title: Evaluation of a Mathematical Model of Rat Body Weight Regulation in Application to Caloric Restriction and Drug Treatment Studies.
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.
authors.affiliation: Cardiovascular and Metabolic Diseases Research Unit, Pfizer Worldwide Research and Development, Cambridge, Massachusetts, United States of America.
authors.forename: Jangir
authors.initials: J
authors.lastname: Selimkhanov
authors.affiliation: Cardiovascular and Metabolic Diseases Research Unit, Pfizer Worldwide Research and Development, Cambridge, Massachusetts, United States of America.
authors.forename: W Clayton
authors.identifier: 0000-0001-7495-8965
authors.initials: WC
authors.lastname: Thompson
authors.affiliation: Cardiovascular and Metabolic Diseases Research Unit, Pfizer Worldwide Research and Development, Cambridge, Massachusetts, United States of America.
authors.forename: Terrell A
authors.initials: TA
authors.lastname: Patterson
authors.affiliation: Cardiovascular and Metabolic Diseases Research Unit, Pfizer Worldwide Research and Development, Cambridge, Massachusetts, United States of America.
authors.forename: John R
authors.identifier: 0000-0001-9719-1189
authors.initials: JR
authors.lastname: Hadcock
authors.affiliation: Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research and Development, Cambridge, Massachusetts, United States of America.
authors.forename: Dennis O
authors.initials: DO
authors.lastname: Scott
authors.affiliation: Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research and Development, Cambridge, Massachusetts, United States of America.
authors.forename: Tristan S
authors.initials: TS
authors.lastname: Maurer
authors.affiliation: Cardiovascular and Metabolic Diseases Research Unit, Pfizer Worldwide Research and Development, Cambridge, Massachusetts, United States of America.
authors.forename: Cynthia J
authors.initials: CJ
authors.lastname: Musante
mesh_terms: D000818:Animals; D001823:Body Composition / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects* / Q000502:physiology; D031204:Caloric Restriction; D063387:Cannabinoid Receptor Antagonists / Q000494:pharmacology*; D002149:Energy Intake; D004734:Energy Metabolism / Q000187:drug effects*; D008297:Male; D008962:Models, Theoretical; D051381:Rats; D017207:Rats, Sprague-Dawley; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors
chemical_list: D063387:Cannabinoid Receptor Antagonists; D043884:Receptor, Cannabinoid, CB1