Glucagon-like peptide-1 (GLP-1) agonists, such as semaglutide and liraglutide, are major anti-obesity and anti-diabetes therapeutics that have produced clinically meaningful metabolic benefits.
While several different rodent models can be used to study obesity and diabetes, the diet-induced obesity (DIO) model exhibits an obese phenotype, glucose intolerance, elevated blood glucose, dyslipidemia, and liver steatosis. It offers unique attributes for studying the efficacy of novel therapeutics that target weight loss and glucose metabolism.
“The DIO is particularly ideal because it replicates the physiological and metabolic changes that we see in human obesity,” explains Crystal West, PhD, Associate Director, Cardiometabolic Disease at Inotiv.
“Using the DIO model’s controlled high-fat diet protocol, we're able to simulate real-world metabolic changes with shifts in adiposity, glucose regulation, and lipid metabolism. Because it takes around 18 weeks to develop the model, we can capture early metabolic adaptations and long-term disease progression, and we also have a more physiologically relevant platform for therapeutic evaluation,” she added.
Understanding other models of obesity
Genetic models of obesity serve as another tool in obesity and Type 2 diabetes studies. Many of these models are characterized by their altered leptin signaling pathway; leptin is a hormone that regulates appetite. A widely used diabetic mouse is the db/db mouse, which is leptin receptor–deficient while the ob/ob mouse is leptin-deficient.
“The db/db, ob/ob, and DIO models are derived from the C57BL strain, which is generally more prone to obesity. One of the main differences between the genetic models and the DIO model is that the DIO retains its leptin signaling pathway. DIO is also considered a pre-diabetic model with milder hyperglycemia than either diabetic model,” said Crystal.
Using the DIO model to extend GLP-1 research
Beyond studying obesity, the C57BL/6 DIO model supports research in metabolic disease, inflammatory disease, cardiovascular disease, pre-diabetes, and liver disease.
“If a client is asking us for a reliable model for obesity, we first determine if they need an intact leptin signaling pathway. We can also determine if they need a model with co-morbidities, for example, one with renal mass reduction or myocardial infarction,” said Crystal.
“We are seeing a lot of interest in the DIO to support research in cardiovascular disease as well as renal disease. In some studies, we are collecting brain samples as the research is evaluating the role of GLP-1 in neuroscience to support potential therapies for anxiety and addiction.”
Offering multiple layers of support
With the various therapeutic areas seeing potential in GLP-1, Inotiv recognizes the value of scientific collaboration. To support GLP-1 studies, they are fostering more cross-collaboration between the metabolic, renal, neuro, and cardio teams.
For example, Inotiv’s pharmacology team can provide readouts on body weight, body composition, food intake, fasting blood glucose, and glucose tolerance, along with other readouts. This can also include screening for comorbid diseases with blood pressure measurements, cardiac ultrasounds, or glomerular filtration rates. The biomarker team can also evaluate samples to assess disease-related biomarkers such as glucose, insulin, liver enzymes, and lipid profiles.
Similarly, the histology team can check for liver steatosis (a major feature of DIO mice), analyze adipocyte volume, or look for markers of browning on fat. Samples can also be sent to Inotiv’s drug metabolism and pharmacokinetics (DMPK) team to better understand a compound's properties. The proteomics core can support target engagement questions or global proteome changes for pathway analysis.
“Whether you need contract breeding, preconditioning, biospecimen, or surgical services or end-to-end disease pharmacology studies, we have an approach that can be tailored to what our clients need on a global scale,” said Crystal. “We believe our comprehensive range of support with GLP-1 studies will help make a difference to address today’s greatest and most costly health challenges.”