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  • 601.
    Waldén, Tomas B.
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Hansen, Ida R.
    Timmons, James A.
    Cannon, Barbara
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Nedergaard, Jan
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Molecular signatures of brown, white and brite adipose tissues.Manuscript (preprint) (Other academic)
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  • 602.
    Waldén, Tomas B.
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute.
    Hansen, Ida R.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute.
    Timmons, James A.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute. The Royal Veterinary College, United Kingdom.
    Cannon, Barbara
    Stockholm University, Faculty of Science, The Wenner-Gren Institute. The Royal Veterinary College, United Kingdom.
    Nedergaard, Jan
    Stockholm University, Faculty of Science, The Wenner-Gren Institute.
    Recruited vs. nonrecruited molecular signatures of brown, “brite,” and white adipose tissues2012In: American Journal of Physiology. Endocrinology and Metabolism, ISSN 0193-1849, E-ISSN 1522-1555, Vol. 302, no 1, p. E19-E31Article in journal (Refereed)
    Abstract [en]

    Mainly from cell culture studies, a series of genes have been identified that have been suggested to be characteristic of different types of adipocytes. Here we have examined gene expression patterns in nine defined adipose depots: interscapular BAT, cervical BAT, axillary BAT, mediastinic BAT, cardiac WAT, inguinal WAT, retroperitoneal WAT, mesenteric WAT and epididymal WAT. We found that each depot displayed a distinct gene expression fingerprint, but that three major types of depots were identifiable: the brown, the brite and the white. Although differences in gene expression pattern were generally quantitative, some gene markers showed, even in-vivo, remarkable depot specificities: Zic1 for the classical brown adipose tissue depots, Hoxc9 for the brite depots, Hoxc8 for the brite and white in contrast to the brown, and Tcf21 for the white depots. The significance of these gene expression patterns both for understanding the developmental background of the depots and as possible master regulators is discussed.

  • 603.
    Waldén, Tomas B
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Petrovic, Natasa
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Nedergaard, Jan
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    PPARalpha does not suppress muscle-associated gene expression in brown adipocytes but does influence expression of factors that fingerprint the brown adipocyte.2010In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 397, no 2, p. 146-51Article in journal (Refereed)
    Abstract [en]

    Brown adipocytes and myocytes develop from a common adipomyocyte precursor. PPARalpha is a nuclear receptor important for lipid and glucose metabolism. It has been suggested that in brown adipose tissue, PPARalpha represses the expression of muscle-associated genes, in this way potentially acting to determine cell fate in brown adipocytes. To further understand the possible role of PPARalpha in these processes, we measured expression of muscle-associated genes in brown adipose tissue and brown adipocytes from PPARalpha-ablated mice, including structural genes (Mylpf, Tpm2, Myl3 and MyHC), regulatory genes (myogenin, Myf5 and MyoD) and a myomir (miR-206). However, in our hands, the expression of these genes was not influenced by the presence or absence of PPARalpha, nor by the PPARalpha activator Wy-14,643. Similarly, the expression of genes common for mature brown adipocyte and myocytes (Tbx15, Meox2) were not affected. However, the brown adipocyte-specific regulatory genes Zic1, Lhx8 and Prdm16 were affected by PPARalpha. Thus, it would not seem that PPARalpha represses muscle-associated genes, but PPARalpha may still play a role in the regulation of the bifurcation of the adipomyocyte precursor into a brown adipocyte or myocyte phenotype.

  • 604.
    Wang, Shenqiu
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Grainy head target genes in epithelial morphogenesis and wound healing2010Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    grainy head (grh) genes encode a family of transcription factors conserved from fly to human. Drosophila grh is the founding member of this gene family and has multiple functions, including tracheal tube size control, epidermal barrier formation and reconstruction after wounding. To understand the underlying molecular mechanism of grh functions, we tried to isolate its direct targets and analyze their function. We identified ten grh targets by combining bioinformatics and genetics. Grh directly controls the expression of stitcher (stit), which encodes a Ret family receptor tyrosine kinase (RTK), during both development and wound healing. Stit promotes actin cable assembly and induces extracellular signal-regulated kinase (ERK) phosphorylation around the wound edges upon injury. Stit also activates barrier repair genes and its own expression at the wound sites in a Grh-dependent manner. This positive feedback loop ensures efficient epidermal wound repair. In addition, Grh regulates the expression of multiple genes involved in chitin biosynthesis or modification. Most of the genes are required for tracheal tube size control. Two of them, verm and serp, encode related putative luminal chitin deacetylases. The functional analysis of verm and serp identifies an important role of luminal chitin matrix modification in limiting tracheal tube elongation. Therefore, it is very likely that Grh controls tracheal tube size through regulating multiple targets involved in the assembly or modification of luminal chitin matrix. Grh also directly activates the epidermal expression of Peptidoglycan recognition protein LC (PGRP-LC) gene that is required for the induction of antimicrobial peptides (AMPs) upon infection. Furthermore, ectopically expressing Grh is sufficient to induce AMP Cecropin A lacZ reporter (CecA-LacZ) in the embryonic epidermis. These results suggest a new function of Grh in the local immune responses in Drosophila barrier epithelia.

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  • 605.
    Wang, Shenqiu
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Dai, Qi
    Lai, Eric C
    Samakovlis, Christos
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Grainy head regulates genes involved in cuticle maturation and immune response in Drosophila.Manuscript (preprint) (Other academic)
  • 606.
    Wang, Shenqiu
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Jayaram, Arcot Jayaram
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Hemphälä, Johanna
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Senti, Kirsten-André
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Tsarouhas, Vasilis
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Jin, Haining
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Samakovlis, Christos
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Septate-Junction-Dependent Luminal Deposition  of Chitin Deacetylases Restricts  Tube Elongation in the Drosophila Trachea2006In: Current Biology, ISSN 0960-9822, E-ISSN 1879-0445, Vol. 16, no 2, p. 180-185Article in journal (Refereed)
    Abstract [en]

    The function of tubular epithelial organs like the kidney and lung is critically dependent on the length and diameter of their constituting branches. Genetic analysis of tube size control during Drosophila tracheal development has revealed that epithelial septate junction (SJ) components and the dynamic chitinous luminal matrix coordinate tube growth. However, the underlying molecular mechanisms controlling tube expansion so far remained elusive. Here, we present the analysis of two luminal chitin binding proteins with predicted polysaccharide deacetylase activities (ChLDs). ChLDs are required to assemble the cable-like extracellular matrix (ECM) and restrict tracheal tube elongation. Overexpression of native, but not of mutated, ChLD versions also interferes with the structural integrity of the intraluminal ECM and causes aberrant tube elongation. Whereas ChLD mutants have normal SJ structure and function, the luminal deposition of the ChLD requires intact cellular SJs. This identifies a new molecular function for SJs in the apical secretion of ChLD and positions ChLD downstream of the SJs in tube length control. The deposition of the chitin luminal matrix first promotes and coordinates radial tube expansion. We propose that the subsequent structural modification of chitin by chitin binding deacetylases selectively instructs the termination of tube elongation to the underlying epithelium.

  • 607.
    Wang, Shenqiu
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute.
    Samakovlis, Christos
    Stockholm University, Faculty of Science, The Wenner-Gren Institute.
    Grainy head and its target genes in epithelial morphogenesis and wound healing2012In: Transcriptional switches during development / [ed] Plaza S., Payre F., San Diego, CA: Elsevier Academic Press , 2012, p. 35-63Chapter in book (Refereed)
    Abstract [en]

    The Grainy head (Grh) family of transcription factors is characterized by a unique DNA-binding domain that binds to a conserved consensus sequence. Nematodes and flies have a single grh gene, whereas mice and humans have evolved three genes encoding Grainy head-like (Grhl) factors. We review the biological function of Grh in different animals and the mechanisms modulating its activity. grh and grhl genes play a remarkably conserved role in epithelial organ development and extracellular barrier repair after tissue damage. Recent studies in flies and vertebrates suggest that Grh factors may be primary determinants of cell adhesion and epithelial tissue formation. Grh proteins can dimerize and act as activators or repressors in different developmental contexts. In flies, tissue-specific, alternative splicing generates different Grh isoforms with different DNA-binding specificities and functions. Grh activity is also modulated by receptor tyrosine kinases: it is phosphorylated by extracellular signal regulated kinase, and this phosphorylation is selectively required for epidermal barrier repair. Two mechanisms have been proposed to explain the repressive function of Grh on target gene transcription. First, Grh can target the Polycomb silencing complex to specific response elements. Second, it can directly compete for DNA binding with transcriptional activators. Understanding the molecular mechanisms of gene regulation by Grh factors is likely to elucidate phylogenetically conserved mechanisms of epithelial cell morphogenesis and regeneration upon tissue damage.

  • 608.
    Wang, Shenqiu
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Tsarouhas, Vasilis
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Xylourgidis, Nikos
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Sabri, Nafiseh
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Tiklová, Katarína
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Nautiyal, Naumi
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Gallio, Marco
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Samakovlis, Christos
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    The tyrosine kinase Stitcher activates Grainy head and epidermal woundhealing in Drosophila.2009In: Nature Cell Biology, ISSN 1465-7392, E-ISSN 1476-4679, Vol. 11, no 7, p. 890-895Article in journal (Refereed)
    Abstract [en]

    Epidermal injury initiates a cascade of inflammation, epithelial remodelling and integument repair at wound sites. The regeneration of the extracellular barrier and damaged tissue repair rely on the precise orchestration of epithelial responses triggered by the injury1, 2. Grainy head (Grh) transcription factors induce gene expression to crosslink the extracellular barrier in wounded flies and mice3, 4. However, the activation mechanisms and functions of Grh factors in re-epithelialization remain unknown. Here we identify stitcher (stit), a new Grh target in Drosophila melanogaster. stit encodes a Ret-family receptor tyrosine kinase required for efficient epidermal wound healing. Live imaging analysis reveals that Stit promotes actin cable assembly during wound re-epithelialization. Stit activation also induces extracellular signal-regulated kinase (ERK) phosphorylation along with the Grh-dependent expression of stit and barrier repair genes at the wound sites. The transcriptional stimulation of stit on injury triggers a positive feedback loop increasing the magnitude of epithelial responses. Thus, Stit activation upon wounding coordinates cytoskeletal rearrangements and the level of Grh-mediated transcriptional wound responses.

  • 609.
    Waters, Sean
    Stockholm University, Faculty of Science, The Wenner-Gren Institute.
    Chromatin structure in liver nuclei of Atlantic salmon after activation of the vitellogenin gene by 17-β estradiol1992Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The present investigations were initiated to study changes in hepatic nucleiduring the 17-ß estradiol induced synthesis of vitellogenin in Atlantic salmon(Salmo salar). As a model system for the naturally maturing fish parr andsmoltified salmon were used and treated with the steroid hormone. Incubation ofliver nuclei with endonucleases made possible a separation of the chromatin intocondensed and dispersed structures. Information on the composition anddistribution of proteins was obtained after fractionation of the chromatin. Theorganization of the hepatic chromatin was altered after treatment of the fishwith 17-ß estradiol. The changes observed depended on the developmental stageof the fish. In parr larger portions of chromatin condensated than in smoltifiedsalmon. In both groups decondensation of the vitellogenin gene regions increasedupon hormone treatment, rendering the gene susceptible to attack by nucleases.The smoltified fish responded more readily than the parr.

    A protein with an apparent molecular weight of 21 kDa increased inconcentration by the hormone treatment. The protein was enriched in thedispersed chromatin and bound to nucleosomes. It was purified and the aminoacid composition and N-terminal sequence was established. The protein wasclassified as a member of the non-histone high mobility group proteins, involvedin the structure of transcriptionally active chromatin.

    The condensation of the chromatin was related to an increase in polyamineconcentration. The polyamines bound preferentially to condensed chromatinsupporting the view of a stabilizing effect of the polyamines on the structuralorganization of inactive chromatin.

    It was concluded that the 17-ß estradiol mediated alterations on hepaticchromatin structure involved a great number of factors among which proteinsand polyamines were predominant in function.

  • 610. Westerberg, Rolf
    et al.
    Tvrdik, Petr
    Undén, A-B
    Månsson, Jan-Erik
    Norlén, Lars
    Jakobsson, Andreas
    Stockholm University, Faculty of Science, Wenner-Gren Institute for Experimental Biology.
    Holleran, Walt
    Elias, Peter M
    Asadi, Abolfasl
    Flodby, Per
    Toftgård, Rune
    Capecchi, Mario
    Jacobsson, Anders
    Role for ELOVL3 and fatty acid chain length in development of hair and skin function2004In: Journal of Biological Chemistry, ISSN 0021-9258, Vol. 279, no 7, p. 5621-5629Article in journal (Refereed)
  • 611. Whittle, Andrew J.
    et al.
    Carobbio, Stefania
    Martins, Luis
    Slawik, Marc
    Hondares, Elayne
    Jesus Vazquez, Maria
    Morgan, Donald
    Csikasz, Robert I.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Physiology.
    Gallego, Rosalia
    Rodriguez-Cuenca, Sergio
    Dale, Martin
    Virtue, Samuel
    Villarroya, Francesc
    Cannon, Barbara
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Physiology.
    Rahmouni, Kamal
    Lopez, Miguel
    Vidal-Puig, Antonio
    BMP8B Increases Brown Adipose Tissue Thermogenesis through Both Central and Peripheral Actions2012In: Cell, ISSN 0092-8674, E-ISSN 1097-4172, Vol. 149, no 4, p. 871-885Article in journal (Refereed)
    Abstract [en]

    Thermogenesis in brown adipose tissue (BAT) is fundamental to energy balance and is also relevant for humans. Bone morphogenetic proteins (BMPs) regulate adipogenesis, and, here, we describe a role for BMP8B in the direct regulation of thermogenesis. BMP8B is induced by nutritional and thermogenic factors in mature BAT, increasing the response to noradrenaline through enhanced p38MAPK/CREB signaling and increased lipase activity. Bmp8b(-/-) mice exhibit impaired thermogenesis and reduced metabolic rate, causing weight gain despite hypophagia. BMP8B is also expressed in the hypothalamus, and Bmp8b(-/-) mice display altered neuropeptide levels and reduced phosphorylation of AMP-activated protein kinase (AMPK), indicating an anorexigenic state. Central BMP8B treatment increased sympathetic activation of BAT, dependent on the status of AMPK in key hypothalamic nuclei. Our results indicate that BMP8B is a thermogenic protein that regulates energy balance in partnership with hypothalamic AMPK. BMP8B may offer a mechanism to specifically increase energy dissipation by BAT.

  • 612.
    Wikstrom, Jakob D
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Brown adipocyte activation is characterized by a wave of mitochondrial fission and depolarization that is dependent on β3 receptor stimulation and Drp1, and is characterized by complete, but reversible, arrest of fusionManuscript (preprint) (Other academic)
    Abstract [en]

    Background and aims:

    Mitochondria are dynamic organelles that frequently undergo fusion and fission. Mitochondrial dynamics has been shown to be essential for a variety of cellular functions and its abrogation has been associated with several diseases. However, the role fusion, fission and architecture play in mitochondrial bioenergetics is still not well understood. Brown adipose tissue (BAT) is a mitochondria dense organ that converts cellular fuels into heat by mitochondrial uncoupling. When activated adrenergically, BAT shows a unique increase in mitochondrial respiratory activity. Therefore, BAT may be a good model to study the interdependence between mitochondrial morphology, dynamics and function. To date, mitochondrial dynamics was not studied in BAT. In this study we set out to examine mitochondrial morphology in BAT and test the hypothesis that mitochondrial morphology is of importance for BAT function.

    Materials and methods:

    BAT was harvested from 3 to 4-week-old wild-type male C57BL6/J mice and from 5-8 day old pups (Mitofusin2 knockout). Brown adipocytes were differentiated in vitro. A LSM 710 laser scanning confocal microscopy (Zeiss) was used for imaging of mitochondrial morphology using several fluorescent dyes and proteins. Oxygen consumption was measured using the XF24 platform (Seahorse Bioscience). The pro fusion protein Mfn2 was knocked out under the AP2 promoter and the pro fission protein Drp1 was inhibited with adenoviral expression of its dominant negative form.

    Results:

    Mitochondria were found to be highly networked and dependent on mitochondrial dynamics proteins. When stimulating cells with a combination of norepinephrine and free fatty acids we found a synergistic response that included a marked increase in oxygen consumption rates and mitochondrial membrane potential (Δψm) depolarization. Somewhat unexpectedly it was also found that mitochondria in parallel underwent a distinct fragmentation. The fragmented mitochondria appeared sphere-like and had dampened fusion; however cells regained normal function as well as mitochondrial morphology and Δψm within 24h.  Interestingly, Δψm depolarized and mitochondria fragmented in a wave-like fashion where depolarization preceded fragmentation. Inhibition of the pro-fission protein Drp1 was found to inhibit the synergistic response, while knock-out of the pro-fusion protein Mfn2 did not. Thus, mitochondrial fission appeared essential for proper BAT function. Finally, we found the synergistic response to go through the β-adrenergic pathway and be dependent on reactive oxygen species but not on Ca++, permeability transition pore or uncoupling protein 1 expression levels.

    Conclusion:

    Taken together, these findings suggest that mitochondrial morphology in general and mitochondrial fission in particular may play an important physiological role in BA. Future studies will reveal if this may represent a therapeutic target for manipulating BAT activity.

  • 613.
    Wikstrom, Jakob D
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Islet bioenergetic efficiency is regulated by nutrientsManuscript (preprint) (Other academic)
    Abstract [en]

    Background and aims

    Excessive or unbalanced nutrient intake may cause diabetes. A growing body of evidence points to that mitochondrial dysfunction plays an important role in

    Materials and methods

    To enable the study we developed a high-throughput islet respirometry approach based on the XF24 platform, originally designed to study monolayers of cells. By applying drugs that act on the respiratory chain we can estimate the level of fuel-stimulated, uncoupled (reflecting proton leak), maximal as well as non-mitochondrial respiration under various conditions. Islets were derived from wildtype and high fat diet fed C57Bl6/J mice as well as from human donors.

    β-cell dysfunction. The reason for this is likely that mitochondria stand in the center of nutrient metabolism. In this study we tested the hypothesis that islets from diabetic animals have defect mitochondrial respiratory function. Results

    We found that due to increased proton leak, islets from diabetic high fat diet fed animals exhibit lower respiratory efficiency as compared to animals fed control chow. Examining the regulation of the leak we found that fuels that stimulate insulin secretion also increase uncoupled respiration, and that this may be mediated by reactive oxygen species. Moreover, dissecting the molecular mechanism, we show that the adenine nucleotide transporter contributes to one-third of the leak while uncoupling protein 2 and permeability transition pore appear not to contribute. Finally, we examined a cohort of human islets and found lower levels of uncoupled respiration as compared to mouse islets. However, as in the mouse islets glucose challenge induced increase in uncoupled respiration. Interestingly, there was a trend towards lower oxygen consumption rates in islets from obese donors.

    Conclusion:

    Islets have relative high levels of proton leak, which is regulated by cellular fuels and reactive oxygen species. Adenine nucleotide transporter but not uncoupling protein 2 or permeability transition pore appears to contribute to the observed uncoupled respiration. Interestingly, levels of uncoupled respiration increase in a diabetes animal model. In theory, tuning islet mitochondrial efficiency may represent a therapeutic target.

  • 614.
    Wikstrom, Jakob D
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Mitochondrial networking protects beta cells from nutrient -induced apoptosis2009In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 58, p. 2303-2315Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: Previous studies have reported that beta-cell mitochondria exist as discrete organelles that exhibit heterogeneous bioenergetic capacity. To date, networking activity, and its role in mediating beta-cell mitochondrial morphology and function, remains unclear. In this article, we investigate beta-cell mitochondrial fusion and fission in detail and report alterations in response to various combinations of nutrients. RESEARCH DESIGN AND METHODS: Using matrix-targeted photoactivatable green fluorescent protein, mitochondria were tagged and tracked in beta-cells within intact islets, as isolated cells and as cell lines, revealing frequent fusion and fission events. Manipulations of key mitochondrial dynamics proteins OPA1, DRP1, and Fis1 were tested for their role in beta-cell mitochondrial morphology. The combined effects of free fatty acid and glucose on beta-cell survival, function, and mitochondrial morphology were explored with relation to alterations in fusion and fission capacity. RESULTS: beta-Cell mitochondria are constantly involved in fusion and fission activity that underlies the overall morphology of the organelle. We find that networking activity among mitochondria is capable of distributing a localized green fluorescent protein signal throughout an isolated beta-cell, a beta-cell within an islet, and an INS1 cell. Under noxious conditions, we find that beta-cell mitochondria become fragmented and lose their ability to undergo fusion. Interestingly, manipulations that shift the dynamic balance to favor fusion are able to prevent mitochondrial fragmentation, maintain mitochondrial dynamics, and prevent apoptosis. CONCLUSIONS: These data suggest that alterations in mitochondrial fusion and fission play a critical role in nutrient-induced beta-cell apoptosis and may be involved in the pathophysiology of type 2 diabetes.

  • 615.
    Wikstrom, Jakob D
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    β-Cell Mitochondria Exhibit Membrane Potential Heterogeneity That Can Be Altered by Stimulatory or Toxic Fuel Levels2007In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 56, p. 2569-2578Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: beta-Cell response to glucose is characterized by mitochondrial membrane potential (Delta Psi) hyperpolarization and the production of metabolites that serve as insulin secretory signals. We have previously shown that glucose-induced mitochondrial hyperpolarization accompanies the concentration-dependent increase in insulin secretion within a wide range of glucose concentrations. This observation represents the integrated response of a large number of mitochondria within each individual cell. However, it is currently unclear whether all mitochondria within a single beta-cell represent a metabolically homogenous population and whether fuel or other stimuli can recruit or silence sizable subpopulations of mitochondria. This study offers insight into the different metabolic states of beta-cell mitochondria. RESULTS: We show that mitochondria display a wide heterogeneity in Delta Psi and a millivolt range that is considerably larger than the change in millivolts induced by fuel challenge. Increasing glucose concentration recruits mitochondria into higher levels of homogeneity, while an in vitro diabetes model results in increased Delta Psi heterogeneity. Exploration of the mechanism behind heterogeneity revealed that temporary changes in Delta Psi of individual mitochondria, ATP-hydrolyzing mitochondria, and uncoupling protein 2 are not significant contributors to Delta Psi heterogeneity. We identified BAD, a proapoptotic BCL-2 family member previously implicated in mitochondrial recruitment of glucokinase, as a significant factor influencing the level of heterogeneity. CONCLUSIONS: We suggest that mitochondrial Delta Psi heterogeneity in beta-cells reflects a metabolic reservoir recruited by an increased level of fuels and therefore may serve as a therapeutic target.

  • 616.
    Wikström, Jakob D
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Mitochondrial form and function in pancreatic β-cells and brown adipocytes2010Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    This thesis is focused on the role of mitochondria in pancreatic β-cells and brown adipose tissue (BAT). Two main aspects of mitochondria were explored; mitochondrial functional efficiency and the interrelationship between mitochondrial shape and function.

    Mitochondria in β-cells were found to exhibit heterogeneity in mitochondrial membrane potential. This functional diversity decreased when cells were challenged with glucose stimuli, suggesting that at higher fuel levels low-activity mitochondria are recruited into a pool of high-activity mitochondria. Glucolipotoxic conditions increased the functional diversity suggesting that this may be of importance for diabetes pathophysiology.

    To examine mitochondrial efficiency in intact islets a high throughput islet respirometry method was developed. Due to increased uncoupling, islets from a diabetic animal model exhibit lower respiratory efficiency. Glucose, free fatty acids and amino acids all decreased respiratory efficiency. A large portion of the respiratory efficiency was mediated by reactive oxygen species and the adenine nucleotide translocase.

    In β-cells mitochondria were found to undergo cycles of fusion and fission. During glucolipotoxicity mitochondria fragmented and lost their fusion ability. Knock down of the fission protein Fis1 rescued the β-cells from glucolipotoxic induced cell death. BAT mitochondria also showed fusion and fission. The mitochondrial dynamics proteins Mfn2 and Drp1 were shown to strongly affect BAT mitochondrial morphology. In response to a combination of adrenergic and free fatty acid stimuli mitochondria drastically changed from long filamentous structures to fragmented spheres. Inhibiting fission by the negative form of Drp1 decreased BAT response to adrenergic stimuli by half.

    In conclusion, mitochondrial efficiency may be of importance for normal as well as compromised β-cell and islet function. Mitochondrial morphology appears critical for mitochondrial function in β-cells and BAT.

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  • 617.
    Wikström, Jakob D.
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute.
    Sereda, Samuel B.
    Stiles, Linsey
    Elorza, Alvaro
    Allister, Emma M.
    Neilson, Andy
    Ferrick, David A.
    Wheeler, Michael B.
    Shirihai, Orian S.
    A novel high throughput assay for islet respiration reveals uncoupling of rodent and human islets2012In: PLOS ONE, E-ISSN 1932-6203, Vol. 7, no 5, p. e33023-Article in journal (Refereed)
    Abstract [en]

    Background: The pancreatic beta cell is unique in its response to nutrient by increased fuel oxidation. Recent studies have demonstrated that oxygen consumption rate (OCR) may be a valuable predictor of islet quality and long term nutrient responsiveness. To date, high-throughput and user-friendly assays for islet respiration are lacking. The aim of this study was to develop such an assay and to examine bioenergetic efficiency of rodent and human islets. Methodology/Principal Findings: The XF24 respirometer platform was adapted to islets by the development of a 24-well plate specifically designed to confine islets. The islet plate generated data with low inter-well variability and enabled stable measurement of oxygen consumption for hours. The F1F0 ATP synthase blocker oligomycin was used to assess uncoupling while rotenone together with myxothiazol/antimycin was used to measure the level of non-mitochondrial respiration. The use of oligomycin in islets was validated by reversing its effect in the presence of the uncoupler FCCP. Respiratory leak averaged to 59% and 49% of basal OCR in islets from C57Bl6/J and FVB/N mice, respectively. In comparison, respiratory leak of INS-1 cells and C2C12 myotubes was measured to 38% and 23% respectively. Islets from a cohort of human donors showed a respiratory leak of 38%, significantly lower than mouse islets. Conclusions/Significance: The assay for islet respiration presented here provides a novel tool that can be used to study islet mitochondrial function in a relatively high-throughput manner. The data obtained in this study shows that rodent islets are less bioenergetically efficient than human islets as well as INS1 cells.

  • 618.
    Wikstöm, Jakob
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Twig, Gilad
    Shirihai, Orian S.
    What can mitochondrial heterogeneity tell us about mitochondrial dynamics and autophagy?2009In: International Journal of Biochemistry and Cell Biology, ISSN 1357-2725, E-ISSN 1878-5875, Vol. 41, no 10, p. 1914-1927Article, review/survey (Refereed)
    Abstract [en]

    A growing body of evidence shows that mitochondria are heterogeneous in terms of structure and function. Increased heterogeneity has been demonstrated in a number of disease models including ischemia-reperfusion and nutrient-induced beta cell dysfunction and diabetes. Subcellular location and proximity to other organelles, as well as uneven distribution of respiratory components have been considered as the main contributors to the basal level of heterogeneity. Recent studies point to mitochondrial dynamics and autophagy as major regulators of mitochondrial heterogeneity. While mitochondrial fusion mixes the content of the mitochondrial network, fission dissects the mitochondrial network and generates depolarized segments. These depolarized mitochondria are segregated from the networking population, forming a pre-autophagic pool contributing to heterogeneity. The capacity of a network to yield a depolarized daughter mitochondrion by a fission event is fundamental to the generation of heterogeneity. Several studies and data presented here provide a potential explanation, suggesting that protein and membranous structures are unevenly distributed within the individual mitochondrion and that inner membrane components do not mix during a fusion event to the same extent as the matrix components do. In conclusion, mitochondrial subcellular heterogeneity is a reflection of the mitochondrial lifecycle that involves frequent fusion events in which components maybe unevenly mixed and followed by fission events generating disparate daughter mitochondria, some of which may fuse again, others will remain solitary and join a pre-autophagic pool. 

  • 619. Xiang, Zou
    et al.
    Cutler, Antony J
    Brownlie, Rebecca J
    Fairfax, Kirsten
    Lawlor, Kate E
    Severinson, Eva
    Stockholm University, Faculty of Science, Wenner-Gren Institute for Experimental Biology.
    Walker, Elizabeth U
    Manz, Rudolf A
    Tarlinton, David M
    Smith, Kenneth G C
    FcgammaRIIb controls bone marrow plasma cell persistence and apoptosis.2007In: Nat Immunol, ISSN 1529-2908, Vol. 8, no 4, p. 419-29Article in journal (Refereed)
  • 620. Xu, Lili
    et al.
    Pei, Xinhong
    Berzins, Klavs
    Stockholm University, Faculty of Science, Wenner-Gren Institute for Experimental Biology.
    Chaudhuri, Asok
    Plasmodium yoelii: experimental evidences for the conserved epitopes between mouse and human malaria parasite, Plasmodium falciparum.2007In: Exp Parasitol, ISSN 0014-4894, Vol. 116, no 3, p. 214-24Article in journal (Refereed)
  • 621.
    Xu, Lili
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute, Immunology.
    Zheng, Xiaoying
    Berzins, Klavs
    Stockholm University, Faculty of Science, The Wenner-Gren Institute, Immunology.
    Chaudhuri, Asok
    Cytokine dysregulation associated with malarial anemia in Plasmodium yoelii infected mice2013In: American Journal of Translational Research, E-ISSN 1943-8141, Vol. 5, no 2, p. 235-245Article in journal (Refereed)
    Abstract [en]

    The mechanisms of malaria anemia remain incompletely understood although much effort has been put on studies in both human and murine systems. Hematopoiesis is regulated by the proliferation, differentiation and maturation of erythropoietic progenitor cells into erythrocytes and is tightly controlled by a complex communication network of cytokines as signal mediators. The present study used the murine P. yoelii 17XNL malaria model to investigate the profile of cytokines and leukocytes throughout the entire infection. Moreover, malaria induced anemia was studied in comparison with anemia induced by hemorrhage and hemolysis. During the P. yoelii infection, the levels of erythropoietic-related cytokines, such as G-CSF, GMCSF, IL-7, and IL-17, were pronouncedly reduced, while those of regulatory cytokines, such as IL-10 and TNF-alpha, were constantly increased. This cytokine profile corresponded well with the cellular composition during the infection, such as drastically decreased levels of CD4(+) and CD8(+) T cells. The profiles of erythropoiesis or hematopoiesis related cytokines during malarial anemia showed striking differences from those during anemia induced by hemorrhage or hemolysis. This study demonstrates that a markedly dysregulated cytokine network occurred in this murine malaria model, which may open a new window of insight into the mechanisms of malaria related anemia.

  • 622. Xue, Yuan
    et al.
    Petrovic, Natasa
    Stockholm University, Faculty of Science, The Wenner-Gren Institute, Physiology.
    Cao, Renhai
    Larsson, Ola
    Lim, Sharon
    Chen, Shaohua
    Feldmann, Helena M.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute, Physiology.
    Liang, Zicai
    Zhu, Zhenping
    Nedergaard, Jan
    Stockholm University, Faculty of Science, The Wenner-Gren Institute, Physiology.
    Cannon, Barbara
    Stockholm University, Faculty of Science, The Wenner-Gren Institute, Physiology.
    Cao, Yihai
    Hypoxia-independent angiogenesis in adipose tissues during cold acclimation.2009In: Cell Metabolism, ISSN 1550-4131, E-ISSN 1932-7420, Vol. 9, no 1, p. 99-109Article in journal (Refereed)
    Abstract [en]

    The molecular mechanisms of angiogenesis in relation to adipose tissue metabolism remain poorly understood. Here, we show that exposure of mice to cold led to activation of angiogenesis in both white and brown adipose tissues. In the inguinal depot, cold exposure resulted in elevated expression levels of brown-fat-associated proteins, including uncoupling protein-1 (UCP1) and PGC-1alpha. Proangiogenic factors such as VEGF were upregulated, and endogenous angiogenesis inhibitors, including thrombospondin, were downregulated. In wild-type mice, the adipose tissues became hypoxic during cold exposure; in UCP1(-/-) mice, hypoxia did not occur, but, remarkably, the augmented angiogenesis was unaltered and was thus hypoxia independent. Intriguingly, VEGFR2 blockage abolished the cold-induced angiogenesis and significantly impaired nonshivering thermogenesis capacity. Unexpectedly, VEGFR1 blockage resulted in the opposite effects: increased adipose vascularity and nonshivering thermogenesis capacity. Our findings have conceptual implications concerning application of angiogenesis modulators for treatment of obesity and metabolic disorders.

  • 623.
    Xylourgidis, Nikos
    Stockholm University, Faculty of Science, Wenner-Gren Institute for Experimental Biology.
    Functional study of Nucleoporins Nup88 and Nup214 during Drosophila Development2005Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    More than a million macromolecules per minute pass through the nuclear envelope of a eukaryotic cell. An important challenge is to understand how the NPC coordinate efficiently the bi-directional trafficking necessary for the basal cellular activities and the rapid translocation of regulatory proteins in response to signaling. In higher eukaryotes each NPC contains approximately 30 different proteins. Some of these have been mapped to distinct parts of the NPC and shown to interact with transport receptors. However, it is not clear whether the different nucleoporins may directly participate in distinct nuclear transport events leading to regulatory changes of gene expression, or if they all may be involved in providing an elaborate but passive channel for general nuclear entry.

    The work presented in this thesis begins with the characterization of Drosophila nucleoporin Nup88, which together with the nucleoporin Nup214 forms a complex in the cytoplasmic filaments of the NPC. Unlike Nup214, Nup88 has a cell specific expression suggesting that different cells types have selective requirement of Nup88s intrinsic function during animal development. Nup88 and Nup214 are selectively required for REL protein translocation upon signaling. In nup88 mutants the upstream signaling cascade leading to the degradation of IkB homolog Cactus is functional however, Dorsal and Dif remain cytoplasmic in both mutants rendering inactive their immune response.

    We showed that both nucleoporins Nup88 and Nup214 are interdependent for their localization at the nuclear envelope. In the absence of Nup214, Nup88 becomes degraded and Nup88 is necessary for localizing Nup214 to the NPC. The complex is required for tethering CRM1 on the nuclear envelope and its major function is to attenuate nuclear export. Immunoprecipitations from embryonic extract suggest that the affinity of the complex for CRM1 could be modulated during embryo development. Reduction of the gene dosage on either Nup88 or Nup214 allow the progression of CRM1 mutants through several developmental stages suggesting that the barrier for protein export provided by anchoring a pool of CRM1 to the Nup88/214 complex has important functions in Drosophila development.

    Finally, detailed analysis of Nup88, Nup214 and CRM1 mutants reveals that the REL protein translocation and the activation of the innate immune responses are dependent on the inhibitory action of the Nup88/Nup214 complex on CRM1 export.

    Our results suggest a new mechanism of regulation through NPC, where dynamic interplay between nucleoporin complexes can accommodate transport of signaling effectors in response to physiological responses.

  • 624.
    Xylourgidis, Nikos
    et al.
    Stockholm University, Faculty of Science, Wenner-Gren Institute for Experimental Biology.
    Roth, Peggy
    Sabri, Nafiseh
    Tsarouhas, Vasilios
    Samakovlis, Christos
    Functional interplay between Drosophila nucleoporins Nup214 and Nup88 regulates the localization and activity of CRM1 and REL proteins Dorsal and DifManuscript (Other academic)
  • 625. Xylourgidis, Nikos
    et al.
    Roth, Peggy
    Stockholm University, Faculty of Science, Wenner-Gren Institute for Experimental Biology.
    Sabri, Nafiseh
    Tsarouhas, Vasilios
    Samakovlis, Christos
    Interplay of Nup214 and Nup88 sequesters CRM1 at the nuclear rim and modulates NF-κB activation in Drosophila.Manuscript (Other academic)
  • 626.
    Xylourgidis, Nikos
    et al.
    Stockholm University, Faculty of Science, Wenner-Gren Institute for Experimental Biology.
    Samakovlis, Christos
    The Drosophila Nup214 regulates NXF1 mediated mRNA exportManuscript (Other academic)
  • 627.
    Yamamoto, Daniel L.
    Stockholm University, Faculty of Science, Wenner-Gren Institute for Experimental Biology.
    Adrenergic signaling in insulin-sensitive tissues2007Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Glucose metabolism in insulin-sensitive tissues such as skeletal muscle and adipose tissue is tightly regulated by external stimuli. Metabolic changes in these tissues have direct effects on whole body metabolism. Such metabolic changes can be induced or influenced by adrenergic stimulation.

    In L6 skeletal muscle cells, we have seen that the β2-adrenergic receptor increases glycogen synthesis to the same extent as insulin. The β2-adrenergically mediated effect is independent of cyclic AMP but dependent on PI3K.

    In brown adipocytes, our data suggest that signaling from the β-adrenergic receptors consists of an acute cyclic AMP effect that is rapidly desensitized and then a prolonged signal involving PI3K.

    In skeletal muscle cells in culture, we have shown that DPI (a NADPH oxidase inhibitor) increases glucose uptake through a signaling pathway independent of NADPH oxidase and insulin signaling. DPI instead inhibits complex 1 in the mitochondrial respiratory chain, which lowers ATP levels. This activates AMPK, an activator of glucose uptake.

    Furthermore, we have developed a model system for ordered fusion of skeletal muscle cells in culture. In this system, differentiating skeletal muscle cells can be studied separately. This system is optimal for microscopy techniques and easily adaptable for micromanipulations. We have seen that the myogenic factor MyoD can have different expression of the protein in different nuclei within the same myotube. This system could be used with advantage for intracellular signaling and metabolic studies.

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    FULLTEXT01
  • 628.
    Yamamoto, Daniel L.
    et al.
    Stockholm University, Faculty of Science, Wenner-Gren Institute for Experimental Biology.
    Chernogubova, Ekaterina
    Hutchinson, Dana S.
    Nevzorova, Julia
    Bengtsson, Tore
    β-adrenergic receptor cAMP and PI3K signaling in primary cultures of brown adipocytes.Manuscript (Other academic)
  • 629.
    Yamamoto, Daniel L.
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Csikasz, Robert I.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Li, Yu
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Sharma, Gunjana
    Hjort, Klas
    Karlsson, Roger
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Bengtsson, Tore
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Myotube Formation on Micro-patterned Glass: Intracellular organization and protein distribution in C2C12 skeletal muscle cells2008In: Journal of Histochemistry and Cytochemistry, ISSN 0022-1554, E-ISSN 1551-5044, Vol. 56, no 10, p. 881-892Article in journal (Refereed)
    Abstract [en]

    Proliferation and fusion of myoblasts are needed for the generation and repair of multinucleated skeletal muscle fibers in vivo. Studies of myocyte differentiation, cell fusion, and muscle repair are limited by an appropriate in vitro muscle cell culture system. We developed a novel cell culture technique [two-dimensional muscle syncytia (2DMS) technique] that results in formation of myotubes, organized in parallel much like the arrangement in muscle tissue. This technique is based on UV lithography-produced micro-patterned glass on which conventionally cultured C2C12 myoblasts proliferate, align, and fuse to neatly arranged contractile myotubes in parallel arrays. Combining this technique with fluorescent microscopy, we observed alignment of actin filament bundles and a peri-nuclear distribution of glucose transporter 4 after myotube formation. Newly formed myotubes contained adjacently located MyoD-positive and MyoD-negative nuclei, suggesting fusion of MyoD-positive and MyoD-negative cells. In comparison, the closely related myogenic factor Myf5 did not exhibit this pattern of distribution. Furthermore, cytoplasmic patches of MyoD colocalized with bundles of filamentous actin near myotube nuclei. At later stages of differentiation, all nuclei in the myotubes were MyoD negative. The 2DMS system is thus a useful tool for studies on muscle alignment, differentiation, fusion, and subcellular protein localization.

  • 630.
    Yamamoto, Daniel L.
    et al.
    Stockholm University, Faculty of Science, Wenner-Gren Institute for Experimental Biology.
    Csikasz, Robert I.
    Li, Yu
    Sharma, Gunjana
    Hjort, Klas
    Karlsson, Roger
    Bengtsson, Tore
    Myotube Formation on UV-lithographically Micro-patterned Glass: A New Experimental System for Studies of Muscle differentiation in vitroArticle in journal (Refereed)
  • 631.
    Yamamoto, Daniel L.
    et al.
    Stockholm University, Faculty of Science, Wenner-Gren Institute for Experimental Biology.
    Hutchinson, Dana S.
    Bengtsson, Tore
    β2-adrenergic activation increases glycogen synthesis in L6 skeletal muscle cells through a signalling pathway independent of cyclic AMP2007In: Diabetologia, ISSN 0012-186X, Vol. 50, no 1, p. 158-167Article in journal (Refereed)
  • 632.
    Zadravec, Damir
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Metabolic Significance of Fatty Acid Elongation2010Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Very long-chain fatty acids (VLCFAs), including polyunsaturated fatty acids (PUFAs), are essential lipids whose functional diversity is made possible by variation in their chain length and degree of unsaturation. Fatty acids can either be derived directly from the diet or they can be synthesized de novo through lipogenesis, up to 16 carbons in length by fatty acid synthase. Further elongation into VLCFAs is catalysed by the enzymes referred to as elongation of very long-chain fatty acids (ELOVLs). Seven ELOVL proteins have been identified, all of which display distinct fatty acid substrate specificity. The enclosed papers discuss issues regarding the regulation, function and contribution to lipid composition of the Elovl genes with special emphasis on Elovl2 and Elovl3.

    In primary brown adipocytes the Elovl3 gene was shown to be regulated by all three PPAR isoforms, involving both transcriptional activation and mRNA stability. In an attempt to clarify the role of ELOVL3 in whole-body lipid homeostasis, the metabolic effects associated with Elovl3 ablation in mice were investigated. Elovl3-ablated mice were lean and showed markedly reduced triglyceride and leptin levels in serum. In addition, the mice were completely resistant to diet-induced obesity, associated with a reduced hepatic lipogenic gene expression and triglyceride content.

    Over-expression of Elovl2 in cells promoted accumulation of lipid droplets, associated with enhanced fatty acid uptake and induction of PPARγ target genes. To further assess the in vivo function of ELOVL2, the Elovl2 gene was disrupted in mice by homologous recombination. Elovl2-ablated mice exhibited a severe reduction of the elongation products of C24:5n-6 in the testis, indicating a novel role of ELOVL2 in the formation of very-long-chain PUFAs ≥C26. In addition, Elovl2+/- male mice displayed both pre- and post-meiotic deficiency of spermatogenesis. These results specify an indispensable function of ELOVL2-derived fatty acids, which can give new insights into nutritional intervention as an aid in assisting male fertility problems.

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    FULLTEXT02
  • 633.
    Zadravec, Damir
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Brolinson, Annelie
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Fisher, Rachel
    Carneheim, Claes
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Csikasz, Robert
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Bertrand-Michel, Justine
    Borén, Jan
    Guillou, Hervé
    Rudling, Mats
    Jacobsson, Anders
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Ablation of the very long chain fatty acid elongase ELOVL3 in mice leads to constrained lipid storage and resistance to diet-induced obesity2010In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 24, no 11, p. 4366-4377Article in journal (Refereed)
    Abstract [en]

    Although saturated and monounsaturated very-long-chain fatty acids (VLCFA) have long been associated with undesirable effects on health, including obesity, heart failure and atherosclerosis, the physiological role of endogenous synthesis is largely unknown. The fatty acid elongase ELOVL3 is involved in the synthesis of C20-C24 saturated and monounsaturated VLCFA mainly in liver, brown and white adipose tissue and in triglyceride rich glands such as the sebaceous and meibomian glands. Here we show that ablation of ELOVL3 leads to reduced adiponectin levels, constrained expansion of adipose tissue and resistance against diet-induced obesity, a situation that is more exaggerated in female mice. Both female and male knockout mice show reduced hepatic lipogenic gene expression and triglyceride content, a situation, which is associated with, reduced expression of PPARg and its target genes. As a consequence, the VLDL-triglyceride level in serum is significantly reduced. Remarkably, despite increased energy expenditure, markedly reduced serum levels of leptin and increased expression of orexigenic peptides in the hypothalamus, the Elovl3-/- mice do not compensate by increased food intake. Thus, these results reveal that C20-C22 saturated and monounsaturated VLCFA produced by ELOVL3 are indispensable for appropriate synthesis of liver triglycerides, fatty acid uptake and storage in adipose tissue.

  • 634.
    Zadravec, Damir
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Brolinson, Annelie
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Jacobsson, Anders
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Concealed metabolic effects in adipose depots and liver of Elovl3-/- miceManuscript (preprint) (Other academic)
    Abstract [en]

    The Elovl3 gene belongs to a highly conserved family of microsomal enzymes involved in the formation of very long-chain fatty acids (VLCFAs). The recognized role for the enzyme is to control the elongation of saturated and monounsaturated fatty acids up to 24 carbons in length. Elovl3 was originally identified as a highly expressed gene in brown adipose tissue (BAT) upon cold exposure, however significant amounts of transcript can also be found in liver, kidney, white adipose tissue (WAT), heart and in the sebaceous glands of the skin. We have recently seen that Elovl3 ablation gives rise to diminished body weight. These mice are resistant to diet-induced obesity and both female and male knockout mice have reduced hepatic lipogenic gene expression and TG secretion as well as a decreased ratio between energy intake and energy expenditure.

    In an attempt to identify early markers of metabolic disturbance, we used mice at an age before the onset of impaired weight gain is recognized to analyze the expression of genes involved in lipid metabolism in liver, brown and inguinal white adipose tissue, where Elovl3 is significantly expressed under normal conditions. Furthermore, we analyzed the expression under conditions when energy intake exceeds energy expenditure and during increased energy demand.

    Here we show that besides BAT, Elovl3 expression is also regulated in depot specific adipose tissue at different ambient temperatures. We also show that, in addition to impaired expression of both liver (MUP1) and adipose derived (leptin and adiponectin) factors, the Elovl3-/- mice have decreased adipose mass and TG levels already at 30°C, suggesting that factors other than skin barrier dysfunction are involved in the metabolic disturbance associated with Elovl3 ablation.

  • 635. Zadravec, Damir
    et al.
    Brolinson, Annelie
    Stockholm University, Faculty of Science, Wenner-Gren Institute for Experimental Biology.
    Jacobsson, Anders
    Gender specific Elovl3 expression and metabolic activity in adipose tissue depotsManuscript (Other academic)
  • 636.
    Zadravec, Damir
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Jacobsson, Anders
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Physiological regulation of fatty acid elongase and desaturase expression in mouse liver and brown adipose tissueManuscript (preprint) (Other academic)
    Abstract [en]

    Fatty acid elongases and desaturases act in concert in modifying the fatty acid acyl chain in respect of length and degree of unsaturation, respectively. The initial and rate-controlling condensation reaction of very-long-chain fatty acid (VLCFA) elongation is catalysed by the elongase enzymes referred to as elongation of very-long-chain fatty acids (ELOVLs). The desaturases introduce a double bond at a specific position on the acyl chain of fatty acids and can be divided into two distinct families referred to as stearoyl-CoA desaturases (SCDs), and fatty acid desaturases (FADS). Both the desaturases and elongases display distinct fatty acid substrate specificity depending on the chain length and degree of unsaturation. Of the elongases; ELOVL1, ELOVL3, ELOVL6 and ELOVL7 prefer saturated and monounsaturated fatty acids as substrate; and ELOVL2, ELOVL4 and ELOVL5 are selective for polyunsaturated fatty acids (PUFAs). Likewise, SCDs prefer saturated fatty acids while FADS favour PUFAs. Although the general function of the Elovl, Scd, and Fads, genes is known, the physiological consequence of the tissue-specific demand for VLCFAs and PUFAs produced by the different elongases is not fully understood. In order to understand their regulation and physiological role, we have investigated the expression of both elongases and desaturases in mouse liver and BAT, in respect of diurnal variation, temperature dependent regulation and nutritional influence.

  • 637.
    Zadravec, Damir
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Physiology.
    Tvrdik, Petr
    Guillou, Hervé
    Haslam, Richard
    Kobayashi, Tsutomu
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Napier, Johnathan A
    Capecchi, Mario R
    Jacobsson, Anders
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Physiology.
    ELOVL2 controls the level of n-6 28:5 and 30:5 fatty acids in testis: a prerequisite for male fertility and sperm maturation in mice2011In: Journal of Lipid Research, ISSN 0022-2275, E-ISSN 1539-7262, Vol. 52, no 2, p. 245-255Article in journal (Refereed)
    Abstract [en]

    ELOVL2 is a member of the mammalian microsomal ELOVL fatty acid enzyme family, involved in the elongation of very long-chain fatty acids including PUFAs required for various cellular functions in mammals. Here, we used ELOVL2-ablated (Elovl2(-/-)) mice to show that the PUFAs with 24-30 carbon atoms of the ω-6 family in testis are indispensable for normal sperm formation and fertility in male mice. The lack of Elovl2 was associated with a complete arrest of spermatogenesis, with seminiferous tubules displaying only spermatogonia and primary spermatocytes without further germinal cells. Furthermore, based on acyl-CoA profiling, heterozygous Elovl2(+/-) male mice exhibited haploinsufficiency, with reduced levels of C28:5 and C30:5n-6 PUFAs, which gave rise to impaired formation and function of haploid spermatides. These new insights reveal a novel mechanism involving ELOVL2-derived PUFAs in mammals and previously unrecognized roles for C28 and C30 n-6 PUFAs in male fertility. In accordance with the function suggested for ELOVL2, the Elovl2(-/-) mice show distorted levels of serum C20 and C22 PUFAs from both the n-3 and the n-6 series. However, dietary supplementation with C22:6n-3 could not restore male fertility to Elovl2(+/-) mice, suggesting that the changes in n-6 fatty acid composition seen in the testis of the Elovl2(+/-) mice, cannot be compensated by increased C22:6n-3 content.

  • 638.
    Zadravec, Damir
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Tvrdik, Petr
    Howard Hughes Medical Institute, University of Utah, USA.
    Guillou, Hervé
    Laboratoire de Pharmacologie et Toxicologie, INRA, Toulouse.
    Haslam, Richard
    Biological Chemistry, Centre for Crop Genetic Improvement, Rothamsted Research, UK.
    Kobayashi, Tsutomu
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Napier, Johnathan
    Biological Chemistry, Centre for Crop Genetic Improvement, Rothamsted Research, UK.
    Capecchi, Mario
    Howard Hughes Medical Institute, University of Utah, USA.
    Jacobsson, Anders
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Dominant negative effect on male fertility and sperm maturation by haploinsufficiency of ELOVL2 in mouseManuscript (preprint) (Other academic)
    Abstract [en]

    ELOVL2 is a member of the mammalian microsomal enzyme family (ELOVL) involved in the elongation of very long-chain fatty acids (VLCFAs) including polyunsaturated fatty acids (PUFAs). Specifically, ELOVL2 is suggested to mediate the rate-limiting condensation reaction in the elongation of PUFAs of C20 and C22 carbons in length. These PUFAs are required for various physiological functions including, regulation of the composition and fluidity of cell membranes, signalling and gene expression. Moreover, certain PUFAs can be oxygenated forming eicosanoids which are implicated in a variety of signalling pathways. The expression of Elovl2 is highest in testis and liver, but significant amounts of transcripts can also be found in kidney, brain, lung and white adipose tissue. Here, we show that ablation of Elovl2 in mice results in a complete absence of VLCPUFAs with 24-30 carbon atoms of the n-6 family in the testis, and that these fatty acids are indispensable for normal spermatogenesis and fertility. Ablation of Elovl2 was associated with a complete arrest of spermatogenesis with seminiferous tubule displaying only spermatogonia and primary spermatocytes without further germinal cells. The Elovl2+/- mice exhibited abnormal sperm morphology with rounded, condensed head, instead of the normal elongated and hooked head seen in wild-type mice. Intercrosses of Elovl2+/- mice displayed both pre- and post-meiotic deficiency of spermatogenesis. These results indicate a novel mechanism involving ELOVL2-derived fatty acids in mammalian spermatogenesis.

  • 639. Zargari, Arezou
    et al.
    Boban, Mirta
    Heessen, Stijn
    Andréasson, Claes
    Thyberg, Johan
    Ljungdahl, Per O
    Stockholm University, Faculty of Science, Wenner-Gren Institute for Experimental Biology.
    Inner nuclear membrane proteins Asi1, Asi2, and Asi3 function in concert to maintain the latent properties of transcription factors Stp1 and Stp2.2007In: J Biol Chem, ISSN 0021-9258, Vol. 282, no 1, p. 594-605Article in journal (Refereed)
  • 640. Zhao, J
    et al.
    Jin, S
    Stockholm University, Faculty of Science, Wenner-Gren Institute for Experimental Biology.
    Björkroth, B
    Wieslander, L
    Department of Molecular Biology and Functional Genomics.
    Daneholt, B
    The mRNA export factor Dbp5 is associated with Balbiani ring mRNP from gene to cytoplasm2002In: The EMBO Journal, Vol. 21, no 5, p. 1177-1187Article in journal (Refereed)
  • 641.
    Zhao, Jin
    Stockholm University, Faculty of Science, The Wenner-Gren Institute, Physiology.
    Adrenergic Receptors Regulating cAMP Generation and Thermogenesis in Isolated Brown Adipocytes1997Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Adrenoceptors are the functional receptors in brown adipocytes. In the present study, the second messenger cAMP - and thermogenesis (which is an index of the energy metabolism of brown adipocytes) - were measured in order to reveal the intricate mechanism of effects generated by various adrenoceptor interactions with agonists and antagonists on brown adipocytes from hamster, mouse and rat. A modified and advanced preparative method for the isolation of brown adipocytes from mouse and rat was established in order to provide cells for carrying out this investigation. Brown adipocytes from 4oC-acclimated rats were successfully and directly isolated by this method.

    b3-Adrenoceptors are the predominant if not exclusive receptors mediating thermogenesis in hamster, rat and mouse brown adipocytes.

    Arotinolol and carteolol behaved as b3-adrenoceptor agonists with low and partial activity. They will perhaps be useful chemical probes for defining adrenoceptor subtypes, recognising the molecular characteristics of the adrenoceptor protein and may be for curing obesity and diabetes.

    Glucagon acutely stimulates thermogenesis in isolated brown adipocytes, but does not seem to be able to stimulate thermogenesis in vivo. The Ca2+-antagonist benidipine stimulates thermogenesis only indirectly, through activation of the sympathetic nervous systerm.

    a1-Adrenoceptors are in themselves unable to increase cAMP accumulation and thermogenesis, but potentiate the thermogenic effect of the b3-adrenoceptor-elicited cAMP accumulation. Only at limiting and ''physiological'' cAMP levels, do the a1-adrenoceptors demonstrate this quantitatively significant effect on b3-adrenoceptor-mediated thermogenesis. The evidence suggests that a1 / b3 and Ca2+/cAMP synergism exists in the regulation of acute thermogenesis, and this may be the normal physiological mechanism.

  • 642.
    Zhao Rathje, Li-Sophie
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    A Connection between the Microtubule System and ERK activation;Picropodophyllin, an Inhibitor of the IGF-1 receptor, and IGF-1 Destabilize Microtubules and Activate ERKManuscript (Other academic)
    Abstract [en]

    Insulin-like growth factor-1 receptor (IGF-1R) is important for growth and survival of cancer cells, but is not obligatory for growth of normal cells. This has led to attempts to target this receptor to terminate growth of malignant cells. The cyclolignan, picropodophyllin (PPP), has proven useful in inhibiting signalling through the IGF-1R. PPP inhibits IGF-1R autophosphorylation and activation of PI3-kinase/Akt, but it activates ERK in an IGF-1R dependent manner, and causes IGF-1R downregulation. Interestingly, ERK activation and IGF-1R downregulation by IGF-1 and PPP both require ubiquitination of IGF-1R by the E3-ligase Mdm2. In this context, beta-arrestin1 acts as an adapter protein bringing Mdm2 to IGF-1R. How beta-arrestin is recruited to the receptor is unknown. It was recently reported, however, that beta-arrestins bind to microtubules (MT), and that this interaction likely influences signaling via G-protein coupled receptors (GPCRs). This paper reports that the ligand IGF-1 and PPP both have distinct effects on the organization of MT in cultured cells as seen by indirect immunofluorescence, and corroborated by biochemical analysis, demonstrating that IGF-1, as well as PPP, induce MT reorganization and depolymerization. Likely, subsequent association of beta-arrestin1:Mdm2 to the IGF-1R is required for ERK activation, receptor ubiquitination and internalization/downregulation.

  • 643.
    Zhao Rathje, Li-Sophie
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Tropomyosin in Normal and Malignant Cells and the Action of Picropodophyllin on the Microfilament and Microtubule Systems2009Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Cell motility is a fundamental process, enabling cells to migrate, for instance during embryogenesis, tissue repair and defense. Force is generated by two protein systems, which also participate in cell proliferation, control macromolecular and organelle distribution and determine the fine structure of the cell interior. The major components of these are actin and tubulin, respectively, and they are referred to as the microfilament and the microtubule systems. This thesis focuses on tropomyosin, one of many microfilament associated proteins coupled to actin dynamics and organization and expressed in several isoform variants. Altered distribution and isoform expression of tropomyosin are signatures of malignant cells and are dealt with in the current thesis. The presence of tropomyosin isoforms in protruding lamellipodia of migrating cells is demonstrated, and a method to fractionate tropomyosin depending on its organization in an easily extractable, and a more tightly bound cytoplasmic form is presented. Analysis of the loosely associated tropomyosin fraction by gel filtration chromatography revealed that most of the tropomyosins in this fraction exist in a multimeric form. It was also observed that the distribution of tropomyosin varied between non-transformed and transformed cells with most of the isoforms enriched in the loosely bound fraction in the latter category of cells. Possibly this reflects the extensive reorganization of the microfilament system observed in cancer cells and which, depending on the context, can be normalized by introduction of certain tropomyosin isoforms.

    Many anti-cancer drugs target the microtubule system, inhibit cell division and promote apoptosis. Here it is shown that picropodophyllin, which has promising anticancer properties has a destabilizing effect on microtubules and via the microfilament system causes cells to detach from their substratum. Furthermore, picropodophyllin interferes with stimulation of the insulin-like growth factor receptor, which is involved in growth stimulation, differentiation and survival and whose expression is up-regulated in cancer cells.   

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  • 644. Zheng, Lin
    et al.
    Terman, Alexei
    Hallbeck, Martin
    Dehvari, Nodi
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Cowburn, Richard F.
    Benedikz, Eirikur
    Kagedal, Katarina
    Cedazo-Minguez, Angel
    Marcusson, Jan
    Macroautophagy-generated increase of lysosomal amyloid beta-protein mediates oxidant-induced apoptosis of cultured neuroblastoma cells2011In: Autophagy, ISSN 1554-8627, E-ISSN 1554-8635, Vol. 7, no 12, p. 1528-1545Article in journal (Refereed)
    Abstract [en]

    Increasing evidence suggests the toxicity of intracellular amyloid beta-protein (A beta) to neurons, as well as the involvement of oxidative stress in Alzheimer disease (AD). Here we show that normobaric hyperoxia (exposure of cells to 400/c oxygen for five days, and consequent activation of macroautophagy and accumulation of A beta within lysosomes, induced apoptosis in differentiated SH-SY5Y neuroblastoma cells. Cells under hyperoxia showed: (1) increased numbers of autophagic vacuoles that contained amyloid precursor protein (APP) as well as A beta monomers and oligomers, (2) increased reactive oxygen species production, and (3) enhanced apoptosis. Oxidant-induced apoptosis positively correlated with cellular A beta production, being the highest in cells that were stably transfected with APP Swedish KM670/671NL double mutation. Inhibition of v-secretase, prior and/or in parallel to hyperoxia, suggested that the increase of lysosomal A beta resulted mainly from its autophagic uptake, but also from APP processing within autophagic vacuoles. The oxidative stress-mediated effects were prevented by macroautophagy inhibition using 3-methyladenine or ATG5 downregulation. Our results suggest that upregulation of macroautophagy and resulting lysosomal A beta accumulation are essential for oxidant-induced apoptosis in cultured neuroblastoma cells and provide additional support for the interactive role of oxidative stress and the lysosomal system in AD-related neurodegeneration.

  • 645. Zhong, Lei
    et al.
    D'Urso, Agustina
    Toiber, Debra
    Sebastian, Carlos
    Henry, Ryan E.
    Vadysirisack, Douangsone D.
    Guimaraes, Alexander
    Marinelli, Brett
    Wikström, Jakob D.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Nir, Tomer
    Clish, Clary B.
    Vaitheesvaran, Bhavapriya
    Iliopoulos, Othon
    Kurland, Irwin
    Dor, Yuval
    Weissleder, Ralph
    Shirihai, Orian S.
    Ellisen, Leif W.
    Espinosa, Joaquin M.
    Mostoslavsky, Raul
    The Histone Deacetylase Sirt6 Regulates Glucose Homeostasis via Hif1 alpha2010In: Cell, ISSN 0092-8674, E-ISSN 1097-4172, Vol. 140, no 2, p. 280-293Article in journal (Refereed)
    Abstract [en]

    SIRT6 is a member of a highly conserved family of NAD(+)-dependent deacetylases with various roles in metabolism, stress resistance, and life span. SIRT6-deficient mice develop normally but succumb to a lethal hypoglycemia early in life; however, the mechanism underlying this hypoglycemia remained unclear. Here, we demonstrate that SIRT6 functions as a histone H3K9 deacetylase to control the expression of multiple glycolytic genes. Specifically, SIRT6 appears to function as a corepressor of the transcription factor Hif1 alpha, a critical regulator of nutrient stress responses. Consistent with this notion, SIRT6-deficient cells exhibit increased Hif1 alpha activity and show increased glucose uptake with upregulation of glycolysis and diminished mitochondrial respiration. Our studies uncover a role for the chromatin factor SIRT6 as a master regulator of glucose homeostasis and may provide the basis for novel therapeutic approaches against metabolic diseases, such as diabetes and obesity.

  • 646. Zingaretti, Maria Cristina
    et al.
    Crosta, Francesca
    Vitali, Alessandra
    Guerrieri, Mario
    Frontini, Andrea
    Cannon, Barbara
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Physiology.
    Nedergaard, Jan
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Physiology.
    Cinti, Saverio
    The presence of UCP1 demonstrates that metabolically active adipose tissue in the neck of adult humans truly represents brown adipose tissue.2009In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 23, no 9, p. 3113-20Article in journal (Refereed)
    Abstract [en]

    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.

  • 647.
    Öberg, Anette I.
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Physiology.
    Dehvari, Nodi
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Physiology.
    Bengtsson, Tore
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Physiology.
    beta-Adrenergic Inhibition of Contractility in L6 Skeletal Muscle Cells2011In: PLOS ONE, E-ISSN 1932-6203, Vol. 6, no 7, p. e22304-Article in journal (Refereed)
    Abstract [en]

    The beta-adrenoceptors (beta-ARs) control many cellular processes. Here, we show that beta-ARs inhibit calcium depletion-induced cell contractility and subsequent cell detachment of L6 skeletal muscle cells. The mechanism underlying the cell detachment inhibition was studied by using a quantitative cell detachment assay. We demonstrate that cell detachment induced by depletion of extracellular calcium is due to myosin-and ROCK-dependent contractility. The beta-AR inhibition of L6 skeletal muscle cell detachment was shown to be mediated by the beta(2)-AR and increased cAMP but was surprisingly not dependent on the classical downstream effectors PKA or Epac, nor was it dependent on PKG, PI3K or PKC. However, inhibition of potassium channels blocks the beta(2)-AR mediated effects. Furthermore, activation of potassium channels fully mimicked the results of beta(2)-AR activation. In conclusion, we present a novel finding that beta(2)-AR signaling inhibits contractility and thus cell detachment in L6 skeletal muscle cells by a cAMP and potassium channel dependent mechanism.

  • 648.
    Öberg, Anette I.
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Physiology.
    Yassin, Kamal
    Csikasz, Robert I.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Physiology.
    Dehvari, Nodi
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Physiology.
    Shabalina, Irina G.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Physiology.
    Hutchinson, Dana S.
    Wilcke, Mona
    Östenson, Claes-Göran
    Bengtsson, Tore
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Physiology.
    Shikonin Increases Glucose Uptake in Skeletal Muscle Cells and Improves Plasma Glucose Levels in Diabetic Goto-Kakizaki Rats2011In: PLOS ONE, E-ISSN 1932-6203, Vol. 6, no 7, p. e22510-Article in journal (Refereed)
    Abstract [en]

    Background: There is considerable interest in identifying compounds that can improve glucose homeostasis. Skeletal muscle, due to its large mass, is the principal organ for glucose disposal in the body and we have investigated here if shikonin, a naphthoquinone derived from the Chinese plant Lithospermum erythrorhizon, increases glucose uptake in skeletal muscle cells. Methodology/Principal Findings: Shikonin increases glucose uptake in L6 skeletal muscle myotubes, but does not phosphorylate Akt, indicating that in skeletal muscle cells its effect is medaited via a pathway distinct from that used for insulin-stimulated uptake. Furthermore we find no evidence for the involvement of AMP-activated protein kinase in shikonin induced glucose uptake. Shikonin increases the intracellular levels of calcium in these cells and this increase is necessary for shikonin-mediated glucose uptake. Furthermore, we found that shikonin stimulated the translocation of GLUT4 from intracellular vesicles to the cell surface in L6 myoblasts. The beneficial effect of shikonin on glucose uptake was investigated in vivo by measuring plasma glucose levels and insulin sensitivity in spontaneously diabetic Goto-Kakizaki rats. Treatment with shikonin (10 mg/kg intraperitoneally) once daily for 4 days significantly decreased plasma glucose levels. In an insulin sensitivity test (s.c. injection of 0.5 U/kg insulin), plasma glucose levels were significantly lower in the shikonin-treated rats. In conclusion, shikonin increases glucose uptake in muscle cells via an insulin-independent pathway dependent on calcium. Conclusions/Significance: Shikonin increases glucose uptake in skeletal muscle cells via an insulin-independent pathway dependent on calcium. The beneficial effects of shikonin on glucose metabolism, both in vitro and in vivo, show that the compound possesses properties that make it of considerable interest for developing novel treatment of type 2 diabetes.

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