The Effect of Diet-induced Obesity on Toxicological Parameters in the Polygenic Sprague-Dawley Rat Model

Abstract

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.

The short term High Fat Diet sparks gut microbiota associated metabolic syndrome pathogenesis and impact of Amoxicillin intervention in mice

“…Long-term HFD studies showed a significant decrease in haematological parameters [54,55]. This study observed a slight decline in the value of Hb, RBC, MCH and a significant decrease in HCT and MCV in HFD fed mice.…”

Recent Developments in Rodent Models of High-Fructose Diet-Induced Metabolic Syndrome: A Systematic Review

“…Both strains can manifest the many characteristics of MetS with no serious inconsistencies or conflicts. SD rats and SHR have been established by decades of research and are considered useful models of DIO [ 47 , 48 , 49 ]. However, the Wistar rat model has a recurring issue.…”

Modelling the effects of variability in feeding rate on growth – a vital step for DEB-TKTD modelling

“…Data from Tekus et al (2018) provide reference values of body fat percentage of rats at various ages up to two years. While the study used only male Wistar (rather than Sprague Dawley) rats, other studies indicate that body fat percentage is similar across the two strains ( Reed et al, 2011 ) and between male and female Sprague Dawley rats ( Rojas et al, 2018 ). Fig.…”