An “obese mouse” in scientific research refers to a mouse specifically bred or induced to develop excess body fat, mimicking human obesity and related health conditions. These models are widely used to study the biological mechanisms behind obesity and its associated diseases, offering insights into human health.
Creating Obese Mouse Models
Developing obese mouse models for research involves several methods, each designed to replicate different aspects of human obesity. Two primary approaches are diet-induced obesity (DIO) models and genetic models, with the choice depending on the specific research question being asked. The C57BL/6J strain is a popular choice for obesity studies due to its susceptibility to weight gain on a high-calorie diet.
Diet-Induced Obesity (DIO) Models
Diet-Induced Obesity (DIO) models are created by feeding genetically normal mice diets high in fat or sugar. A common approach involves feeding C57BL/6J mice a diet where 60% of calories come from fat, compared to a control diet with 10% fat. After 16–20 weeks on a high-fat diet, mice typically show a 20–30% increase in body weight compared to controls. This method closely mirrors how human dietary habits contribute to obesity and metabolic dysfunctions.
Genetic Models
Genetic models of obesity involve specific mutations that lead to weight gain and metabolic issues. A well-known example is the ob/ob mouse, which has a mutation in the leptin gene, leading to a complete lack of leptin production. Leptin is a hormone that helps regulate appetite and energy balance, so its absence results in hyperphagia (excessive eating) and early-onset obesity. Another widely used genetic model is the db/db mouse, which has a mutation in the leptin receptor gene, making them unable to respond to leptin even though their leptin levels are high. While both ob/ob and db/db mice develop severe obesity, db/db mice tend to be more diabetic.
Researchers select models based on their specific needs. For instance, DIO models are often used to study how diet contributes to metabolic diseases, while genetic models like ob/ob or db/db mice are valuable for understanding the role of specific genes in obesity and diabetes.
Investigating Metabolic Diseases
Obese mouse models are extensively used to investigate a range of metabolic and related diseases, offering insights into their progression and potential treatments.
Type 2 Diabetes
Type 2 Diabetes is a primary focus, with obese mice providing a platform to study insulin resistance, beta-cell dysfunction, and glucose metabolism. For example, diet-induced obese C57BL/6J mice develop insulin resistance and hyperglycemia, mirroring the early stages of type 2 diabetes in humans. These mice exhibit impaired glucose tolerance and hyperinsulinemia, indicating a reduced sensitivity to insulin. Researchers use these models to test new therapeutic agents designed to improve insulin sensitivity, such as rosiglitazone, before they are considered for human trials.
Non-alcoholic Fatty Liver Disease (NAFLD)
Non-alcoholic Fatty Liver Disease (NAFLD) and its more severe form, Non-alcoholic Steatohepatitis (NASH), are also studied using obese mouse models. High-fat diets in mice can lead to hepatic steatosis, or fatty liver, where excess fat accumulates in the liver. Some dietary models, particularly those including high fat, high sugar, and cholesterol, can induce inflammation and fibrosis in the liver, resembling human NASH. For instance, a diet high in trans-fat, fructose, and cholesterol can lead to key histological hallmarks of NASH in mice, including steatosis, inflammation, ballooning degeneration, and fibrosis.
Obesity-Induced Cardiovascular Issues
Obesity-induced cardiovascular issues, such as hypertension, dyslipidemia, and atherosclerosis, are also investigated in these models. High-fat diets can promote obesity-accelerated atherosclerosis in apolipoprotein E deficient (apoE−/−) mice, accompanied by impaired fasting glucose and dyslipidemia. Leptin, a hormone produced by fat tissue, has been shown to trigger the growth of blood vessels in the hypothalamus, a part of the brain that regulates blood pressure, potentially contributing to hypertension in obese mice.
Metabolic Syndrome
Metabolic Syndrome, a cluster of conditions that increase the risk of heart disease, stroke, and type 2 diabetes, is also explored using obese mouse models. Researchers can use these models to test new drugs and interventions, such as plant polysaccharides, which have shown potential in modulating liver lipid metabolism and gut microbiota in high-fat diet-induced obese mice. The C57BL/6J mouse, when fed a high-fat diet, develops features resembling human metabolic syndrome, including high adiposity, insulin resistance, hyperglycemia, hyperlipidemia, and hypertension.
Insights for Human Health
Findings from obese mouse studies contribute significantly to our understanding of human obesity and metabolic diseases, demonstrating their translational value. For example, discoveries related to the leptin pathway in mice have been foundational for understanding energy homeostasis.
These models are also crucial for drug discovery and testing, serving as a preclinical platform for new medications and interventions before human trials. Many new treatments, including GLP1s for obesity, have had their mechanisms partially discovered in mice. Researchers can assess how potential compounds affect weight gain, insulin sensitivity, and liver health in these models, providing early indications of efficacy and safety.
Despite their utility, inherent differences between mouse and human physiology exist, meaning mouse findings do not always directly translate to humans and require further validation. For instance, while mice are frequently used, their lipoprotein metabolism differs from humans, as mice primarily transport cholesterol in high-density lipoprotein (HDL) particles, unlike humans where low-density lipoprotein (LDL) is the main carrier. Some diet-induced obesity models in mice do not fully replicate the dietary patterns most closely associated with human obesity and cancer, which often involve very high refined sugars.
However, these models continue to evolve and contribute to personalized medicine approaches, with ongoing research refining their ability to mimic human conditions more closely. The insights gained from obese mouse models remain important in addressing the global health challenges posed by obesity and related metabolic disorders.