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- Kramarova, Tatiana V., et al.
(författare)
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Mitochondrial ATP synthase levels in brown adipose tissue are governed by the c-Fo subunit P1 isoform
- 2008
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Ingår i: The FASEB Journal. - : Wiley. - 0892-6638 .- 1530-6860. ; 22:1, s. 55-63
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Tidskriftsartikel (refereegranskat)abstract
- Despite the significance of mitochondrial ATP synthase for mammalian metabolism, the regulation of the amount of ATP synthase in mammalian systems is not understood. As brown adipose tissue mitochondria contain very low amounts of ATP synthase, relative to respiratory chain components, they constitute a physiological system that allows for examination of the control of ATP synthase assembly. To examine the role of the expression of the P1-isoform of the c-F-o subunit in the biogenesis of ATP synthase, we made transgenic mice that express the P1-c subunit isoform under the promoter of the brown adipose tissue-specific protein UCP1. In the resulting UCP1p1 transgenic mice, total P1-c subunit mRNA levels were increased; mRNA levels of other F1F(o)-ATPase subunits were unchanged. In isolated brown-fat mitochondria, protein levels of the total c-Fo subunit were increased. Remarkably, protein levels of ATP synthase subunits that are part of the F-1-ATPase complex were also increased, as was the entire Complex V. Increased ATPase and ATP synthase activities demonstrated an increased functional activity of the F1Fo-ATPase. Thus, the levels of the c-F-o subunit P1-isoform are crucial for defining the final content of the ATP synthase in brown adipose tissue. The level of c-F-o subunit may be a determining factor for F1Fo-ATPase assembly in all higher eukaryotes.-Kramarova, T. V., Shabalina, I. G., Andersson, U., Westerberg, R., Carlberg, I., Houstek, J., Nedergaard, J., Cannon, B. Mitochondrial ATP synthase levels in brown adipose tissue are governed by the c-F-o subunit P1 isoform.
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- Scheele, Camilla, et al.
(författare)
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Altered regulation of the PINK1 locus: a link between Type 2 diabetes and neurodegeneration?
- 2007
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Ingår i: The FASEB Journal. - : Wiley. - 0892-6638 .- 1530-6860. ; 21:13, s. 3653-3665
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Tidskriftsartikel (refereegranskat)abstract
- Mutations in PINK1 cause the mitochondrial-related neurodegenerative disease Parkinson’s. Here we investigate whether obesity, type 2 diabetes, or inactivity alters transcription from the PINK1 locus. We utilized a cDNA-array and quantitative real-time PCR for gene expression analysis of muscle from healthy volunteers following physical inactivity, and muscle and adipose tissue from nonobese or obese subjects with normal glucose tolerance or type 2 diabetes. Functional studies of PINK1 were performed utilizing RNA interference in cell culture models. Following inactivity, the PINK1 locus had an opposing regulation pattern (PINK1 was down-regulated while natural antisense PINK1 was up-regulated). In type 2 diabetes skeletal muscle, all transcripts from the PINK1 locus were suppressed and gene expression correlated with diabetes status. RNA interference of PINK1 in human neuronal cell lines impaired basal glucose uptake. In adipose tissue, mitochondrial gene expression correlated with PINK1 expression although remained unaltered following siRNA knockdown of Pink1 in primary cultures of brown preadipocytes. In conclusion, regulation of the PINK1 locus, previously linked to neurodegenerative disease, is altered in obesity, type 2 diabetes and inactivity, while the combination of RNAi experiments and clinical data suggests a role for PINK1 in cell energetics rather than in mitochondrial biogenesis.
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- Zingaretti, Maria Cristina, et al.
(författare)
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The presence of UCP1 demonstrates that metabolically active adipose tissue in the neck of adult humans truly represents brown adipose tissue.
- 2009
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Ingår i: The FASEB Journal. - : Wiley. - 0892-6638 .- 1530-6860. ; 23:9, s. 3113-20
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Tidskriftsartikel (refereegranskat)abstract
- Classically, adult humans have been considered not to possess active brown adipose tissue (BAT). However, positron-emission-tomography has shown fluorodeoxyglucose uptake that is distributed in such a way (e.g., in the neck) that it would seem to be BAT. Until now this has not been supported by direct evidence that these areas truly represented BAT, that is, the presence of the BAT-unique uncoupling protein-1 (UCP1). Samples of adipose tissue from the neck of 35 patients undergoing surgery for thyroid diseases were obtained and analyzed. In 1/3 of the subjects (the younger and leaner), distinct islands composed of UCP1 immunoreactive brown adipocytes could clearly be discerned, accounting for up to 1/3 of all adipocytes. The brown-adipose islands were richly sympathetically innervated (indicating acute central control); adjacent white adipose areas were not. The capillary density was high, implying a high capacity for oxygen delivery. Cells with features of brown adipocyte precursors were found in pericapillary areas. These data demonstrate that human adults indeed possess BAT and thus imply possibilities of future therapeutic strategies for the treatment of obesity, including maintenance of brown adipocytes and stimulation of the growth of preexisting brown precursors.
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