You are what you eat, or are you? The challenges of translating high-fat-fed rodents to human obesity and diabetes

Abstract

Obesity and type 2 diabetes mellitus (T2DM) are rapidly growing worldwide epidemics with major health consequences. Various human-based studies have confirmed that both genetic and environmental factors (particularly high-caloric diets and sedentary lifestyle) greatly contribute to human T2DM. Interactions between obesity, insulin resistance and β-cell dysfunction result in human T2DM, but the mechanisms regulating the interplay among these impairments remain unclear. Rodent models of high-fat diet (HFD)-induced obesity have been used widely to study human obesity and T2DM. With >9000 publications on PubMed over the past decade alone, many aspects of rodent T2DM have been elucidated; however, correlation to human obesity/diabetes remains poor. This review investigates the reasons for this translational discrepancy by critically evaluating rodent HFD models. Dietary modification in rodents appears to have limited translatable benefit for understanding and treating human obesity and diabetes due-at least in part-to divergent dietary compositions, species/strain and gender variability, inconsistent disease penetrance, severity and duration and lack of resemblance to human obesogenic pathophysiology. Therefore future research efforts dedicated to acquiring translationally relevant data-specifically human data, rather than findings based on rodent studies-would accelerate our understanding of disease mechanisms and development of therapeutics for human obesity/T2DM.

Figure 1

Primary factors contributing to the variability observed in HFD-fed rodent models. Variability observed within and among laboratories using HFD-based rodent models can be broadly classified into biological, dietary and experimental variability primarily arising from factors such as species, strain, sex, age, HFD fat content and type, other dietary components, control diet and duration of HFD feeding. This variability is further exacerbated when combined with chemical, surgical and genetic manipulations as well as physiological and environmental factors affecting data acquisition.