The Effect of Diet-induced Obesity on Toxicological Parameters in the Polygenic Sprague-Dawley Rat Model
| Autor: | Johannes Josef Fels, Henrik Søeborg, Inger Thorup, Mikala Skydsgaard, Lærke W. Andersen, Hanne Offenberg, Kevin A. Keane, Charlotte M. Dalsgaard, Ingrid Sjögren, Jennifer M. Rojas, Line Olrik Berthelsen, Jette Nowak, Florian Bolze, Jes Tovborg Jensen, Majken Dalgaard |
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| Rok vydání: | 2018 |
| Předmět: |
Male
0301 basic medicine Drug Evaluation Preclinical Physiology Estrous Cycle 030209 endocrinology & metabolism White adipose tissue Disease Diet High-Fat Toxicology Proof of Concept Study Pathology and Forensic Medicine Rats Sprague-Dawley 03 medical and health sciences 0302 clinical medicine medicine Animals Obesity Molecular Biology business.industry Body Weight Skeletal muscle Organ Size Cell Biology medicine.disease Pathophysiology Disease Models Animal 030104 developmental biology medicine.anatomical_structure Organ Specificity Toxicity Female Anti-Obesity Agents Pancreas Reproductive toxicity business Biomarkers |
| Zdroj: | Toxicologic Pathology. 46:777-798 |
| ISSN: | 1533-1601 0192-6233 |
| Popis: | The obese rodent serves as an indispensable tool for proof-of-concept efficacy and mode-of-action pharmacology studies. Yet the utility of this disease model as an adjunct to the conventional healthy animal in the nonclinical safety evaluation of anti-obesity pharmacotherapies has not been elucidated. Regulatory authorities have recommended employing disease models in toxicology studies when necessary. Our study investigated standard and exploratory toxicology parameters in the high-fat diet (HFD)-induced obese, polygenic Sprague-Dawley rat model in comparison to chow diet (CD)-fed controls. We sought to establish feasibility of the model for safety testing and relevance to human obesity pathophysiology. We report that both sexes fed a 45% kcal HFD for 29 weeks developed obesity and metabolic derangements that mimics to a certain extent, common human obesity. Minor clinical pathologies were observed in both sexes and considered related to CD versus HFD differences. Histopathologically, both sexes exhibited mild obesity-associated findings in brown and subcutaneous white fat, bone, kidneys, liver, lung, pancreas, salivary parotid glands, and skeletal muscle. We conclude that chronic HFD feeding in both sexes led to the development of an obese but otherwise healthy rat. Therefore, the diet-induced obese Sprague-Dawley rat may serve as a suitable model for evaluating toxicity findings encountered with anti-obesity compounds. |
| Databáze: | OpenAIRE |
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