vehicle‑gavage control for chow and HFD groups. Orlistat groups were gavaged with an aqueous suspension; if rats belonging to control and HFD groups rats were not gavaged, procedure‑related stress may confound outcomes. The choice of not using this group should be explained. The number of rodents in study group (n=5/group) is underpowered for multi‑endpoint toxicology and histology, and authors did not report a priori power calculation. Please, provide a power analysis (effect size, α=0.05, 1–β≥0.8) and justify n. Although the authors cited a work describing HFD diet, some basic data concerning this diet should be provided for easier interpretation and classification of diet by phenotype severity (%kcal, fat content and type). Current literature generally reports that HFD elevates TG, LDL‑C and liver enzymes, and increases inflammatory markers, although effects vary with diet composition and the duration of diet administration to rodent. In this study HFD-fed animals are healthier than control (lower LDL-C and better liver enzymes levels). Perhaps outliers in the experiments were not properly handled or quantitation method was not accurate? Currents results make it difficult to compare and draw conclusions from treatment groups. Authors should add body weight, adiposity, and fecal fat to verify HFD phenotype and orlistat target involvement. Consider Some results contradict one another. Table 6 indicates severe liver damage following orlistat 600 mg/kg dosage based on pathology results. Still same dose appears to decrease ALT and AST as compared to control. This should be discussed thoroughly. The authors often imply that orlistat/HFD modulate oxidative stress and inflammatory cytokines (TNF‑α, IL‑6), yet no inflammatory biomarkers were measured. If you measured inflammatory markers, please show results. If this is a hypothesis, please reason with literature evidence. As similar mechanistic claims (ROS, TNF‑α/IL‑6 upregulation) are speculative without measurements. Reason with relevant literature, e.g.[Reference 3] Some claims need to be corrected, 1. in Abstract: ‘Orlistat is an antihypertensive agent…’ – no, it’s anti-obesity; 2. In Methods: “desiccation” is incorrect—perhaps authors meant “dissection” Please, keep your manuscript tidy and consistent: use HFD+XE‑600 consistently (not XE‑600) in all tables/figures, as you use HFD+XE‑360 and HFD+XE‑480 Some grammar polishing could be employed, e.g.: ‘In male rats given an HFD, on the histology and function of the liver and kidneys.’ Please change to ‘This study examines the dose-dependent effects of orlistat on the histology and function of the liver and kidneys in male rats given an HFD’ Most literature is 5 years or older, some references are from the last century. Some newer literature should be considered for citations, even if quantitation methods are well established. Is the work clearly and accurately presented and does it cite the current literature? Partly Is the study design appropriate and is the work technically sound? Yes Are sufficient details of methods and analysis provided to allow replication by others? Yes If applicable, is the statistical analysis and its interpretation appropriate? Partly Are all the source data underlying the results available to ensure full reproducibility? Yes Are the conclusions drawn adequately supported by the results? No References 1. Javed M, Ahmed W, Khan A, Rabbani I: Comparison of Efficacy of Fermented Garlic and Orlistat (Lipase Inhibitor) in Obesity Management Using an Experimental Rodent Model. Foods . 2023; 12 (21). Publisher Full Text 2. Alsolami K, Hamza R: Orlistat and Metformin Effectively Reduce Pancreatic Dysfunction, Insulin Resistance and Blood Glucose Levels in Male Rats Experimentally Induced with Obesity. International Journal of Pharmacology . 2024; 20 (5): 726-734 Publisher Full Text 3. Cavaliere G, Viggiano E, Trinchese G, De Filippo C, et al.: Long Feeding High-Fat Diet Induces Hypothalamic Oxidative Stress and Inflammation, and Prolonged Hypothalamic AMPK Activation in Rat Animal Model. Frontiers in Physiology . 2018; 9 . Publisher Full Text Competing Interests No competing interests were disclosed. Reviewer Expertise effect of high fat diet on metabolism I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above. reply Respond to this report Responses (0) Sobczyński J. Peer Review Report For: Effect of anti-obesity drug orlistat (Xenical™) on liver and kidney function in male rats fed a high-fat diet [version 2; peer review: 1 approved, 2 approved with reservations, 1 not approved] . F1000Research 2026, 15 :136 ( https://doi.org/10.5256/f1000research.191966.r458448) NOTE: it is important to ensure the information in square brackets after the title is included in this citation. The direct URL for this report is: https://f1000research.com/articles/15-136/v1#referee-response-458448 keyboard_arrow_left Back to all reports Reviewer Report 0 Views copyright © 2026 Dutta B. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 28 Feb 2026 | for Version 1 Babi Dutta , Manipal Academy of Higher Education, Manipal, Karnataka, India 0 Views copyright © 2026 Dutta B. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. format_quote Cite this report speaker_notes Responses (0) Approved With Reservations info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions 1. Introduction (Line 6) Rinella et al 2023. Reference is about new fatty liver disease nomenclature. Modify the reference 2. Introduction (Line 12) Dludla et al 2018. This reference does not include orlistat as good treatment, it talks about gallic acid treatment 3. Introduction (line 16-17). Obesity is caused by these disorders, or obesity increases the risk of these disorders (rewrite for clarity) 4. Orlistat reduces dietary fat absorption by 30% (Is there any reference for the reduction by 30% statement) 5. Orlistat has less than 1% bioavailability and scarcely produce systemic toxicity (Reference Al-Sabah the economic impact of obesity in Kuwait: a micro-costing study evaluating the burden of obesity related comorbidities), Check the reference clearly 6. For orlistat dosage: 360 mg/kg dosage how was the solution prepared, three tablet contents in how much ml of water to prepare stock solution of what concentration/ml for oral gavage? Reproducibility may be difficult since it is not clearly mentioned. 7. Experimental animals (line 10). The rats were put to sleep with isoflurane and killed after 60 days. Following their desiccation, (anesthetized is a better word, desiccation meaning?) 8. "Anesthesia of the rat was induced with inhaled isoflurane" this section should be before the previous section "putting the rats to sleep", since it explains about blood collection after sacrifice. 9. Table 2 onwards HFD+XE-600 is written as XE-600, maintain uniformity 10. After Table 4, 5th line.. HF-diet or KF diet? what is KF diet? Rectify 11. Explain why hepatic enzymes are reduced in HFD group than normal controls? What is meant by adaptive metabolic reactions or model distinctions? since hepatic histopathology shows steatotic changes, explain the reason why it is not reflected in liver enzyme serum profile? 12. Liver histopathological pictures at what magnifcation is not mentioned. ** mark is not visible in the picture Curved arrows are not clearly visible what about 480 mg/kg dosage, no mention of that.. the effect of 480mg/kg dosage on hepatic histology is missing? 13. After Figure 5 of liver histopathology, HFD+XE-480 effects explanation missing? 14. Orlistat hepatoprotective effect is probably due to (After image 5 line no 15 onwards) Contradictory statements since earlier the authors have written orlistat may cause oxidative stress caused by overproduction of reactive oxygen species (ROS), which results in lipid peroxidation and degradation of antioxidant defense mechanisms SOD, CAT, and GSH. This may cause increase of liver enzymes and structural hepatic degeneration that was observed in the treated groups. Also, orlistat is said to cause inflammatory reactions by upregulating pro-inflammatory cytokines (e.g., TNF- a, IL- 6), which add to the aggravation of hepatocellular and renal damages (contradictory statements) 14. Kidney histology magnification not mentioned, every image should be from same set of area in the kidney, for example, comparison of glomerular section across the groups at same magnification. 15. Figure 7A is completely distorted. Provide a better picture 16. Figure 8B shows a lot of vacuoles and epithelial damage, so how is it relatively normal. explain 17. Image 9 and 10 picture shows renal tissue with orlistat dose of 480 and 600 and denotes renal pathology is almost normal, so why overt renal toxicity at high dose in table 6. Justify 18. Table 6: Explanation of XE-480 dosage Figure 9. Rats fed a high-fat diet (HFD) and treated with Orlistat (XE-480) appear mostly normal, although there might be some slight changes in the structure of the renal tubules,suggesting a possible mild effect of the high-fat diet that is being mitigated by the dose of XE. 19. Table 6: Explanation of XE-600 dosage Figure 10. Rats fed a high-fat diet (HFD) and treated with Orlistat (XE-600) appear mostly normal... So is it damaged or not.. if damage, the pictures do not justify damage Is the work clearly and accurately presented and does it cite the current literature? Partly Is the study design appropriate and is the work technically sound? Yes Are sufficient details of methods and analysis provided to allow replication by others? Partly If applicable, is the statistical analysis and its interpretation appropriate? Yes Are all the source data underlying the results available to ensure full reproducibility? No source data required Are the conclusions drawn adequately supported by the results? Partly Competing Interests No competing interests were disclosed. Reviewer Expertise HFD induced changes, effect of herbal extracts on serum lipid profile in HFD rats I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above. reply Respond to this report Responses (0) Dutta B. Peer Review Report For: Effect of anti-obesity drug orlistat (Xenical™) on liver and kidney function in male rats fed a high-fat diet [version 2; peer review: 1 approved, 2 approved with reservations, 1 not approved] . F1000Research 2026, 15 :136 ( https://doi.org/10.5256/f1000research.191966.r458447) NOTE: it is important to ensure the information in square brackets after the title is included in this citation. The direct URL for this report is: https://f1000research.com/articles/15-136/v1#referee-response-458447 Alongside their report, reviewers assign a status to the article: Approved - the paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations - A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. 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