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| 9. |
- Baeckdahl, Jesper, et al.
(author)
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Spatial mapping reveals human adipocyte subpopulations with distinct sensitivities to insulin
- 2021
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In: Cell Metabolism. - : Elsevier BV. - 1550-4131 .- 1932-7420. ; 33:9, s. 1869-
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Journal article (peer-reviewed)abstract
- The contribution of cellular heterogeneity and architecture to white adipose tissue (WAT) function is poorly understood. Herein, we combined spatially resolved transcriptional profiling with single-cell RNA sequencing and image analyses to map human WAT composition and structure. This identified 18 cell classes with unique propensities to form spatially organized homo-and heterotypic clusters. Of these, three constituted mature adipocytes that were similar in size, but distinct in their spatial arrangements and transcriptional profiles. Based on marker genes, we termed these Adipo(LEP), Adipo(PLIN), and Adipo(SAA). We confirmed, in independent datasets, that their respective gene profiles associated differently with both adipocyte and whole-body insulin sensitivity. Corroborating our observations, insulin stimulation in vivo by hyperinsulinemic-euglycemic clamp showed that only Adipo(PLIN) displayed a transcriptional response to insulin. Altogether, by mining this multimodal resource we identify that human WAT is composed of three classes of mature adipocytes, only one of which is insulin responsive.
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| 10. |
- Balaz, M., et al.
(author)
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Inhibition of Mevalonate Pathway Prevents Adipocyte Browning in Mice and Men by Affecting Protein Prenylation
- 2019
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In: Cell Metabolism. - : Elsevier BV. - 1550-4131 .- 1932-7420. ; 29:4
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Journal article (peer-reviewed)abstract
- Recent research focusing on brown adipose tissue (BAT) function emphasizes its importance in systemic metabolic homeostasis. We show here that genetic and pharmacological inhibition of the mevalonate pathway leads to reduced human and mouse brown adipocyte function in vitro and impaired adipose tissue browning in vivo. A retrospective analysis of a large patient cohort suggests an inverse correlation between statin use and active BAT in humans, while we show in a prospective clinical trial that fluvastatin reduces thermogenic gene expression in human BAT. We identify geranylgeranyl pyrophosphate as the key mevalonate pathway intermediate driving adipocyte browning in vitro and in vivo, whose effects are mediated by geranylgeranyltransferases (GGTases), enzymes catalyzing geranylgeranylation of small GTP-binding proteins, thereby regulating YAP1/TAZ signaling through F-actin modulation. Conversely, adipocyte-specific ablation of GGTase I leads to impaired adipocyte browning, reduced energy expenditure, and glucose intolerance under obesogenic conditions, highlighting the importance of this pathway in modulating brown adipocyte functionality and systemic metabolism.
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| 11. |
- Barres, R., et al.
(author)
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Acute exercise remodels promoter methylation in human skeletal muscle
- 2012
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In: Cell Metabolism. - : Elsevier BV. - 1550-4131 .- 1932-7420. ; 15:3, s. 405-11
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Journal article (peer-reviewed)abstract
- DNA methylation is a covalent biochemical modification controlling chromatin structure and gene expression. Exercise elicits gene expression changes that trigger structural and metabolic adaptations in skeletal muscle. We determined whether DNA methylation plays a role in exercise-induced gene expression. Whole genome methylation was decreased in skeletal muscle biopsies obtained from healthy sedentary men and women after acute exercise. Exercise induced a dose-dependent expression of PGC-1alpha, PDK4, and PPAR-delta, together with a marked hypomethylation on each respective promoter. Similarly, promoter methylation of PGC-1alpha, PDK4, and PPAR-delta was markedly decreased in mouse soleus muscles 45 min after ex vivo contraction. In L6 myotubes, caffeine exposure induced gene hypomethylation in parallel with an increase in the respective mRNA content. Collectively, our results provide evidence that acute gene activation is associated with a dynamic change in DNA methylation in skeletal muscle and suggest that DNA hypomethylation is an early event in contraction-induced gene activation.
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| 12. |
- Barres, R., et al.
(author)
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Non-CpG methylation of the PGC-1alpha promoter through DNMT3B controls mitochondrial density
- 2009
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In: Cell Metabolism. - : Elsevier BV. - 1550-4131 .- 1932-7420. ; 10:3, s. 189-98
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Journal article (peer-reviewed)abstract
- Epigenetic modification through DNA methylation is implicated in metabolic disease. Using whole-genome promoter methylation analysis of skeletal muscle from normal glucose-tolerant and type 2 diabetic subjects, we identified cytosine hypermethylation of peroxisome proliferator-activated receptor gamma (PPARgamma) coactivator-1 alpha (PGC-1alpha) in diabetic subjects. Methylation levels were negatively correlated with PGC-1alpha mRNA and mitochondrial DNA (mtDNA). Bisulfite sequencing revealed that the highest proportion of cytosine methylation within PGC-1alpha was found within non-CpG nucleotides. Non-CpG methylation was acutely increased in human myotubes by exposure to tumor necrosis factor-alpha (TNF-alpha) or free fatty acids, but not insulin or glucose. Selective silencing of the DNA methyltransferase 3B (DNMT3B), but not DNMT1 or DNMT3A, prevented palmitate-induced non-CpG methylation of PGC-1alpha and decreased mtDNA and PGC-1alpha mRNA. We provide evidence for PGC-1alpha hypermethylation, concomitant with reduced mitochondrial content in type 2 diabetic patients, and link DNMT3B to the acute fatty-acid-induced non-CpG methylation of PGC-1alpha promoter.
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| 18. |
- Bossart, Martin, et al.
(author)
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Effects on weight loss and glycemic control with SAR441255, a potent unimolecular peptide GLP-1/GIP/GCG receptor triagonist
- 2022
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In: Cell Metabolism. - : CELL PRESS. - 1550-4131 .- 1932-7420. ; 34:1, s. 59-
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Journal article (peer-reviewed)abstract
- Unimolecular triple incretins, combining the activity of glucagon-like peptide-1 (GLP-1), glucose -dependent insulinotropic polypeptide (GIP), and glucagon (GCG), have demonstrated reduction in body weight and improved glucose control in rodent models. We developed SAR441255, a synthetic peptide agonist of the GLP-1, GCG, and GIP receptors, structurally based on the exendin-4 sequence. SAR441255 displays high potency with balanced activation of all three target receptors. In animal models, metabolic outcomes were superior to results with a dual GLP-1/GCG receptor agonist. Preclinical in vivo positron emission tomography imaging demonstrated SAR441255 binding to GLP-1 and GCG receptors. In healthy subjects, SAR441255 improved glycemic control during a mixed-meal tolerance test and impacted biomarkers for GCG and GIP receptor activation. Single doses of SAR441255 were well tolerated. The results demonstrate that integrating GIP activity into dual GLP-1 and GCG receptor agonism provides improved effects on weight loss and glycemic control while buffering the diabetogenic risk of chronic GCG receptor agonism.
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| 22. |
- Caesar, Robert, 1973, et al.
(author)
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Crosstalk between gut microbiota and dietary lipids aggravates WAT inflammation through TLR signaling
- 2015
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In: Cell Metabolism. - : Elsevier BV. - 1550-4131 .- 1932-7420. ; 22:4, s. 658-668
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Journal article (peer-reviewed)abstract
- Dietary lipids may influence the abundance of circulating inflammatory microbial factors. Hence, inflammation in white adipose tissue (WAT) induced by dietary lipids may be partly dependent on their interaction with the gut microbiota. Here, we show that mice fed lard for 11 weeks have increased Toll-like receptor (TLR) activation and WAT inflammation and reduced insulin sensitivity compared with mice fed fish oil and that phenotypic differences between the dietary groups can be partly attributed to differences in microbiota composition. Trif-/- and Myd88-/- mice are protected against lard-induced WAT inflammation and impaired insulin sensitivity. Experiments in germ-free mice show that an interaction between gut microbiota and saturated lipids promotes WAT inflammation independent of adiposity. Finally, we demonstrate that the chemokine CCL2 contributes to microbiota-induced WAT inflammation in lard-fed mice. These results indicate that gut microbiota exacerbates metabolic inflammation through TLR signaling upon challenge with a diet rich in saturated lipids. © 2015 The Authors.
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| 23. |
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| 24. |
- Cannon, Barbara, et al.
(author)
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What Ignites UCP1?
- 2017
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In: Cell Metabolism. - : Elsevier BV. - 1550-4131 .- 1932-7420. ; 26:5, s. 697-698
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Journal article (other academic/artistic)abstract
- We thought we knew how the heat-producing uncoupling protein 1 in brown adipose tissue was activated: by fatty acids released upon lipid droplet breakdown in the brown adipocytes. However, two studies in this issue (Schreiber et al., 2017; Shin et al., 2017) imply that this classical model may not be valid: heat can be produced in brown fat without intracellular lipolysis.
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| 26. |
- Cao, Yihai
(author)
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Angiogenesis and Vascular Functions in Modulation of Obesity, Adipose Metabolism, and Insulin Sensitivity
- 2013
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In: Cell Metabolism. - : CELL PRESS, 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA. - 1550-4131 .- 1932-7420. ; 18:4, s. 478-489
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Research review (peer-reviewed)abstract
- White and brown adipose tissues are hypervascularized and the adipose vasculature displays phenotypic and functional plasticity to coordinate with metabolic demands of adipocytes. Blood vessels not only supply nutrients and oxygen to nourish adipocytes, they also serve as a cellular reservoir to provide adipose precursor and stem cells that control adipose tissue mass and function. Multiple signaling molecules modulate the complex interplay between the vascular system and the adipocytes. Understanding fundamental mechanisms by which angiogenesis and vasculatures modulate adipocyte functions may provide new therapeutic options for treatment of obesity and metabolic disorders by targeting the adipose vasculature.
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| 29. |
- Cedernaes, Jonathan, et al.
(author)
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Transcriptional Basis for Rhythmic Control of Hunger and Metabolism within the AgRP Neuron
- 2019
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In: Cell Metabolism. - : Elsevier BV. - 1550-4131 .- 1932-7420. ; 29:5, s. 1078-1091.e5
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Journal article (peer-reviewed)abstract
- The alignment of fasting and feeding with the sleep/ wake cycle is coordinated by hypothalamic neurons, though the underlying molecular programs remain incompletely understood. Here, we demonstrate that the clock transcription pathway maximizes eating during wakefulness and glucose production during sleep through autonomous circadian regulation of NPY/AgRP neurons. Tandem profiling of whole-cell and ribosome-bound mRNAs in morning and evening under dynamic fasting and fed conditions identified temporal control of activity-dependent gene repertoires in AgRP neurons central to synaptogenesis, bioenergetics, and neurotransmitter and peptidergic signaling. Synaptic and circadian pathways were specific to whole-cell RNA analyses, while bioenergetic pathways were selectively enriched in the ribosome-bound transcriptome. Finally, we demonstrate that the AgRP clock mediates the transcriptional response to leptin. Our results reveal that time-of-day restriction in transcriptional control of energy-sensing neurons underlies the alignment of hunger and food acquisition with the sleep/wake state.
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| 30. |
- Cederroth, CR, et al.
(author)
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Medicine in the Fourth Dimension
- 2019
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In: Cell metabolism. - : Elsevier BV. - 1932-7420 .- 1550-4131. ; 30:2, s. 238-250
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Journal article (peer-reviewed)
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| 31. |
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| 32. |
- Clifford, B. L., et al.
(author)
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FXR activation protects against NAFLD via bile-acid-dependent reductions in lipid absorption
- 2021
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In: Cell Metabolism. - : Elsevier BV. - 1550-4131 .- 1932-7420. ; 33:8
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Journal article (peer-reviewed)abstract
- FXR agonists are used to treat non-alcoholic fatty liver disease (NAFLD), in part because they reduce hepatic lipids. Here, we show that FXR activation with the FXR agonist GSK2324 controls hepatic lipids via reduced absorption and selective decreases in fatty acid synthesis. Using comprehensive lipidomic analyses, we show that FXR activation in mice or humans specifically reduces hepatic levels of mono-and polyunsaturated fatty acids (MUFA and PUFA). Decreases in MUFA are due to FXR-dependent repression of Scd1, Dgat2, and Lpin1 expression, which is independent of SHP and SREBP1c. FXR-dependent decreases in PUFAs are mediated by decreases in lipid absorption. Replenishing bile acids in the diet prevented decreased lipid absorption in GSK2324-treated mice, suggesting that FXR reduces absorption via decreased bile acids. We used tissue-specific FXR KO mice to show that hepatic FXR controls lipogenic genes, whereas intestinal FXR controls lipid absorption. Together, our studies establish two distinct pathways by which FXR regulates hepatic lipids.
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| 33. |
- Correia, Jorge C., et al.
(author)
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Muscle-secreted neurturin couples myofiber oxidative metabolism and slow motor neuron identity
- 2021
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In: Cell Metabolism. - : Elsevier BV. - 1550-4131 .- 1932-7420. ; 33:11, s. 2215-2230
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Journal article (peer-reviewed)abstract
- Endurance exercise promotes skeletal muscle vascularization, oxidative metabolism, fiber-type switching, and neuromuscular junction integrity. Importantly, the metabolic and contractile properties of the muscle fiber must be coupled to the identity of the innervating motor neuron (MN). Here, we show that muscle-derived neurturin (NRTN) acts on muscle fibers and MNs to couple their characteristics. Using a muscle-specific NRTN transgenic mouse (HSA-NRTN) and RNA sequencing of MN somas, we observed that retrograde NRTN signaling promotes a shift toward a slow MN identity. In muscle, NRTN increased capillary density and oxidative capacity and induced a transcriptional reprograming favoring fatty acid metabolism over glycolysis. This combination of effects on muscle and MNs makes HSA-NRTN mice lean with remarkable exercise performance and motor coordination. Interestingly, HSA-NRTN mice largely recapitulate the phenotype of mice with muscle-specific expression of its upstream regulator PGC-1a1. This work identifies NRTN as a myokine that couples muscle oxidative capacity to slow MN identity.
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| 34. |
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| 35. |
- Davies, Brandon S J, et al.
(author)
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GPIHBP1 is responsible for the entry of lipoprotein lipase into capillaries.
- 2010
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In: Cell metabolism. - : Elsevier BV. - 1932-7420 .- 1550-4131. ; 12:1, s. 42-52
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Journal article (peer-reviewed)abstract
- The lipolytic processing of triglyceride-rich lipoproteins by lipoprotein lipase (LPL) is the central event in plasma lipid metabolism, providing lipids for storage in adipose tissue and fuel for vital organs such as the heart. LPL is synthesized and secreted by myocytes and adipocytes, but then finds its way into the lumen of capillaries, where it hydrolyzes lipoprotein triglycerides. The mechanism by which LPL reaches the lumen of capillaries has remained an unresolved problem of plasma lipid metabolism. Here, we show that GPIHBP1 is responsible for the transport of LPL into capillaries. In Gpihbp1-deficient mice, LPL is mislocalized to the interstitial spaces surrounding myocytes and adipocytes. Also, we show that GPIHBP1 is located at the basolateral surface of capillary endothelial cells and actively transports LPL across endothelial cells. Our experiments define the function of GPIHBP1 in triglyceride metabolism and provide a mechanism for the transport of LPL into capillaries.
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| 38. |
- Dong, Mei, et al.
(author)
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Cold Exposure Promotes Atherosclerotic Plaque Growth and Instability via UCP1-Dependent Lipolysis
- 2013
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In: Cell Metabolism. - : Elsevier (Cell Press). - 1550-4131 .- 1932-7420. ; 18:1, s. 118-129
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Journal article (peer-reviewed)abstract
- Molecular mechanisms underlying the cold-associated high cardiovascular risk remain unknown. Here, we show that the cold-triggered food-intake-independent lipolysis significantly increased plasma levels of small low-density lipoprotein (LDL) remnants, leading to accelerated development of atherosclerotic lesions in mice. In two genetic mouse knockout models (apolipoprotein E-/- [ApoE(-/-)] and LDL receptor(-/-) [Ldlr(-/-)] mice), persistent cold exposure stimulated atherosclerotic plaque growth by increasing lipid deposition. Furthermore, marked increase of inflammatory cells and plaque-associated microvessels were detected in the cold-acclimated ApoE(-/-) and Ldlr(-/-) mice, leading to plaque instability. Deletion of uncoupling protein 1 (UCP1), a key mitochondrial protein involved in thermogenesis in brown adipose tissue (BAT), in the ApoE(-/-) strain completely protected mice from the cold-induced atherosclerotic lesions. Cold acclimation markedly reduced plasma levels of adiponectin, and systemic delivery of adiponectin protected ApoE(-/-) mice from plaque development. These findings provide mechanistic insights on low-temperature-associated cardiovascular risks.
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| 39. |
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| 40. |
- Dyachok, Oleg, 1965-, et al.
(author)
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Glucose-induced cyclic AMP oscillations regulate pulsatile insulin secretion
- 2008
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In: Cell Metabolism. - : Cell Press. - 1550-4131 .- 1932-7420. ; 8:1, s. 26-37
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Journal article (peer-reviewed)abstract
- Cyclic AMP (cAMP) and Ca2+ are key regulators of exocytosis in many cells, including insulin-secreting β-cells. Glucose-stimulated insulin secretion from β cells is pulsatile and involves oscillations of the cytoplasmic Ca2+ concentration ([Ca2+]i), but little is known about the detailed kinetics of cAMP signalling. Using evanescent-wave fluorescence imaging we found that glucose induces pronounced oscillations of cAMP in the sub-membrane space of single MIN6-cells and primary mouse β-cells. These oscillations were preceded and enhanced by elevations of [Ca2+]i. However, conditions raising cytoplasmic ATP could trigger cAMP elevations without accompanying [Ca2+]i rise, indicating that adenylyl cyclase activity may be controlled also by the substrate concentration. The cAMP oscillations correlated with pulsatile insulin release. Whereas elevation of cAMP enhanced secretion, inhibition of adenylyl cyclases suppressed both cAMP oscillations and pulsatile insulin release. We conclude that cell metabolism directly controls cAMP, and that glucose-induced cAMP oscillations regulate the magnitude and kinetics of insulin exocytosis.
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| 41. |
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| 42. |
- Edgar, Daniel, et al.
(author)
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Random point mutations with major effects on protein-coding genes are the driving force behind premature aging in mtDNA mutator mice.
- 2009
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In: Cell metabolism. - : Elsevier BV. - 1932-7420 .- 1550-4131. ; 10:2, s. 131-8
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Journal article (peer-reviewed)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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| 43. |
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| 45. |
- Egan, B, et al.
(author)
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SnapShot: Exercise Metabolism
- 2016
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In: Cell metabolism. - : Elsevier BV. - 1932-7420 .- 1550-4131. ; 24:2, s. 342-
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Journal article (peer-reviewed)
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| 46. |
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| 47. |
- Enerbäck, Sven, 1958
(author)
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An enzymatic chromatin switch that directs formation of active brown fat
- 2014
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In: Cell Metabolism. - : Elsevier BV. - 1550-4131 .- 1932-7420. ; 19:1, s. 3-4
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Journal article (peer-reviewed)abstract
- How is the recruitment of brown adipocytes regulated? Ohno et al. (2013) show that the euchromatic histone-lysine N-metyltransferase 1 (EHMT1) is essential for the specification of the brown adipocyte fate, a finding with important implications for the pathophysiology of obesity and obesity-related maladies. © 2014 Elsevier Inc.
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| 48. |
- Enerbäck, Sven, 1958
(author)
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Casein Kinase 2 - A Kinase that Inhibits Brown Fat Formation
- 2015
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In: Cell Metabolism. - : Elsevier BV. - 1550-4131 .- 1932-7420. ; 22:6, s. 958-959
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Journal article (peer-reviewed)abstract
- In adipose tissue, there is a delicate balance between storing and expending energy. In this issue, Shinoda et al. (2015) use phosphoproteomics to identify casein kinase 2 (CK2) as a suppressor of brown adipocyte formation, providing insights into how adipose tissue regulates its composition of white versus brown adipocytes. © 2015 Elsevier Inc.
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| 49. |
- Enerbäck, Sven, 1958
(author)
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Human brown adipose tissue.
- 2010
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In: Cell metabolism. - : Elsevier BV. - 1932-7420 .- 1550-4131. ; 11:4, s. 248-52
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Journal article (peer-reviewed)abstract
- The BAT organ is unique in that it has evolved to safely dissipate large amounts of chemical energy--a quality that might be harnessed to help humans deal with a dangerously hypercaloric environment and still remain in good health.
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| 50. |
- Eriksson, U, et al.
(author)
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Visualizing Fatty Acid Flux
- 2018
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In: Cell metabolism. - : Elsevier BV. - 1932-7420 .- 1550-4131. ; 27:6, s. 1161-1162
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Journal article (peer-reviewed)
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