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Dissertation zugänglich unter
Obesity – environmental factors and/or genetic influence
Fettleibigkeit – Umweltfaktoren und/oder genetische Steuerung
||Fettsucht , Erbkrankheit , Carrier-Proteine
|Freie Schlagwörter (Englisch):
||obesity , metabolism , uncoupling protein , genomic structure , mutation
||Müller, Paul; Prof. Dr. Dr. h. c. mult.
|Tag der mündlichen Prüfung:
|Kurzfassung auf Englisch:
||Today obesity has been recognized as a disease. Evidence suggests that obesity often has Genetic, environmental, psychological and other factors. Growing evidence points to heredity as a strong determining factor of obesity. The characterization of uncoupling proteins (UCP) represents a major breakthrough of genetic factors towards understanding the molecular basis for energy expenditure and therefore likely to have important implication for the cause and treatment of human obesity. UCPs as mitochondrial anion carriers which creates a pathway that allows dissipation of the proton electrochemical gradient therefore which when deregulated are key risk factors in the development of obesity and other eating disorders. In order to better understand the roles of both UCP2 and UCP3 which considered as prime candidate genes involved in the pathogenesis of obesity, this study elucidate (1) Genomic organization: The human UCP2 (3) gene spans over 8.7 kb (7.5 kb) distributed on 8 (7) exons. Three UCP genes may have evolved from a common ancestor or are the result from gene duplication events. Two mRNA transcripts are generated from hUCP3 gene, the long and short form of hUCP3 is differing by the presence or absence of 37 amino acid residues at the C-terminus. (2) Mutational analysis revealed a mutation in exon 4 of hUCP2 resulting in the substitution of an alanine by a valine at codon 55 and an insertion polymorphism in exon 8 consisted of a 45 bp repeat located 150 bp downstream of the stop codon in the 3'-UTR. The allele frequencies of both polymorphisms were not significantly elevated in a subgroup of children characterized by low Resting Metabolic Rates (RMR). (3) Promoter Analysis showed that the promoter region of hUCP2 lacks a classical TATA or CAAT box. Functional characterization of hUCP2 promoter showed that minimal promoter activity was observed within 65 bp upstream of the transcriptional start site. 75 bp further upstream a strong cis-acting regulatory element was identified which significantly enhanced basal promoter activity. The regulation of human UCP2 gene expression involves complex interactions among positive and negative regulatory elements. the 5’-flanking region of the hUCP3 gene were characterized in which contains both TATA and CAAT boxes as well as consensus motifs for PPRE, TRE, CRE and muscle-specific MyoD and MEF2 sites. Functional characterization identified a cis-acting negative regulatory element between - 2983 and -982 while the region between -982 and -284 showed greatly increased basal promoter activity suggesting the presence of a strong enhancer element. Promoter activity was particularly enhanced in the murine skeletal muscle cell line C2C12 reflecting the tissue-selective expression pattern of UCP3.
|Kurzfassung auf Deutsch: