Grant: Operating Grant

Obesity is associated with an increased risk of diabetes and cardiovascular disease. Although genetic predisposition contributes significantly to obesity, our knowledge of causative genes is far from complete. We have discovered a novel protein with a structure suggesting that it controls the expression of many of genes. We found that down-regulation of ZBTB8A (named based on its structure) in mouse stem cells led to cell differentiation and an upregulation of genes that control fat cell differentiation and function. We therefore engineered mice to lack ZBTB8A. We found that mice lacking both copies of ZBTB8A became obese within 8 months and that mice lacking one copy of ZBTB8A had an intermediate level of weight and fat gain. We also found that these animals demonstrated many clinical features shared by individuals that are considered pre-diabetic. All of these experiments were performed in which that mice were fed standard (low fat) rodent food. We propose to thoroughly analyze the ZBTB8A mutant mice under specific dietary conditions including high fat and low fat diets. We also propose to analyze the molecular function of ZBTB8A in fat cells. Our findings that ZBTB8A mutant mice demonstrate dose-dependent abnormalities fat accumulation and metabolism that changes in ZBTB8A expression or function in the general population may genetically predispose individuals to obesity and type 2 diabetes. We expect that our work will be used in future studies to identify and test novel therapeutics designed to prevent or treat type 2 diabetes.