DESCRIPTION (provided by applicant): Obesity is associated with metabolic abnormalities that increase the risk of type 2 diabetes and cardiovascular disease (CVD). Obese patients with a substantial accumulation of visceral adipose tissue are characterized by higher insulinemic and glycemic responses during an oral glucose challenge and a deteriorated plasma lipoprotein-lipid profile compared to normal body weight or obese individuals with low level visceral adiposity. We will use a mouse model with a primary impairment in insulin-mediated glucose flux into adipocytes to define the molecular mechanisms underlying the pathogenesis of obesity associated CVD. Male mice carrying only one functional copy of the insulin-stimulatable GLUT4 transporter (GLUT4) first display reduced GLUT4 expression specifically in white adipose tissue (WAT). Reduced GLUT4 in WAT leads to visceral obesity, progressive impairment in insulin sensitivity, altered lipid metabolism, and eventually to type 2 diabetes with associated CVD. As such, male GLUT4 mice represent an excellent model to study pathophysiological changes associated with visceral obesity in humans. Interestingly, changes in adipose cell secretory proteins, such as the adipocyte-specific Acrp30, precede the onset of measurable changes in other metabolic parameters in GLUT4 mice. We and others have demonstrated profound effects of Acrp30 on insulin resistance in liver and muscle through specific effects on carbohydrate and lipid metabolism. The objectives of this proposal are I) to understand the molecular mechanisms underlying the metabolic changes that specifically affect male, but not female GLUT4 mice or GLUT4 mice that overexpress GLUT4 in muscle; lI) to test genetically whether correction of Acrp30 downregulation in male GLUT4 will prevent or delay the onset of insulin resistance, visceral obesity and/or CVD. Additionally, we will test whether complete lack of circulating Acrp30 in Acrp30-/-mice will provoke metabolic disturbance in female GLUT4 and exacerbate disease in male GLUT4 mice; III) to assess the effects of high fat diet-induced changes in disease progression in GLUT4 compared to C57BL/6J mice; and IV) to determine transcripitional and translational changes in WAT associated with visceral obesity and alterations following treatment with thiazolidinedione insulin sensitizers in hope of identifying novel therapeutic targets. Combined, this approach will provide a comprehensive systematic characterization of a mouse model of obesity associated CVD derived from early impairment of insulin-mediated glucose flux into WAT, and directly address for the first time whether alterations in Acrp30 influence disease progression.
|Effective start/end date||8/1/03 → 7/31/09|
- National Heart, Lung, and Blood Institute: $713,566.00
- National Heart, Lung, and Blood Institute: $723,786.00
- National Heart, Lung, and Blood Institute: $810,543.00
- National Heart, Lung, and Blood Institute: $785,418.00
- National Heart, Lung, and Blood Institute: $726,279.00
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