An estimated 18.2 million people (6.3 percent of the population) in the United States have diabetes; 90 to 95 percent of all diagnosed cases are type II diabetes (NIDDK, 2005). Obesity and metabolic syndrome are the leading causes of type II diabetes. The search for new and more effective therapies to address the growing number of Americans with type II diabetes and related conditions is currently hindered by the lack of an obese research animal model that closely resembles the conditions that lead to the human type II diabetic condition. Most rodent models currently available commercially, related to obesity, metabolic syndrome and type II diabetes, have genetic defects in leptin-receptors, leptin or in other hypothalamic peptides. These defects are not common causes for the etiology of obesity and diabetes in the human population. A new mouse model without these defects would more closely resemble the human condition and thus be more appropriate for the study of diabetic-related conditions and metabolic syndrome. PreClinOmics (PCO) has begun to develop a new mouse model without leptin/leptin-receptor and other genetic defects, which would affect hypothalamic function, by crossing two inbred mouse models with the propensity to develop diet induced obesity with insulin resistance. The long-term goal of this project is to create a mouse model that will be accepted by the biotech or pharmaceutical industries, and the research community to advance the study and development of obesity and type II diabetic therapies in humans. Phase I of the project will focus on the continued development, defining, and characterization of this new obese mouse model. The project has four specific aims. First, continue the development of a mouse model (Fatzo) for obesity, metabolic syndrome, and type II diabetes without leptin/leptin-receptor defects using both phenotypic and genetic monitoring to achieve phenotypic and genetic homogeneity. Second, investigate the effects of diet manipulation on the onset, consistency and synchronicity of the phenotypic expression (obesity and type II diabetes). Third, demonstrate the efficacy of typical anti-obesity/anti-diabetic compounds on the reversal of obesity and prevention of diabetes to show the utility of this mouse model. Fourth, examine the effect of leptin on food consumption in Fatzo and control strains.
Public Health Relevance:: Current commercially available animal models that are used for obesity, metabolic syndrome and diabetes research and drug development have leptin and leptin-related genetic defects that cause obesity. These defects are not found in the typical obese and diabetic individuals where multiple genes seem to be responsible for the condition. The purpose of this project is to develop and produce a new obese and diabetes-prone mouse model which has multiple contributing genetic factors but without a leptin or leptin receptor defect. This will be a very important model for the development of drugs that will control obesity and adult onset diabetes.
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