Navigating the Strengths and Constraints of Mouse Models in Obesity Research

Abstract

Obesity is a major health problem, being a risk factor for many metabolic diseases. Obesity results from an imbalance in energy intake and energy expenditure. Animal models, particularly naturally occurring mouse models of obesity, have provided a framework of the basic mechanisms regulating energy homeostasis. However, there remain gaps in our understanding of the mechanisms underlying the pathophysiology of obesity. Mouse models of obesity remain an essential tool to further our knowledge, due to advanced tools for genetic manipulation and the possibility to study interaction with environmental factors, such as diet. While there are advantages to using mice as models of obesity, it should be recognized that there are limitations. In this mini-review we provide a brief overview of the monogenic mouse models of obesity that have led to the discovery of important physiological systems that regulate energy homeostasis, such as the leptin-melanocortin pathway, that translate well to humans. We also discuss confounding factors that, when taken into account, might improve translatability of these findings. Finally, we discuss potential strategies to determine functional consequences of non-coding genome-wide association study (GWAS) signals in mouse models.

Keywords: cross-species conservation; monogenic obesity; mouse models; sex differences; thermogenesis.

Figure 1.

Schematic overview of mouse models of obesity. The main advantages and disadvantages of monogenic, genetically modified, and diet-induced mouse models of obesity are shown. In addition, confounding factors discussed in this review impacting obesity development in mice are shown. Created in BioRender. Visser, J. (2025) https://BioRender.com/ezsrmpu.