Abstract

In the present proposal, techniques will be applied towards a transgenic analysis of brown adipose tissue (BAT) function. BAT is distinguished by its unique ability to convert metabolic fuels to heat. This property is attributed to its unusual mitochondrial proton transporter, the uncoupling protein (UCP). Because of this capability, BAT is uniquely situated to play a central role in the pathogenesis of obesity. Previous studies have attempted to examine this possibility by correlating altered states of energy balance with altered BAT metabolism. Unfortunately, these studies have generated somewhat conflicting results. In this proposal, two alternative approaches are put forward. The first will use gene targeting in embryonic stem (ES) cells to disrupt the UCP gene. These targeted ES cells will be used to produce UCP deficient mice. The second approach will utilize suicide DNA vectors consisting of a toxin cDNA whose expression is driven by the UCP promoter/enhancer to specifically ablate BAT in transgenic mice. These complementary approaches should provide new insight into the role of BAT in the regulation of energy balance.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08DK002119-02
Application #
3081049
Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
Project Start
1992-07-01
Project End
1997-06-30
Budget Start
1993-07-01
Budget End
1994-06-30
Support Year
2
Fiscal Year
1993
Total Cost
Indirect Cost

  Institution

Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
076593722
City
Boston
State
MA
Country
United States
Zip Code
02215

  Publications

Ito, M; Grujic, D; Abel, E D et al. (1998) Mice expressing human but not murine beta3-adrenergic receptors under the control of human gene regulatory elements. Diabetes 47:1464-71
Lowell, B B; Flier, J S (1997) Brown adipose tissue, beta 3-adrenergic receptors, and obesity. Annu Rev Med 48:307-16
Grujic, D; Susulic, V S; Harper, M E et al. (1997) Beta3-adrenergic receptors on white and brown adipocytes mediate beta3-selective agonist-induced effects on energy expenditure, insulin secretion, and food intake. A study using transgenic and gene knockout mice. J Biol Chem 272:17686-93
Solanes, G; Vidal-Puig, A; Grujic, D et al. (1997) The human uncoupling protein-3 gene. Genomic structure, chromosomal localization, and genetic basis for short and long form transcripts. J Biol Chem 272:25433-6
Hollenberg, A N; Susulic, V S; Madura, J P et al. (1997) Functional antagonism between CCAAT/Enhancer binding protein-alpha and peroxisome proliferator-activated receptor-gamma on the leptin promoter. J Biol Chem 272:5283-90
Cinti, S; Frederich, R C; Zingaretti, M C et al. (1997) Immunohistochemical localization of leptin and uncoupling protein in white and brown adipose tissue. Endocrinology 138:797-804
Vidal-Puig, A; Solanes, G; Grujic, D et al. (1997) UCP3: an uncoupling protein homologue expressed preferentially and abundantly in skeletal muscle and brown adipose tissue. Biochem Biophys Res Commun 235:79-82
Hamann, A; Flier, J S; Lowell, B B (1996) Decreased brown fat markedly enhances susceptibility to diet-induced obesity, diabetes, and hyperlipidemia. Endocrinology 137:21-9
Mantzoros, C S; Qu, D; Frederich, R C et al. (1996) Activation of beta(3) adrenergic receptors suppresses leptin expression and mediates a leptin-independent inhibition of food intake in mice. Diabetes 45:909-14
Hamann, A; Benecke, H; Le Marchand-Brustel, Y et al. (1995) Characterization of insulin resistance and NIDDM in transgenic mice with reduced brown fat. Diabetes 44:1266-73

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