Introduction
Finding the most translationally-relevant mouse model is vital to generating meaningful and reproducible data, and critical in the development of disease therapeutics. However, for metabolic research including nonalcoholic steatohepatitis (NASH), finding a mouse model that most accurately recapitulates the physiology, histology, and any transcriptomic changes observed in humans can be a research project by itself (if it exists at all!).
In the case of nonalcoholic fatty liver disease (NAFLD), which includes fatty liver and steatosis, there are a large number of in vivo models, each with their own limitations. These models do not always accurately mimic the human pathology of the disease, by either requiring a specific gene knockout (not often seen in patient populations) or requiring non-physiological dietary manipulations. Furthermore, most models have not been observed to develop progressive fibrosis (Asgharpour et al., 2016), a key hallmark of NASH.
The MSNASH/PcoJ mouse model (#030888), the latest model to aid in the study of obesity, metabolic syndrome, including NASH, and diabetes, is now available from JAX. This model offers several benefits to researchers as compared to previously published models for metabolism research such as providing a polygenic model compared to the more common monogenic models, an intact leptin pathway, and rapid weight gain on a standard diet. Furthermore, this model responds to commonly used anti-diabetic treatments, Semaglutide and Rosiglitazone, similar to patients
MSNASH/PcoJ model - The latest cutting-edge model for metabolic research
The MSNASH/PcoJ model was developed by crossing the C57BL6/J and AKR/J models and selectively breeding for obesity, insulin resistance, and hyperglycemia phenotypes (Peterson et al., 2017). Model development also included inbreeding for more than 30 generations and has resulted in a strain that exhibits obesity in a pre-diabetic condition that progresses to overt diabetes.
The C57BL6/J and AKR/J models were chosen based on their respective metabolic characteristics. Both strains are sensitive to developing obesity and metabolic syndrome under the influence of high-fat diets, and they also develop leptin resistance while gaining adiposity (Peterson et al., 2017).
These models combined to generate the MSNASH/PcoJ model: a polygenic model of obesity, metabolic syndrome, and diabetes. This mouse strain progressively develops several features of metabolic syndrome that are similar to humans while on a regular chow diet, including obesity, dyslipidemia, and insulin resistance. MSNASH/PcoJ also develops NAFLD that can progress to NASH while on a combination of a high-fat diet and fructose. This novel model can be used for therapeutic testing for a range of metabolic diseases – from diabetes to NASH, due to its translational relevance.
Conclusion
In vivo models that accurately mimic human disease are a crucial element of preclinical research to better model the condition, identify potential therapeutic targets, and for translationally-relevant preclinical efficacy testing. For nearly 90 years, JAX has been providing researchers worldwide with access to the most up-to-date in vivo models and services. The availability of the MSNASH/PcoJ model for the study of metabolic diseases, including NASH, further illustrates the commitment of JAX to enable researchers to reach their milestones with translationally-relevant models.
To learn more about the MSNASH/PcoJ mouse model, visit the comparison of widely used JAX mice for obesity and diabetes research page.
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References
Asgharpour A., Cazanave SC, Pacana T, Seneshaw M, Vincent R, Banini BA, Kumar DP, Daita K, Min H-K, Mirshahi F, Bedossa P, Sun X, Hoshida Y, Koduru SV, Contaifer D Jr., Warncke UO, Wijesinghe DS, Sanyal AJ. (2016). A diet-induced animal model of non-alcoholic fatty liver disease and hepatocellular cancer. J. Hepatol. 65(3): 579-588. DOI: 10.1016/j.jhep.2016.05.005 [PMID: PMC5012902]
Peterson RG., Van Jackson C, Zimmerman KM, Alsina-Fernandez J., Michael MD, Emmerson PJ, Coskun T. (2017). Glucose dysregulation and response to common anti-diabetic agents in the FATZO/Pfc mouse. PLoSOne. 12(6):e0179856. DOI: 10.1371/journal.pone.0179856 [PMID: PMC5480999]
https://www.crownbio.com/hubfs/assets/DoT-FATZO-NAFLD-Model.pdf?hsLang=en