The investigator has recently reported the discovery of a novel mitochondrial uncoupling protein (UCP2) that is widely expressed in human and rodent tissues. UCP2 has good homology to UCP1 of brown fat and has been linked to dietary obesity in rodents. Preliminary data show that level of UCP2 mRNA in adipocyte cell lines is increased by peroxisome proliferator activated receptor ligands. In vivo, the expression of UCP2 in adipose tissue was increased by a high fat diet in the obesity resistant A/J strain of mice, but not in the obesity prone C57BL/6J nice. From these day the applicant proposes 3 hypothesis: (1) Fatty acids and their metabolites regulate UC2 gene transcription in A/J mice; (2) sequence elements in the UCP2 promoter control this dietary induction of the UCP2 gene, and (3) sequence differences in the UCP2 promoter exist between the obesity prone and obesity resistant strains of mice, and that this form the basis for the genetic mapping of a ZTL for obesity and diabetes at the UCP2 locus. To examine these hypothesis three aims have been proposed: (1) determine the sequence and functional activity of the A/J mouse UCP2 gene using the UCP2 5'-flanking sequence and deletion constructs; (2) examine the ability of fatty acids, eicosanoids and thiazolidinediones to increase promoter activity of the A/J UCP2 promoter reporter constructs in adipocytes, and compare these effects on the expression of the endogenous UCP2 genes; and (3) compare the sequence and functional activity of A/J UCP2 gene in the A/J and B6 mice. By comparing the UCP2 promoters from obesity prone and resistant mice the applicant will be able to determine whether sequence differences in UCP2 contribute to the genetic linkages of obesity.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Nutrition Study Section (NTN)
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Haft, Carol R
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Duke University
Schools of Medicine
United States
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