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Sökning: WFRF:(Nedergaard L)

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  • Cheung, L., et al. (författare)
  • Human mediastinal adipose tissue displays certain characteristics of brown fat
  • 2013
  • Ingår i: Nutrition & Diabetes. - 2044-4052 .- 2044-4052. ; 3:UNSP e66
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: The amount of intra-thoracic fat, of which mediastinal adipose tissue comprises the major depot, is related to various cardiometabolic risk factors. Autopsy and imaging studies indicate that the mediastinal depot in adult humans could contain brown adipose tissue (BAT). To gain a better understanding of this intra-thoracic fat depot, we examined possible BAT characteristics of human mediastinal in comparison with subcutaneous adipose tissue. MATERIALS AND METHODS: Adipose tissue biopsies from thoracic subcutaneous and mediastinal depots were obtained during open-heart surgery from 33 subjects (26 male, 63.7 +/- 13.8 years, body mass index 29.3 +/- 5.1 kg m(-2)). Microarray analysis was performed on 10 patients and genes of interest confirmed by quantitative PCR (qPCR) in samples from another group of 23 patients. Adipocyte size was determined and uncoupling protein 1 (UCP1) protein expression investigated with immunohistochemistry. RESULTS: The microarray data showed that a number of BAT-specific genes had significantly higher expression in the mediastinal depot than in the subcutaneous depot. Higher expression of UCP1 (24-fold, P < 0.001) and PPARGC1A (1.7-fold, P = 0.0047), and lower expression of SHOX2 (0.12-fold, P < 0.001) and HOXC8 (0.14-fold, P < 0.001) in the mediastinal depot was confirmed by qPCR. Gene set enrichment analysis identified two gene sets related to mitochondria, which were significantly more highly expressed in the mediastinal than in the subcutaneous depot (P < 0.01). No significant changes in UCP1 gene expression were observed in the subcutaneous or mediastinal depots following lowering of body temperature during surgery. UCP1 messenger RNA levels in the mediastinal depot were lower than those in murine BAT and white adipose tissue. In some mediastinal adipose tissue biopsies, a small number of multilocular adipocytes that stained positively for UCP1 were observed. Adipocytes were significantly smaller in the mediastinal than the subcutaneous depot (cross-sectional area 2400 +/- 810 versus 3260 +/- 980 mu m(2), P < 0.001). CONCLUSIONS: Human mediastinal adipose tissue displays some characteristics of BAT when compared with the subcutaneous depot at microscopic and molecular levels.
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  • Sweeney, M. D., et al. (författare)
  • Vascular dysfunction-The disregarded partner of Alzheimer's disease
  • 2019
  • Ingår i: Alzheimers & Dementia. - 1552-5260. ; 15:1, s. 158-167
  • Tidskriftsartikel (refereegranskat)abstract
    • Increasing evidence recognizes Alzheimer's disease (AD) as a multifactorial and heterogeneous disease with multiple contributors to its pathophysiology, including vascular dysfunction. The recently updated AD Research Framework put forth by the National Institute on Aging-Alzheimer's Association describes a biomarker-based pathologic definition of AD focused on amyloid, tau, and neuronal injury. In response to this article, here we first discussed evidence that vascular dysfunction is an important early event in AD pathophysiology. Next, we examined various imaging sequences that could be easily implemented to evaluate different types of vascular dysfunction associated with, and/or contributing to, AD pathophysiology, including changes in blood-brain barrier integrity and cerebral blood flow. Vascular imaging biomarkers of small vessel disease of the brain, which is responsible for >50% of dementia worldwide, including AD, are already established, well characterized, and easy to recognize. We suggest that these vascular biomarkers should be incorporated into the AD Research Framework to gain a better understanding of AD pathophysiology and aid in treatment efforts. (C) 2018 the Alzheimer's Association. Published by Elsevier Inc. All rights reserved.
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  • Hagberg, C. E., et al. (författare)
  • Flow Cytometry of Mouse and Human Adipocytes for the Analysis of Browning and Cellular Heterogeneity
  • 2018
  • Ingår i: Cell Reports. - 2211-1247. ; 24:10, s. 2746-
  • Tidskriftsartikel (refereegranskat)abstract
    • Adipocytes, once considered simple lipid-storing cells, are rapidly emerging as complex cells with many biologically diverse functions. A powerful high-throughput method for analyzing single cells is flow cytometry. Several groups have attempted to analyze and sort freshly isolated adipocytes; however, using an adipocyte-specific reporter mouse, we demonstrate that these studies fail to detect the majority of white adipocytes. We define critical settings required for adipocyte flow cytometry and provide a rigid strategy for analyzing and sorting white and brown adipocyte populations. The applicability of our protocol is shown by sorting mouse adipocytes based on size or UCP1 expression and demonstrating that a subset of human adipocytes lacks the beta(2)-adrenergic receptor, particularly in the insulin-resistant state. In conclusion, the present study confers key technological insights for analyzing and sorting mature adipocytes, opening up numerous downstream research applications.
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  • Abreu-Vieira, Gustavo, 1987-, et al. (författare)
  • Adrenergically-stimulated blood flow in brown adipose tissue is not dependent on thermogenesis : Regulation of brown adipose tissue blood flow
  • 2015
  • Ingår i: American Journal of Physiology. Endocrinology and Metabolism. - 0193-1849 .- 1522-1555. ; 308:9, s. E822-E829
  • Tidskriftsartikel (refereegranskat)abstract
    • Brown adipose tissue (BAT) thermogenesis relies on blood flow to be supplied with nutrients and oxygen, and for the distribution of the generated heat to the rest of the body. It is therefore fundamental to understand the mechanisms by which blood flow is regulated and its relation to thermogenesis. Here we present high-resolution laser-Doppler imaging (HR-LDR) as a novel method for noninvasive, in vivo measurement of BAT blood flow in mice. Using HR-LDR, we found that norepinephrine stimulation increases BAT blood flow in a dose-dependent manner, and that this response is profoundly modulated by environmental temperature acclimation. Surprisingly, we found that mice lacking uncoupling protein 1 (UCP1) have fully preserved BAT blood flow response to norepinephrine, despite failing to perform thermogenesis. BAT blood flow was not directly correlated to systemic glycaemia, but glucose injections could transiently increase tissue perfusion. Inguinal white adipose tissue, also known as a brite/beige adipose tissue, was also sensitive to cold acclimation and similarly increased blood flow in response to norepinephrine. In conclusion, using a novel non-invasive method to detect BAT perfusion, we demonstrate that adrenergically-stimulated BAT blood flow is qualitatively and quantitatively fully independent of thermogenesis, and is therefore not a reliable parameter for the estimation of BAT activation and heat generation.
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  • Dixen, Karen, et al. (författare)
  • ERR gamma Enhances UCP1 Expression and Fatty Acid Oxidation in Brown Adipocytes
  • 2013
  • Ingår i: Obesity. - 1930-7381 .- 1930-739X. ; 21:3, s. 516-524
  • Tidskriftsartikel (refereegranskat)abstract
    • Objective: Estrogen-related receptors (ERRs) are important regulators of energy metabolism. Here we investigated the hypothesis that ERR gamma impacts on differentiation and function of brown adipocytes. Design and Methods: We characterize the expression of ERR gamma in adipose tissues and cell models and investigate the effects of modulating ERR? activity on UCP1 gene expression and metabolic features of brown and white adipocytes. Results: ERR gamma was preferentially expressed in brown compared to white fat depots, and ERR gamma was induced during cold-induced browning of subcutaneous white adipose tissue and brown adipogenesis. Overexpression of ERR gamma positively regulated uncoupling protein 1 (UCP1) expression levels during brown adipogenesis. This ERR gamma-induced augmentation of UCP1 expression was independent of the presence of peroxisome proliferator-activated receptor coactivator-1 (PGC-1 alpha) but was associated with increased rates of fatty acid oxidation in adrenergically stimulated cells. ERR? did not influence mitochondrial biogenesis, and its reduced expression in white adipocytes could not explain their low expression level of UCP1. Conclusions: Through its augmenting effect on expression of UCP1, ERR gamma may physiologically be involved in increasing the potential for energy expenditure in brown adipocytes, a function that is becoming of therapeutic interest.
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  • Edgar, Daniel, et al. (författare)
  • Random point mutations with major effects on protein-coding genes are the driving force behind premature aging in mtDNA mutator mice.
  • 2009
  • Ingår i: Cell metabolism. - 1932-7420. ; 10:2, s. 131-8
  • Tidskriftsartikel (refereegranskat)abstract
    • The mtDNA mutator mice have high levels of point mutations and linear deletions of mtDNA causing a progressive respiratory chain dysfunction and a premature aging phenotype. We have now performed molecular analyses to determine the mechanism whereby these mtDNA mutations impair respiratory chain function. We report that mitochondrial protein synthesis is unimpaired in mtDNA mutator mice consistent with the observed minor alterations of steady-state levels of mitochondrial transcripts. These findings refute recent claims that circular mtDNA molecules with large deletions are driving the premature aging phenotype. We further show that the stability of several respiratory chain complexes is severely impaired despite normal synthesis of the corresponding mtDNA-encoded subunits. Our findings reveal a mechanism for induction of aging phenotypes by demonstrating a causative role for amino acid substitutions in mtDNA-encoded respiratory chain subunits, which, in turn, leads to decreased stability of the respiratory chain complexes and respiratory chain deficiency.
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