title: Obesity and hepatosteatosis in mice with enhanced oxidative DNA damage processing in mitochondria.
abstract: Mitochondria play critical roles in oxidative phosphorylation and energy metabolism. Increasing evidence supports that mitochondrial DNA (mtDNA) damage and dysfunction play vital roles in the development of many mitochondria-related diseases, such as obesity, diabetes mellitus, infertility, neurodegenerative disorders, and malignant tumors in humans. Human 8-oxoguanine-DNA glycosylase 1 (hOGG1) transgenic (TG) mice were produced by nuclear microinjection. Transgene integration was analyzed by PCR. Transgene expression was measured by RT-PCR and Western blot analysis. Mitochondrial DNA damage was analyzed by mutational analyses and measurement of mtDNA copy number. Total fat content was measured by a whole-body scan using dual-energy X-ray absorptiometry. The hOGG1 overexpression in mitochondria increased the abundance of intracellular free radicals and major deletions in mtDNA. Obesity in hOGG1 TG mice resulted from increased fat content in tissues, produced by hyperphagia. The molecular mechanisms of obesity involved overexpression of genes in the central orexigenic (appetite-stimulating) pathway, peripheral lipogenesis, down-regulation of genes in the central anorexigenic (appetite-suppressing) pathway, peripheral adaptive thermogenesis, and fatty acid oxidation. Diffuse hepatosteatosis, female infertility, and increased frequency of malignant lymphoma were also seen in these hOGG1 TG mice. High levels of hOGG1 expression in mitochondria, resulting in enhanced oxidative DNA damage processing, may be an important factor in human metabolic syndrome, infertility, and malignancy.
authors: Department of Pathology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
authors: Haihong
authors: H
authors: Zhang
authors: Chenghui
authors: C
authors: Xie
authors: Horace J
authors: HJ
authors: Spencer
authors: Chunlai
authors: C
authors: Zuo
authors: Masahiro
authors: M
authors: Higuchi
authors: Gouri
authors: G
authors: Ranganathan
authors: Philip A
authors: PA
authors: Kern
authors: Ming W
authors: MW
authors: Chou
authors: Qin
authors: Q
authors: Huang
authors: Bartosz
authors: B
authors: Szczesny
authors: Sankar
authors: S
authors: Mitra
authors: Amanda J
authors: AJ
authors: Watson
authors: Geoffrey P
authors: GP
authors: Margison
authors: Chun-Yang
authors: CY
authors: Fan
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D004249:DNA Damage; D045647:DNA Glycosylases / Q000235:genetics*; D004272:DNA, Mitochondrial / Q000235:genetics; D005234:Fatty Liver / Q000473:pathology*; D005260:Female; D017353:Gene Deletion; D008099:Liver / Q000473:pathology*; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism*; D009765:Obesity / Q000235:genetics / Q000378:metabolism*; D010100:Oxygen / Q000737:chemistry / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D001786:Blood Glucose; D004272:DNA, Mitochondrial; D045647:DNA Glycosylases; C479058:oxoguanine glycosylase 1, human; D010100:Oxygen