To understand the complexities of obesity, scientists use the diet-induced obesity (DIO) mouse model, a laboratory mouse that develops obesity and related metabolic issues after being fed a diet high in fat and sugar. The DIO mouse is not genetically engineered to be obese; its condition is a direct result of its diet. This makes it a useful analogue for studying how lifestyle factors contribute to metabolic disease in humans.
Creating the Diet-Induced Obesity Model
Creating a DIO mouse begins with selecting an appropriate strain, most commonly the C57BL/6J. This strain is widely used due to its genetic susceptibility to gaining weight on a high-calorie diet. Its predisposition to developing obesity-related conditions makes it a reliable model, allowing scientists to compare results across different studies.
The specialized diet is central to the model. Unlike standard low-fat laboratory chow, the high-fat diet (HFD) is formulated to induce obesity, deriving 45% to 60% of its calories from fat. Many formulations also include high levels of simple sugars, such as sucrose, to mimic a “Western” diet.
Mice are placed on this HFD for several weeks to months, often starting shortly after weaning. The feeding continues until they exhibit significant weight gain and increased body fat, which mirrors the gradual onset of diet-related obesity in humans.
Physiological Changes in DIO Mice
Prolonged exposure to a high-fat diet causes physiological changes that parallel human obesity. The most visible change is an increase in body weight and adiposity, or body fat. Male C57BL/6J mice experience rapid weight gain, with an expansion of fat depots, including visceral fat around the organs and subcutaneous fat under the skin.
Beyond weight gain, the DIO mouse develops metabolic dysfunctions. One of the earliest changes is hyperinsulinemia, where the pancreas produces excessive insulin to manage blood sugar. This is a response to insulin resistance, a state where the body’s cells, particularly in the liver, muscle, and fat tissue, become less responsive to insulin’s signals, leading to hyperglycemia, or high blood sugar.
This metabolic stress also promotes chronic, low-grade inflammation, as adipose tissue releases inflammatory molecules called cytokines. Concurrently, these mice develop dyslipidemia, characterized by elevated levels of triglycerides and cholesterol. This combination of issues makes the DIO mouse a comprehensive model for the metabolic syndrome seen in humans.
Applications in Medical Research
The physiological changes in DIO mice make them useful for studying human diseases linked to obesity. Researchers use this model to investigate the progression of type 2 diabetes, as the mouse’s development of insulin resistance and hyperglycemia mirrors the disease’s early stages in people. This allows for testing new therapeutic agents designed to improve insulin sensitivity before human trials.
The model is also used to study non-alcoholic fatty liver disease (NAFLD), a condition where excess fat accumulates in the liver. In DIO mice, the high-fat diet leads to hepatic steatosis, or fatty liver, which can progress to more severe inflammation and liver damage. This provides a platform to test interventions aimed at preventing or reversing this condition.
Cardiovascular research benefits from the DIO model as well. The dyslipidemia and chronic inflammation contribute to conditions like endothelial dysfunction, a precursor to atherosclerosis, allowing scientists to evaluate treatments that might protect the cardiovascular system. The model is also applied in cancer research to understand how obesity creates a pro-inflammatory environment that can promote tumor growth.
Translational Relevance to Human Obesity
The DIO mouse model is a relevant, though imperfect, representation of human obesity. Its strength lies in mimicking how many humans develop the condition: through the long-term consumption of a calorie-dense, high-fat diet. This allows scientists to gain insights into disease mechanisms and screen potential drugs based on shared metabolic pathways.
The model has limitations when applying findings to human health. Laboratory mice are genetically homogenous and housed in controlled environments, which contrasts with the genetic diversity and varied lifestyles of humans. Female mice are also often resistant to the full metabolic effects of a high-fat diet, a notable difference. Despite these issues, the DIO model provides knowledge that helps guide human-focused research.