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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL073163-02
Application #
6739651
Study Section
Special Emphasis Panel (ZHL1-CSR-S (F1))
Program Officer
Barouch, Winifred
Project Start
2003-08-01
Project End
2008-07-31
Budget Start
2004-08-01
Budget End
2005-07-31
Support Year
2
Fiscal Year
2004
Total Cost
$723,786
Indirect Cost
Name
Albert Einstein College of Medicine
Department
Biochemistry
Type
Schools of Medicine
DUNS #
110521739
City
Bronx
State
NY
Country
United States
Zip Code
10461
Hartil, Kirsten; Vuguin, Patricia M; Kruse, Michael et al. (2009) Maternal substrate utilization programs the development of the metabolic syndrome in male mice exposed to high fat in utero. Pediatr Res 66:368-73
Ranalletta, Mollie; Du, Xiu Quan; Seki, Yoshinori et al. (2007) Hepatic response to restoration of GLUT4 in skeletal muscle of GLUT4 null mice. Am J Physiol Endocrinol Metab 293:E1178-87
Nawrocki, Andrea R; Rajala, Michael W; Tomas, Eva et al. (2006) Mice lacking adiponectin show decreased hepatic insulin sensitivity and reduced responsiveness to peroxisome proliferator-activated receptor gamma agonists. J Biol Chem 281:2654-60
Seki, Yoshinori; Berggren, Jason R; Houmard, Joseph A et al. (2006) Glucose transporter expression in skeletal muscle of endurance-trained individuals. Med Sci Sports Exerc 38:1088-92
Charron, Maureen J; Gorovits, Naira; Laidlaw, J Skye et al. (2005) Use of GLUT-4 null mice to study skeletal muscle glucose uptake. Clin Exp Pharmacol Physiol 32:308-13
Combs, Terry P; Nagajyothi; Mukherjee, Shankar et al. (2005) The adipocyte as an important target cell for Trypanosoma cruzi infection. J Biol Chem 280:24085-94
Pajvani, Utpal B; Trujillo, Maria E; Combs, Terry P et al. (2005) Fat apoptosis through targeted activation of caspase 8: a new mouse model of inducible and reversible lipoatrophy. Nat Med 11:797-803
Lin, Ying; Berg, Anders H; Iyengar, Puneeth et al. (2005) The hyperglycemia-induced inflammatory response in adipocytes: the role of reactive oxygen species. J Biol Chem 280:4617-26
Berg, Anders H; Lin, Ying; Lisanti, Michael P et al. (2004) Adipocyte differentiation induces dynamic changes in NF-kappaB expression and activity. Am J Physiol Endocrinol Metab 287:E1178-88