Iranian Journal of War and Public Health

eISSN (English): 2980-969X
eISSN (Persian): 2008-2630
pISSN (Persian): 2008-2622
Volume 14, Issue 3 (2022)                   Iran J War Public Health 2022, 14(3): 295-302 | Back to browse issues page

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Abed Hussein B, Fawzi M, Al-Saray S, Abed Hussein R. High-Fat-Low-Carbohydrate Diet Applied to Mice: a Model for Studying Physiological and Histological Changes in the Liver and Pancreas. Iran J War Public Health 2022; 14 (3) : 7
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1- Department of Sciences, College of Basic Education, University of Misan, Maysan, Iraq
2- Department of Pharmacy, AL-Manara College for Medical Sciences, Maysan, Iraq
* Corresponding Author Address: (
Abstract   (932 Views)
Aims: The high-fat-low-carbohydrate diet is an efficient diet for reducing body weight, with increased satiety and diminishing energy consumption. This study aimed to determine the effects of a high-fat-low-carbohydrate diet on the metabolic function of the liver and pancreas in a mouse model.
Materials & Methods: This experimental research was conducted in 2021 on 60 albino mice that were divided into 6 groups (each group containing 10 mice). At the beginning of the experiment, 40 mice were fed a high-fat-high-carbohydrate diet for 12 weeks to enhance gaining weight;  then the 4 groups were fed a high-fat-low-carbohydrate diet, while the other two groups were considered as control groups. For sample collection, animals were sacrificed and blood samples were collected for biochemical analysis, tissue samples were taken for histopathological assay. Data were analyzed by SPSS 26 using the ANOVA.
Findings: The result of this study showed that mice fed a high-fat-low-carbohydrate diet had high levels of aspartate aminotransferase, alanine aminotransferase, and cholesterol in the blood serum. In addition, the level of triglycerides and blood glucose decreased in the same groups. Histopathological study showed severe fatty changes that led to edema and degeneration of hepatocytes in the periportal area due to degeneration of the microvasculature and the formation of bridging fibrosis between the central hepatic lobes and the peripheral area in the high-fat-low-carbohydrate diet group. The tissue sections of the pancreas did not show any signs of pathology.
Conclusion: Long-term administration of a high-fat-low-carbohydrate diet affects histologically and functionally in mice liver.
Article number: 7

1. Yang Q, Lang X, Li W, Liang Y. The effects of low-fat, high-carbohydrate diets vs. low-carbohydrate, high-fat diets on weight, blood pressure, serum liquids and blood glucose: a systematic review and meta-analysis. Eur J Clin Nutr. 2022;76:16-27. [Link] [DOI:10.1038/s41430-021-00927-0]
2. Noakes TD, Windt J. Evidence that supports the prescription of low-carbohydrate high-fat diets: a narrative review. Br J Sports Med. 2017;51(2):133-9.‏ [Link] [DOI:10.1136/bjsports-2016-096491]
3. De P, Mukhopadhya S. Low-carbohydrate high-fat (LCHF) diet: evidence of its benefits. In: Waisundara V, editor. Diabetes food plan. London: IntechOpen; 2018. [Link] [DOI:10.5772/intechopen.73138]
4. Weigle DS, Breen PA, Matthys CC, Callahan HS, Meeuws KE, Burden VR, et al. A high-protein diet induces sustained reductions in appetite, ad libitum caloric intake, and body weight despite compensatory changes in diurnal plasma leptin and ghrelin concentrations. Am J Clin Nutr. 2005;82(1):41-8.‏ [Link] [DOI:10.1093/ajcn.82.1.41]
5. Roekenes J, Martins C. Ketogenic diets and appetite regulation. Curr Opin Clin Nutr Metab Care. 2021;24(4):359-63.‏ [Link] [DOI:10.1097/MCO.0000000000000760]
6. Volek JS, Freidenreich DJ, Saenz C, Kunces LJ, Creighton BC, Bartley JM, et al. Metabolic characteristics of KETO-adapted ultra-endurance runners. Metabolism. 2016;65(3):100-10.‏ [Link] [DOI:10.1016/j.metabol.2015.10.028]
7. Dyson PA, Kelly T, Deakin T, Duncan A, Frost G, Harrison Z, et al. Diabetes UK evidence‐based nutrition guidelines for the prevention and management of diabetes. Diabet Med. 2011;28(11):1282-8. [Link] [DOI:10.1111/j.1464-5491.2011.03371.x]
8. Ellenbroek JH, van Dijck L, Töns HA, Rabelink TJ, Carlotti F, Ballieux BE, et al. Long-term ketogenic diet causes glucose intolerance and reduced β-and α-cell mass but no weight loss in mice. Am J Physiol Endocrinol Metab. 2014;306(5):552-8. [Link] [DOI:10.1152/ajpendo.00453.2013]
9. Gannon MC, Nuttall FQ. Effect of a high-protein, low-carbohydrate diet on blood glucose control in people with type 2 diabetes. Diabetes. 2004;53(9):2375-82.‏ [Link] [DOI:10.2337/diabetes.53.9.2375]
10. Nuttall FQ, Almokayyad RM, Gannon MC. Comparison of a carbohydrate-free diet vs. fasting on plasma glucose, insulin and glucagon in type 2 diabetes. Metabolism. 2015;64(2):253-62.‏ [Link] [DOI:10.1016/j.metabol.2014.10.004]
11. Jagadish S, Payne ET, Wong-Kisiel L, Nickels KC, Eckert S, Wirrell EC. The ketogenic and modified Atkins diet therapy for children with refractory epilepsy of genetic etiology. Pediatr Neurol. 2019;94:32-7. [Linkvv] [DOI:10.1016/j.pediatrneurol.2018.12.012]
12. Laffel L. Ketone bodies: a review of physiology, pathophysiology and application of monitoring to diabetes. Diabetes Metab Res Rev. 1999;15(6):412-26.<412::AID-DMRR72>3.0.CO;2-8 [Link] [DOI:10.1002/(SICI)1520-7560(199911/12)15:63.0.CO;2-8]
13. Ayer A, Borel F, Moreau F, Prieur X, Neunlist M, Cariou B, et al. Techniques of sleeve gastrectomy and modified Roux-en-Y gastric bypass in mice. J Vis Exp. 2017;121:54905.‏ [Link] [DOI:10.3791/54905]
14. Hansen SL, Nielsen AH, Knudsen KE, Artmann A, Petersen G, Kristiansen U, et al. Ketogenic diet is antiepileptogenic in pentylenetetrazole kindled mice and decrease levels of N-acylethanolamines in hippocampus. Neurochem Int. 2009;54(3-4):199-204.‏ [Link] [DOI:10.1016/j.neuint.2008.10.012]
15. Kennedy AR, Pissios P, Otu H, Xue B, Asakura K, Furukawa N, et al. High-fat, ketogenic diet induces a unique metabolic state in mice. Am J Physiol Endocrinol Metab,. 2007;292(6):E1724-39. [Link] [DOI:10.1152/ajpendo.00717.2006]
16. Ma D, Wang AC, Parikh I, Green SJ, Hoffman JD, Chlipala G, et al. Ketogenic diet enhances neurovascular function with altered gut microbiome in young healthy mice. Sci Rep. 2018;8:6670. [Link] [DOI:10.1038/s41598-018-25190-5]
17. Martuscello RT, Vedam-Mai V, McCarthy DJ, Schmoll ME, Jundi MA, Louviere CD, et al. A supplemented high-fat low-carbohydrate diet for the treatment of glioblastoma. Clin Cancer Res. 2016;22(10):2482-95. [Link] [DOI:10.1158/1078-0432.CCR-15-0916]
18. Meidenbauer JJ, Ta N, Seyfried TN. Influence of a ketogenic diet, fish-oil, and calorie restriction on plasma metabolites and lipids in C57BL/6J mice. Nutr Metab. 2014;11:23.‏ [Link] [DOI:10.1186/1743-7075-11-23]
19. Rosenbaum M, Hall KD, Guo J, Ravussin E, Mayer LS, Reitman ML, et al. Glucose and lipid homeostasis and inflammation in humans following an isocaloric ketogenic diet. Obesity. 2019;27(6):971-81.‏ [Link] [DOI:10.1002/oby.22468]
20. Samuel RJ, Joy O, KrishnaMurthy P, Iyer S, Ramachandra SG, Thamaraiselvi K. Effect of feeding high fat diet on reproductive parameters in male mice. Indian J Anim Res. 2019;53(4):505-9.‏ [Link] [DOI:10.18805/ijar.B-3528]
21. Pissios P, Hong S, Kennedy AR, Prasad D, Liu FF, Maratos-Flier E. Methionine and choline regulate the metabolic phenotype of a ketogenic diet. Mol Metab. 2013;2(3):306-13.‏ [Link] [DOI:10.1016/j.molmet.2013.07.003]
22. Geisler CE, Renquist BJ. Hepatic lipid accumulation: cause and consequence of dysregulated glucoregulatory hormones. J Endocrinol. 2017;234(1):R1-21.‏ [Link] [DOI:10.1530/JOE-16-0513]
23. Ingawale DK, Mandlik SK, Naik SR. Models of hepatotoxicity and the underlying cellular, biochemical and immunological mechanism(s): a critical discussion. Environ Toxicol Pharmacol. 2014;37(1):118-33.‏ [Link] [DOI:10.1016/j.etap.2013.08.015]
24. Douris N, Melman T, Pecherer JM, Pissios P, Flier JS, Cantley LC, et al. Adaptive changes in amino acid metabolism permit normal longevity in mice consuming a low-carbohydrate ketogenic diet. Biochim Biophys Acta. 2015;1852(10):2056-65.‏ [Link] [DOI:10.1016/j.bbadis.2015.07.009]
25. Goldberg IJ, Ibrahim N, Bredefeld C, Foo S, Lim V, Gutman D, et al. Ketogenic diets, not for everyone. J Clin Lipidol. 2021;15(1):61-7.‏ [Link] [DOI:10.1016/j.jacl.2020.10.005]
26. Twu YC, Lee TS, Lin YL, Hsu SM, Wang YH, Liao CY, et al. Niemann-Pick type C2 protein mediates hepatic stellate cells activation by regulating free cholesterol accumulation. Int J Mol Sci. 2016;17(7):1122.‏ [Link] [DOI:10.3390/ijms17071122]
27. Westman EC, Yancy WS, Edman JS, Tomlin KF, Perkins CE. Effect of 6-month adherence to a very low carbohydrate diet program. Am J Med. 2002;113(1):30-6.‏ [Link] [DOI:10.1016/S0002-9343(02)01129-4]
28. Guo P. Protective effect of aerobic exercise combined with Paeonol PLGA nanoparticles on obese rats with hyperlipidemia. Revista Científica de la Facultad de Ciencias Veterinarias. 2020;30(2):766-75.‏ [Link]
29. Diamond DM, O'Neill BJ, Volek JS. Low carbohydrate diet: Are concerns with saturated fat, lipids, and cardiovascular disease risk justified?. Curr Opin Endocrinol Diabetes Obes. 2020;27(5):291-300. [Link] [DOI:10.1097/MED.0000000000000568]
30. Yang Z, Mi J, Wang Y, Xue L, Liu J, Fan M, et al. Effects of low-carbohydrate diet and ketogenic diet on glucose and lipid metabolism in type 2 diabetic mice. Nutrition. 2021;89:111230.‏ [Link] [DOI:10.1016/j.nut.2021.111230]
31. Badman MK, Kennedy AR, Adams AC, Pissios P, Maratos-Flier E. A very low carbohydrate ketogenic diet improves glucose tolerance in ob/ob mice independently of weight loss. Am J Physiol Endocrinol Metab. 2009;297(5):E1197-204. [Link] [DOI:10.1152/ajpendo.00357.2009]
32. Iannello S, Cavaleri A, Milazzo P, Cantarella S, Belfiore F. Low fasting serum triglyceride level as a precocious marker of autoimmune disorders. Med Gen Med. 2003;5(3):20.‏ [Link]
33. Kozdag G, Ertas G, Emre E, Akay Y, Celikyurt U, Sahin T, et al. Low serum triglyceride levels as predictors of cardiac death in heart failure patients. Tex Heart Inst J. 2013;40(5):521-8.‏ [Link]
34. Perna S, Ferraris C, Guglielmetti M, Alalwan TA, Mahdi AM, Guido D, et al. Effects of classic ketogenic diet in children with refractory epilepsy: a retrospective cohort study in Kingdom of Bahrain. Nutrients. 2022;14(9):1744. [Link] [DOI:10.3390/nu14091744]
35. Nizamuddin J, Turner Z, Rubenstein JE, Pyzik PL, Kossoff EH. Management and risk factors for dyslipidemia with the ketogenic diet. J Child Neurol. 2008;23:758-61. [Link] [DOI:10.1177/0883073808318061]
36. Kwiterovich Jr PO, Vining EP, Pyzik P, Skolasky Jr R, Freeman JM. Effect of a high-fat ketogenic diet on plasma levels of lipids, lipoproteins, and apolipoproteins in children. JAMA. 2003;290(7):912-20.‏ [Link] [DOI:10.1001/jama.290.7.912]
37. Zhang X, Qin J, Zhao Y, Shi J, Lan R, Gan Y, et al. Long-term ketogenic diet contributes to glycemic control but promotes lipid accumulation and hepatic steatosis in type 2 diabetic mice. Nutr Res. 2016;36(4):349-58. [Link] [DOI:10.1016/j.nutres.2015.12.002]
38. Garbow JR, Doherty JM, Schugar RC, Travers S, Weber ML, Wentz AE, et al. Hepatic steatosis, inflammation, and ER stress in mice maintained long term on a very low-carbohydrate ketogenic diet. Am J Physiol Gastrointest Liver Physiol. 2011;300(6):G956-67.‏ [Link] [DOI:10.1152/ajpgi.00539.2010]
39. Takahashi Y, Fukusato T. Histopathology of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis. World J Gastroenterol. 2014;20(42):15539-48.‏ [Link] [DOI:10.3748/wjg.v20.i42.15539]

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