Abstract
The purpose of this work is to develop a mathematical model of energy balance and body weight regulation that can predict species-specific response to common pre-clinical interventions. To this end, we evaluate the ability of a previously published mathematical model of mouse metabolism to describe changes in body weight and body composition in rats in response to two short-term interventions. First, we adapt the model to describe body weight and composition changes in Sprague-Dawley rats by fitting to data previously collected from a 26-day caloric restriction study. The calibrated model is subsequently used to describe changes in rat body weight and composition in a 23-day cannabinoid receptor 1 antagonist (CB1Ra) study. While the model describes body weight data well, it fails to replicate body composition changes with CB1Ra treatment. Evaluation of a key model assumption about deposition of fat and fat-free masses shows a limitation of the model in short-term studies due to the constraint placed on the relative change in body composition components. We demonstrate that the model can be modified to overcome this limitation, and propose additional measurements to further test the proposed model predictions. These findings illustrate how mathematical models can be used to support drug discovery and development by identifying key knowledge gaps and aiding in the design of additional experiments to further our understanding of disease-relevant and species-specific physiology.
Highlights
Obesity is a growing epidemic worldwide with significant health and economic impacts [1]
In this work we find that the adapted two-dimensional model is unable to capture caloric restriction (CR)- and CB1Ra-induced fat mass (FM) and fat-free mass (FFM) changes simultaneously, which suggests a potential limitation of the model for application to short-term studies involving body composition
The model consists of 2 ordinary differential equations describing changes in fat mass (FM) and fat-free mass (FFM) that are driven by the energy imbalance caused by the difference in food intake (FI) (I) and EE (E): rFM
Summary
Obesity is a growing epidemic worldwide with significant health and economic impacts [1]. Our ability to identify and understand metabolically-relevant differences between species may improve translation of pre-clinical research to clinical success. Guo and Hall [8] were successful in using this model to predict BW and BC changes in several long term caloric restriction studies, while Gennemark et al [9] applied the model to describe mouse BW changes due to several pharmacotherapies. We are interested in adapting this model to another commonly used rodent model, the Sprague-Dawley (SD) rat, to evaluate how well it can capture the effects of short-term caloric restriction and pharmacotherapy studies in a different species. The ability of a model to predict the effects of pharmacotherapy as well as caloric restriction is key for its application to common study designs in obesity research that utilize pair-feeding arms
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