Comparing Traditional Rodent Models for Metabolic Research
Metabolic Disease Rodent Model Types
Several species of animals are used for the preclinical study of obesity and metabolic disorders; of these, rodents are the most common. Rodent models of metabolic disease include both monogenic and diet-induced obesity (DIO) models. Monogenic animals are the best choice if one pathway or a single target is being investigated, whereas DIO animals tend to better when investigating interactions between disease, environment, and genetics.
Here we introduce some of the more commonly used models in today’s metabolic disease research and share their main advantages and disadvantages.
Genetically Modified Models
The ob/ob Mouse
The most common monogenic animal used in the study of obesity and metabolic syndrome is the ob/ob mouse. Around since the 1950’s, the ob/ob mouse was known for a spontaneous mutation leading to obesity, but it wasn’t until 1994 that the ob gene product, leptin, began to draw attention.
The ob/ob mouse does not produce leptin, the hormone responsible for satiety. The mice do still respond to exogenous leptin, meaning they do have an intact leptin signaling pathway. The pronounced obesity that occurs in these animals has other causes besides a lack of leptin, such as a defect in thermogenesis of brown adipose tissue and increased hepatic lipogenesis.
The first phenotypical feature in this model is the early pronounced obese phenotype. This is characterized by hyperphagia. Hyperinsulinemia soon follows, with moderate hyperglycemia and insulin resistance. The model, in this aspect, lacks translatability to human disease.
Ob/ob mice do develop hepatic steatosis, but due to their biochemical and pathological characteristics, progression to hepatitis does not occur. This is in contrast to humans, where hepatitis progression is a natural consequence of NASH.
Furthermore, most obese individuals do not develop obesity due to a deficiency in leptin production. In fact, this hormone is usually elevated due to a resistance to leptin, demonstrating that the animal's physiology does not fully reflect humans.
The db/db Mouse
The db/db mouse is phenotypically similar to ob/ob, characterized by hyperphagia and reduced energy expenditure leading to marked early-onset obesity. This model is also hypothermic, and has decreased linear growth due to growth hormone deficiency.
The major difference between db/db and ob/ob mice is which part of the leptin pathway is deficient. In db/db, there’s no defect in leptin production, and leptin levels are high. The leptin receptor is absent though, meaning the leptin signaling pathway is missed.
Db/db presents a more severe hyperglycemia than ob/ob, with plasma glucose levels in seven week old animals averaging 700mg/dl, which is sustained throughout their life. This sustained hyperglycemia is an advantage in certain experiments where age and length of the study impacts results.
Db/db mice do not develop the full phenotype of type 2 diabetes compared to humans as they lack pancreatic amyloid deposition. Like the ob gene mutation, the mutation of the leptin receptor gene is also found in some human families; however, the mutation is very rare.
The Zucker Rat
The obese Zucker rat, like the db/db mouse, develops obesity due to mutated forms of the extracellular domain of the leptin receptor. The obese Zucker also known as the fa/fa or ‘fatty’ rat, develops a similar phenotype of hyperphagia and reduced energy expenditure, leading to morbid obesity, with the adult Zucker rat having 40% fat mass. These rats have impaired glucose tolerance as well as insulin resistance, and fertility is reduced.
Unlike the db/db mouse, glycemia in the Zucker rat is normal and type 2 diabetes does not develop. This is similar to a proportion of the human population that presents obesity and insulin resistance, but it is not diabetic. This animal model is typically used for pharmacological studies of antiobesity drugs and insulin sensitizers, as well as incretins.
A sub strain of the obese Zucker fatty rat is the Zucker Diabetic Fatty (ZDF) rat, that displays early dysregulation of glucose metabolism. ZDF rats have propensity to develop early diabetes when presented with a high-fat diet and are typically used for studying antidiabetic agents.
Diet-Induced Obesity Models
DIO animal models are usually used to study the role of diet, pathophysiology, and etiology of the disease, as well as pharmacological interventions. The DIO strains most commonly used are outbred Sprague-Dawley (SD) rats and C57BL6/J mice. These animals are prone to dietary weight gain at a young age and potentially hyperinsulinemia, and develop obesity over time, similar to slow progression in humans.
The modern diet in humans is usually composed of high levels of fat and carbohydrate. Rodent studies are based on these diets, but there is variation in the amount of fat and carbohydrates used, as well as in their source. This may alter an animal's phenotype and end up developing a model of obesity and type 2 diabetes with non-standardized characteristics.
In general, diets with high levels of fructose mimic the human diet and, when associated with high fat content, promote weight gain, abdominal fat, hyperglycemia, and hyperinsulinemia in mice. Fructose appears to be important in the development of metabolic syndrome, as well as obesity itself, since sugar leads not only to insulin resistance, but also to leptin resistance, resulting in weight gain.
Advantages and Disadvantages of Common Metabolic Disease Models
There are some main advantages and limitations which need to be taken into account when selecting the most appropriate model for your studies.
Monogenic models have the advantage of developing severe phenotypes which provides a much larger, almost exaggerated, window for therapeutic intervention. Monogenic models can also save researchers time as disease progression is more rapid and does not require long term feeding programs to induce obesity, as needed for DIO model studies. As the genetic basis is homogeneous and the environmental factors are controlled, the variability of the results tend to be smaller, allowing the use of smaller samples.
Observations derived from monogenic models may differ from the human population, since obesity is known to be a multifactorial disease. In this respect, DIO models are closer mechanistically to obesity and metabolic syndrome in humans.
Another disadvantage of monogenic animals is high mortality due to ketosis in certain strains, as in the case of the db/db mouse. Sophisticated care is also needed for these animals, which can result in higher study costs.
We’ve discussed several traditional animal models that have impacted the metabolic disease research community. Sometimes, these well validated historical models can drive an early drug discovery program. More often, because of the complexity of the disease, multiple animal models across different species are needed investigate the full pathophysiology and treatment of obesity and metabolic syndrome.