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  • 1.
    Andersson, Ulf
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för fysiologi.
    On the biosynthesis of ATP synthase1998Doktoravhandling, med artikler (Annet vitenskapelig)
  • 2. Anisimov, Vladimir N.
    et al.
    Egorov, Maxim V.
    Krasilshchikova, Marina S.
    Lyamzaev, Konstantin G.
    Manskikh, Vasily N.
    Moshkin, Mikhail P.
    Novikov, Evgeny A.
    Popovich, Irina G.
    Rogovin, Konstantin A.
    Shabalina, Irina G.
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för fysiologi.
    Shekarova, Olga N.
    Skulachev, Maxim V.
    Titova, Tatiana V.
    Vygodin, Vladimir A.
    Vyssokikh, Mikhail Yu.
    Yurova, Maria N.
    Zabezhinsky, Mark A.
    Skulachev, Vladimir P.
    Effects of the mitochondria-targeted antioxidant SkQ1 on lifespan of rodents2011Inngår i: Aging, ISSN 1945-4589, E-ISSN 1945-4589, Vol. 3, nr 11, 1110-1119 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The effect of the mitochondria-targeted, plastoquinone-containing antioxidant SkQ1 on the lifespan of outbred mice and of three strains of inbred mice was studied. To this end, low pathogen (LP) or specific pathogen free (SPF) vivaria in St. Petersburg, Moscow, and Stockholm were used. For comparison, we also studied mole-voles and dwarf hamsters, two wild species of small rodents kept under simulated natural conditions. It was found that substitution of a LP vivarium for a conventional (non-LP) one doubled the lifespan of female outbred mice, just as SkQ1 did in a non-LP vivarium. SkQ1 prevented age-dependent disappearance of estrous cycles of outbred mice in both LP and non-LP vivaria. In the SPF vivarium in Moscow, male BALB/c mice had shorter lifespan than females, and SkQ1 increased their lifespan to the values of the females. In the females, SkQ1 retarded development of such trait of aging as heart mass increase. Male C57Bl/6 mice housed individually in the SPF vivarium in Stockholm lived as long as females. SkQ1 increased the male lifespan, the longevity of the females being unchanged. SkQ1 did not change food intake by these mice. Dwarf hamsters and mole-voles kept in outdoor cages or under simulated natural conditions lived longer if treated with SkQ1. The effect of SkQ1 on longevity of females is assumed to mainly be due to retardation of the age-linked decline of the immune system. For males under LP or SPF conditions, SkQ1 increased the lifespan, affecting also some other system(s) responsible for aging.

  • 3. Bruton, Joseph D.
    et al.
    Aydin, Jan
    Yamada, Takashi
    Shabalina, Irina G.
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för fysiologi.
    Ivarsson, Niklas
    Zhang, Shi-Jin
    Wada, Masanobu
    Tavi, Pasi
    Nedergaard, Jan
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för fysiologi.
    Katz, Abram
    Westerblad, Håkan
    Increased fatigue resistance linked to Ca(2+)-stimulated mitochondrial biogenesis in muscle fibres of cold-acclimated mice2010Inngår i: Journal of Physiology, ISSN 0022-3751, E-ISSN 1469-7793, Vol. 588, nr 21, 4275-4288 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Mammals exposed to a cold environment initially generate heat by repetitive muscle activity (shivering). Shivering is successively replaced by the recruitment of uncoupling protein-1 (UCP1)-dependent heat production in brown adipose tissue. Interestingly, adaptations observed in skeletal muscles of cold-exposed animals are similar to those observed with endurance training. We hypothesized that increased myoplasmic free [Ca2+] ([Ca2+]i) is important for these adaptations. To test this hypothesis, experiments were performed on flexor digitorum brevis (FDB) muscles, which do not participate in the shivering response, of adult wild-type (WT) and UCP1-ablated (UCP1-KO) mice kept either at room temperature (24 ºC) or cold-acclimated (4 ºC) for 4-5 weeks. [Ca2+]i (measured with indo-1) and force were measured under control conditions and during fatigue induced by repeated tetanic stimulation in intact single fibres. The results show no differences between fibres from WT and UCP1-KO mice. However, muscle fibres from cold-acclimated mice showed significant increases in basal [Ca2+]i (~50%), tetanic [Ca2+]i (~40%), and sarcoplasmic reticulum (SR) Ca2+ leak (~four-fold) as compared to fibres from room-temperature mice. Muscles of cold-acclimated mice showed increased expression of peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) and increased citrate synthase activity (reflecting increased mitochondrial content). Fibres of cold-acclimated mice were more fatigue resistant with higher tetanic [Ca2+]i and less force loss during fatiguing stimulation. In conclusion, cold exposure induces changes in FDB muscles similar to those observed with endurance training and we propose that increased [Ca2+]i is a key factor underlying these adaptations.

  • 4.
    Cannon, Barbara
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för fysiologi.
    Nedergaard, Jan
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för fysiologi.
    Metabolic and angiogenic consequences of the presence or absence of UCP12010Inngår i: Research and Perspectives in Endocrine Interactions, 111-120 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Adaptive adrenergic thermogenesis – both the form that develops subsequent to cold acclimation and the form that develops subsequent to a palatable diet challenge – is entirely dependent on the presence and activity of the brown fat uncoupling protein, UCP1. In a cold environment, the absence of UCP1 can be compensated by alternative means, such as shivering or exercise. Upon a challenge with a palatable diet, similar alternatives are not available, and mice become obese in the absence of UCP1. The recent identification of active brown fat in adult humans raises questions as to its role in protection from obesity and in a potential therapeutic context.

  • 5.
    Cannon, Barbara
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för fysiologi.
    Nedergaard, Jan
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för fysiologi.
    Metabolic consequences of the presence or absence of the thermogenic capacity of brown adipose tissue in mice (and probably in humans)2010Inngår i: International Journal of Obesity, ISSN 0307-0565, E-ISSN 1476-5497, Vol. 34, nr 1, S7-S16 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Only with the development of the uncoupling protein 1 (UCP1)-ablated mouse has it become possible to strictly delineate the physiological significance of the thermogenic capacity of brown adipose tissue. Considering the presence of active brown adipose tissue in adult humans, these insights may have direct human implications. In addition to classical nonshivering thermogenesis, all adaptive adrenergic thermogeneses, including diet-induced thermogenesis, is fully dependent on brown adipocyte activity. Any weight-reducing effect of β(3)-adrenergic agonists is fully dependent on UCP1 activity, as is any weight-reducing effect of leptin (in excess of its effect on reduction of food intake). Consequently, in the absence of the thermogenic activity of brown adipose tissue, obesity develops spontaneously. The ability of brown adipose tissue to contribute to glucose disposal is also mainly related to thermogenic activity. However, basal metabolic rate, cold-induced thermogenesis, acute cold tolerance, fevers, nonadaptive adrenergic thermogenesis and processes such as angiogenesis in brown adipose tissue itself are not dependent on UCP1 activity. Whereas it is likely that these conclusions are also qualitatively valid for adult humans, the quantitative significance of brown adipose tissue for human metabolism--and the metabolic consequences for a single individual possessing more or less brown adipose tissue--awaits clarification.

  • 6.
    Cannon, Barbara
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för fysiologi.
    Nedergaard, Jan
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för fysiologi.
    Thermogenesis challenges the adipostat hypothesis for body-weight control.2009Inngår i: Proceedings of the Nutrition Society, ISSN 0029-6651, E-ISSN 1475-2719, Vol. 68, nr 4, 401-7 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    According to the adipostat hypothesis for body-weight control, alterations in body weight should always be compensated by adequate alterations in food intake and thermogenesis. Thus, increased thermogenesis should not be able to counteract obesity because food intake would be increased. However evidence is presented here that thermogenesis in different forms (through artificial uncouplers, exercise, cold exposure) may counteract obesity and is not always fully compensated by increased food intake. Correspondingly, a decreased capacity for metaboloregulatory thermogenesis (i.e. non-functional brown adipose tissue) may in itself lead to obesity. This is evident in mice and may be valid for human subjects, as a substantial proportion of adults possess brown adipose tissue, and those with less or without brown adipose tissue would seem to be more prone to obesity. Thus, increased thermogenesis may counteract obesity, without dietary intervention.

  • 7.
    Cannon, Barbara
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för fysiologi.
    Nedergaard, Jan
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för fysiologi.
    Thyroid hormones: igniting brown fat via the brain.2010Inngår i: Nature medicine, ISSN 1546-170X, Vol. 16, nr 9, 965-7 s.Artikkel i tidsskrift (Fagfellevurdert)
  • 8. Dahlman, I
    et al.
    Mejhert, N
    Linder, K
    Agustsson, T
    Mutch, D M
    Kulyte, A
    Isaksson, B
    Permert, J
    Petrovic, Natasa
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för fysiologi.
    Nedergaard, Jan
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för fysiologi.
    Sjölin, E
    Brodin, D
    Clement, K
    Dahlman-Wright, K
    Rydén, M
    Arner, P
    Adipose tissue pathways involved in weight loss of cancer cachexia2010Inngår i: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 102, nr 10, 1541-8 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND: The regulatory gene pathways that accompany loss of adipose tissue in cancer cachexia are unknown and were explored using pangenomic transcriptome profiling. METHODS: Global gene expression profiles of abdominal subcutaneous adipose tissue were studied in gastrointestinal cancer patients with (n=13) or without (n=14) cachexia. RESULTS: Cachexia was accompanied by preferential loss of adipose tissue and decreased fat cell volume, but not number. Adipose tissue pathways regulating energy turnover were upregulated, whereas genes in pathways related to cell and tissue structure (cellular adhesion, extracellular matrix and actin cytoskeleton) were downregulated in cachectic patients. Transcriptional response elements for hepatic nuclear factor-4 (HNF4) were overrepresented in the promoters of extracellular matrix and adhesion molecule genes, and adipose HNF4 mRNA was downregulated in cachexia. CONCLUSIONS: Cancer cachexia is characterised by preferential loss of adipose tissue; muscle mass is less affected. Loss of adipose tissue is secondary to a decrease in adipocyte lipid content and associates with changes in the expression of genes that regulate energy turnover, cytoskeleton and extracellular matrix, which suggest high tissue remodelling. Changes in gene expression in cachexia are reciprocal to those observed in obesity, suggesting that regulation of fat mass at least partly corresponds to two sides of the same coin.

  • 9.
    Dehvari, Nodi
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för fysiologi.
    Mahmud, Tapan
    Persson, Johanna
    Bengtsson, Tore
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för fysiologi.
    Graff, Caroline
    Winblad, Bengt
    Ronnback, Annica
    Behbahani, Homira
    Amyloid precursor protein accumulates in aggresomes in response to proteasome inhibitor2012Inngår i: Neurochemistry International, ISSN 0197-0186, E-ISSN 1872-9754, Vol. 60, nr 5, 533-542 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Aggresomes are cytoplasmic inclusions which are localized at the microtubule organizing center (MTOC) as a result of induced proteasome inhibition, stress or over-expression of certain proteins. Aggresomes are linked to the pathogenesis of many neurodegenerative diseases. Here we studied whether amyloid precursor protein (APP), a type-I transmembrane glycoprotein, is localized in aggresomes after exposure to stress condition. Using confocal microscopy we found that APP is located in aggresomes and co-localized with vimentin, gamma-tubulin, 20S and ubiquitin at the MTOC in response to proteasome dysfunction. An interaction between vimentin and APP was found after proteasome inhibition suggesting that APP is an additional protein constituent of aggresomes. Suppression of the proteasome system in APP-HEK293 cells overexpressing APP or transfected with APP Swedish mutation caused an accumulation of stable, detergent-insoluble forms of APP containing poly-ubiquitinated proteins. In addition, brain homogenates from transgenic mice expressing human APP with the Arctic mutation demonstrated an interaction between APP and the aggresomal-marker vimentin. These data suggest that malfunctioning of the proteasome system caused by mutation or overexpression of pathological or non-pathological proteins may lead to the accumulation of stable aggresomes, perhaps contributing to the neurodegeneration.

  • 10. Edgar, Daniel
    et al.
    Shabalina, Irina
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för fysiologi.
    Camara, Yolanda
    Wredenberg, Anna
    Calvaruso, Maria Antonietta
    Nijtmans, Leo
    Nedergaard, Jan
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för fysiologi.
    Cannon, Barbara
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för fysiologi.
    Larsson, Nils-Göran
    Trifunovic, Aleksandra
    Random point mutations with major effects on protein-coding genes are the driving force behind premature aging in mtDNA mutator mice.2009Inngår i: Cell metabolism, ISSN 1932-7420, Vol. 10, nr 2, 131-8 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    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.

  • 11.
    Feldmann, Helena M
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för fysiologi.
    Golozoubova, Valeria
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut.
    Cannon, Barbara
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för fysiologi.
    Nedergaard, Jan
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för fysiologi.
    UCP1 ablation induces obesity and abolishes diet-induced thermogenesis in mice exempt from thermal stress by living at thermoneutrality.2009Inngår i: Cell metabolism, ISSN 1932-7420, Vol. 9, nr 2, 203-9 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    As original studies of UCP1-ablated mice failed to demonstrate an obesogenic effect, alternative mechanisms for adaptive adrenergic thermogenesis have been sought. However, we demonstrate here that in C57Bl6 mice exempt from thermal stress (i.e., kept at thermoneutrality), UCP1 ablation in itself induced obesity, even in mice fed control diet, and vastly augmented diet-induced obesity (high-fat diet); i.e., the mice exhibited increased metabolic efficiency. In wild-type mice, high-fat diet increased norepinephrine-induced thermogenesis; i.e., diet-induced thermogenesis was observed, but no such effect was observed in UCP1-ablated mice, demonstrating that diet-induced thermogenesis fully emanates from UCP1 activity. We conclude that ambient temperature is qualitatively determinative for the outcome of metabolic studies, that no other protein and no other mechanism can substitute for UCP1 in mediating diet-induced adrenergic thermogenesis, and that UCP1 activity can be determinative for obesity development in mice and possibly in humans.

  • 12. Gburcik, Valentina
    et al.
    Cawthorn, William P.
    Nedergaard, Jan
    Timmons, James A.
    Cannon, Barbara
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för fysiologi.
    An essential role for Tbx15 in the differentiation of brown and "brite" but not white adipocytes2012Inngår i: American Journal of Physiology. Endocrinology and Metabolism, ISSN 0193-1849, E-ISSN 1522-1555, Vol. 303, nr 8, e1053-E1060 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The transcription factor Tbx15 is expressed predominantly in brown adipose tissue and in those white adipose depots that are capable of giving rise to brown-in-white ("brite"/"beige") adipocytes. Therefore, we have investigated a possible role here of Tbx15 in brown and brite adipocyte differentiation in vitro. Adipocyte precursors were isolated from interscapular and axilliary brown adipose tissues, inguinal white ("brite") adipose tissue, and epididymal white adipose tissue in 129/Sv mouse pups and differentiated in culture. Differentiation was enhanced by chronic treatment with the PPAR gamma agonist rosiglitazone plus the sympathetic neurotransmitter norepinephrine. Using short interfering RNAs (siRNA) directed toward Tbx15 in these primary adipocyte cultures, we decreased Tbx15 expression >90%. This resulted in reduced expression levels of adipogenesis markers (PPAR gamma, aP2). Importantly, Tbx15 knockdown reduced the expression of brown phenotypic marker genes (PRDM16, PGC-1 alpha, Cox8b/Cox4, UCP1) in brown adipocytes and even more markedly in inguinal white adipocytes. In contrast, Tbx15 knockdown had no effect on white adipocytes originating from a depot that is not brite competent in vivo (epididymal). Therefore, Tbx15 may be essential for the development of the adipogenic and thermogenic programs in adipocytes/adipomyocytes capable of developing brown adipocyte features.

  • 13. Giha, Hayder A
    et al.
    ElGhazali, Gehad
    Nasr, Amre
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för immunologi.
    Iriemenam, Nnaemeka C
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för immunologi.
    Berzins, Klavs
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för immunologi.
    Troye-Blomberg, Marita
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för fysiologi.
    Theander, Thor G
    Arnot, David
    Clustering of malaria treatment failure (TF) in Daraweesh: hints for host genetic susceptibility to TF with emphasis on immune-modulating SNPs2010Inngår i: Infection, Genetics and Evolution, ISSN 1567-1348, E-ISSN 1567-7257, Vol. 10, nr 4, 481-6 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    In malaria, drug resistance and treatment failure (TF) are not synonymous, although are escalating together. Over 9 years of surveillances for malaria morbidity and TF in Daraweesh village in eastern Sudan (1991-2004), 136 donors (15-78 years) from 43 households, treated for 278 malaria episodes and had experienced 46 incident of TF, were included in this study. Blood obtained from the donors in 2005, was used for measurement of IgG subclasses against Pf332-C231 antigen and GM/KM allotyping and for genotyping of the donors for; FcgammaRIIA 131 (HH, RH, RR), CRP 286 (C

  • 14. Keller, Pernille
    et al.
    Gburcik, Valentina
    Petrovic, Natasa
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för fysiologi.
    Gallagher, Iain J
    Nedergaard, Jan
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för fysiologi.
    Cannon, Barbara
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för fysiologi.
    Timmons, James A
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för fysiologi.
    Gene-chip studies of adipogenesis-regulated microRNAs in mouse primary adipocytes and human obesity2011Inngår i: BMC Endocrine Disorders, ISSN 1472-6823, E-ISSN 1472-6823, Vol. 11, 7- s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND: Adipose tissue abundance relies partly on the factors that regulate adipogenesis, i.e. proliferation and differentiation of adipocytes. While components of the transcriptional program that initiates adipogenesis is well-known, the importance of microRNAs in adipogenesis is less well studied. We thus set out to investigate whether miRNAs would be actively modulated during adipogenesis and obesity.

    METHODS: Several models exist to study adipogenesis in vitro, of which the cell line 3T3-L1 is the most well known, albeit not the most physiologically appropriate. Thus, as an alternative, we produced EXIQON microarray of brown and white primary murine adipocytes (prior to and following differentiation) to yield global profiles of miRNAs.

    RESULTS: We found 65 miRNAs regulated during in vitro adipogenesis in primary adipocytes. We evaluated the similarity of our responses to those found in non-primary cell models, through literature data-mining. When comparing primary adipocyte profiles, with those of cell lines reported in the literature, we found a high degree of difference in 'adipogenesis' regulated miRNAs suggesting that the model systems may not be accurately representing adipogenesis. The expression of 10 adipogenesis-regulated miRNAs were studied using real-time qPCR and then we selected 5 miRNAs, that showed robust expression, were profiled in subcutaneous adipose tissue obtained from 20 humans with a range of body mass indices (BMI, range = 21-48, and all samples have U133+2 Affymetrix profiles provided). Of the miRNAs tested, mir-21 was robustly expressed in human adipose tissue and positively correlated with BMI (R2 = 0.49, p < 0.001).

    CONCLUSION: In conclusion, we provide a preliminary analysis of miRNAs associated with primary cell in vitro adipogenesis and demonstrate that the inflammation-associated miRNA, mir-21 is up-regulated in subcutaneous adipose tissue in human obesity. Further, we provide a novel transcriptomics database of EXIQON and Affymetrix adipocyte profiles to facilitate data mining.

  • 15. Madsen, Lise
    et al.
    Pedersen, Lone M
    Lillefosse, Haldis Haukaas
    Fjaere, Even
    Bronstad, Ingeborg
    Hao, Qin
    Petersen, Rasmus K
    Hallenborg, Philip
    Ma, Tao
    De Matteis, Rita
    Araujo, Pedro
    Mercader, Josep
    Bonet, M Luisa
    Hansen, Jacob B
    Cannon, Barbara
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för fysiologi.
    Nedergaard, Jan
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för fysiologi.
    Wang, Jun
    Cinti, Saverio
    Voshol, Peter
    Døskeland, Stein Ove
    Kristiansen, Karsten
    UCP1 induction during recruitment of brown adipocytes in white adipose tissue is dependent on cyclooxygenase activity.2010Inngår i: PloS one, ISSN 1932-6203, Vol. 5, nr 6, e11391- s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND: The uncoupling protein 1 (UCP1) is a hallmark of brown adipocytes and pivotal for cold- and diet-induced thermogenesis. METHODOLOGY/PRINCIPAL FINDINGS: Here we report that cyclooxygenase (COX) activity and prostaglandin E(2) (PGE(2)) are crucially involved in induction of UCP1 expression in inguinal white adipocytes, but not in classic interscapular brown adipocytes. Cold-induced expression of UCP1 in inguinal white adipocytes was repressed in COX2 knockout (KO) mice and by administration of the COX inhibitor indomethacin in wild-type mice. Indomethacin repressed beta-adrenergic induction of UCP1 expression in primary inguinal adipocytes. The use of PGE(2) receptor antagonists implicated EP(4) as a main PGE(2) receptor, and injection of the stable PGE(2) analog (EP(3/4) agonist) 16,16 dm PGE(2) induced UCP1 expression in inguinal white adipose tissue. Inhibition of COX activity attenuated diet-induced UCP1 expression and increased energy efficiency and adipose tissue mass in obesity-resistant mice kept at thermoneutrality. CONCLUSIONS/SIGNIFICANCE: Our findings provide evidence that induction of UCP1 expression in white adipose tissue, but not in classic interscapular brown adipose tissue is dependent on cyclooxygenase activity. Our results indicate that cyclooxygenase-dependent induction of UCP1 expression in white adipose tissues is important for diet-induced thermogenesis providing support for a surprising role of COX activity in the control of energy balance and obesity development.

  • 16.
    Mattsson, Charlotte L
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för fysiologi.
    Andersson, Emma R
    Nedergaard, Jan
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut.
    Differential involvement of caveolin-1 in brown adipocyte signaling: impaired beta3-adrenergic, but unaffected LPA, PDGF and EGF receptor signaling.2010Inngår i: Biochimica et Biophysica Acta, ISSN 0006-3002, E-ISSN 1878-2434, Vol. 1803, nr 8, 983-9 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Caveolae and caveolin have been implicated as being involved in the signal transduction of many receptors, including the EGF, PDGF, LPA and beta3-adrenergic receptors. To investigate the role of caveolin-1 (Cav1) in these signaling pathways in brown adipose tissue, primary brown adipocyte cultures from Cav1-ablated mice and wild-type mice were investigated. In pre-adipocytes, Cav1-ablation affected neither the G-protein coupled LPA receptor signaling to Erk1/2, nor the receptor tyrosine kinases PDGF- or EGF-receptor signaling to Erk1/2. Mature primary Cav1-/- brown adipocytes accumulated lipids and expressed aP2 to the same extent as did wild-type cells. However, the cAMP levels induced by the beta3-adrenergic receptor agonist CL316,243 were lower in the Cav1-/- cultures, with an unchanged EC50 for CL316,243. Also the response to the direct adenylyl cyclase agonist forskolin was reduced. Thus, in brown adipocytes, Cav1 is apparently required for an intact response to adenylyl cyclase-linked agonists/activators, whereas other signaling pathways examined function without Cav1

  • 17.
    Mattsson, Charlotte L.
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för fysiologi.
    Csikasz, Robert I.
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för fysiologi.
    Chernogubova, Ekaterina
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för fysiologi.
    Yamamoto, Daniel L.
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för fysiologi.
    Högberg, Helena T.
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för fysiologi.
    Amri, Ez-Zoubir
    Hutchinson, Dana S.
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för fysiologi.
    Bengtsson, Tore
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för fysiologi.
    β₁-Adrenergic receptors increase UCP1 in human MADS brown adipocytes and rescue cold-acclimated β₃-adrenergic receptor-knockout mice via nonshivering thermogenesis2011Inngår i: American Journal of Physiology. Endocrinology and Metabolism, ISSN 0193-1849, E-ISSN 1522-1555, Vol. 301, nr 6, E1108-E1118 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    With the finding that brown adipose tissue is present and negatively correlated to obesity in adult man, finding the mechanism(s) of how to activate brown adipose tissue in humans could be important in combating obesity, type 2 diabetes, and their complications. In mice, the main regulator of nonshivering thermogenesis in brown adipose tissue is norepinephrine acting predominantly via β(3)-adrenergic receptors. However, vast majorities of β(3)-adrenergic agonists have so far not been able to stimulate human β(3)-adrenergic receptors or brown adipose tissue activity, and it was postulated that human brown adipose tissue could be regulated instead by β(1)-adrenergic receptors. Therefore, we have investigated the signaling pathways, specifically pathways to nonshivering thermogenesis, in mice lacking β(3)-adrenergic receptors. Wild-type and β(3)-knockout mice were either exposed to acute cold (up to 12 h) or acclimated for 7 wk to cold, and parameters related to metabolism and brown adipose tissue function were investigated. β(3)-knockout mice were able to survive both acute and prolonged cold exposure due to activation of β(1)-adrenergic receptors. Thus, in the absence of β(3)-adrenergic receptors, β(1)-adrenergic receptors are effectively able to signal via cAMP to elicit cAMP-mediated responses and to recruit and activate brown adipose tissue. In addition, we found that in human multipotent adipose-derived stem cells differentiated into functional brown adipocytes, activation of either β(1)-adrenergic receptors or β(3)-adrenergic receptors was able to increase UCP1 mRNA and protein levels. Thus, in humans, β(1)-adrenergic receptors could play an important role in regulating nonshivering thermogenesis.

  • 18.
    Mattsson, Charlotte L
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för fysiologi.
    Csikasz, Robert I
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för fysiologi.
    Shabalina, Irina G
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för fysiologi.
    Nedergaard, Jan
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för fysiologi.
    Cannon, Barbara
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för fysiologi.
    Caveolin-1-ablated mice survive in cold by nonshivering thermogenesis despite desensitized adrenergic responsiveness2010Inngår i: American Journal of Physiology. Endocrinology and Metabolism, ISSN 0193-1849, E-ISSN 1522-1555, Vol. 299, nr 3, E374-83 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Caveolin-1 (Cav1)-ablated mice display impaired lipolysis in white adipose tissue. They also seem to have an impairment in brown adipose tissue function, implying that Cav1-ablated mice could encounter problems in surviving longer periods in cold temperatures. To investigate this, Cav1-ablated mice and wild-type mice were transferred to cold temperatures for extended periods of time, and parameters related to metabolism and thermogenesis were investigated. Unexpectedly, the Cav1-ablated mice survived in the cold. There were no differences between Cav1-ablated and wild-type mice with regard to food intake, in behavior related to shivering, or in body temperature. The Cav1-ablated mice had a halved total fat content independently of acclimation temperature. There was no difference in brown adipose tissue uncoupling protein-1 (UCP1) protein amount, and isolated brown fat mitochondria were thermogenically competent but displayed 30% higher thermogenic capacity. However, the beta(3)-adrenergic receptor amount was reduced by about one-third in the Cav1-ablated mice at all acclimation temperatures. Principally in accordance with this, a higher than standard dose of norepinephrine was needed to obtain full norepinephrine-induced thermogenesis in the Cav1-ablated mice; the higher dose was also needed for the Cav1-ablated mice to be able to utilize fat as a substrate for thermogenesis. In conclusion, the ablation of Cav1 impairs brown adipose tissue function by a desensitization of the adrenergic response; however, the desensitization is not evident in the animal as it is overcome physiologically, and Cav1-ablated mice can therefore survive in prolonged cold by nonshivering thermogenesis.

  • 19. Merlin, Jon
    et al.
    Evans, Bronwyn A
    Csikasz, Robert I
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för fysiologi.
    Bengtsson, Tore
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för fysiologi.
    Summers, Roger J
    Hutchinson, Dana S
    The M3-muscarinic acetylcholine receptor stimulates glucose uptake in L6 skeletal muscle cells by a CaMKK-AMPK-dependent mechanism2010Inngår i: Cellular Signalling, ISSN 0898-6568, E-ISSN 1873-3913, Vol. 22, nr 7, 1104-13 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The role of muscarinic acetylcholine receptors (mAChRs) in regulating glucose uptake in L6 skeletal muscle cells was investigated. [(3)H]-2-Deoxyglucose uptake was increased in differentiated L6 cells by insulin, acetylcholine, oxotremorine-M and carbachol. mAChR-mediated glucose uptake was inhibited by the AMPK inhibitor Compound C. Whole cell radioligand binding using [(3)H]-N-methyl scopolamine chloride identified mAChRs in differentiated but not undifferentiated L6 cells and M(3) mAChR mRNA was detected only in differentiated cells. M(3) mAChRs are Gq-coupled, and cholinergic stimulation by the mAChR agonists acetylcholine, oxotremorine-M and carbachol increased Ca(2+) in differentiated but not undifferentiated L6 cells. This was due to muscarinic but not nicotinic activation as responses were antagonised by the muscarinic antagonist atropine but not the nicotinic antagonist tubocurarine. Western blotting showed that both carbachol and the AMPK activator AICAR increased phosphorylation of the AMPKalpha subunit at Thr172, with responses to carbachol blocked by Compound C and the CaMKK inhibitor STO609 but not by the PI3K inhibitor wortmannin. AICAR-stimulated AMPK phosphorylation was not sensitive to STO-609, confirming that this compound inhibits CaMKK but not the classical AMPK kinase LKB1. The TAK1 inhibitor (5Z)-7-oxozeaenol and the G(i) inhibitor pertussis toxin both failed to block AMPK phosphorylation in response to carbachol. Using CHO-K1 cells stably expressing each of the mAChR subtypes (M(1)-M(4)), it was determined that only the M(1) and M(3) mAChRs phosphorylate AMPK, confirming a G(q)-dependent mechanism. This study demonstrates that activation of M(3) mAChRs in L6 skeletal muscle cells stimulates glucose uptake via a CaMKK-AMPK-dependent mechanism, independent of the insulin-stimulated pathway.

  • 20.
    Nedergaard, Jan
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för fysiologi.
    Bengtsson, Tore
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för fysiologi.
    Cannon, Barbara
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för fysiologi.
    Three years with adult human brown adipose tissue2010Inngår i: Annals of the New York Academy of Sciences, ISSN 0077-8923, E-ISSN 1749-6632, Vol. 1212, E20-E36 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The presence of active brown adipose tissue in adult humans has been recognized in general physiology only since 2007. The intervening three years established that the depots originally observed by (18)F-fluoro-deoxy-glucose positron emission tomography (FDG PET) scanning techniques really are brown adipose tissue depots because they are enriched for uncoupling protein 1 (UCP1). Reports of low apparent prevalence of brown adipose tissue based on retrospective studies of hospital records of FDG PET scans markedly underestimate true prevalence because such studies only reflect acute activity state; consequently, such retrospective studies cannot be conclusively analysed for factors influencing activity and amount of brown adipose tissue. Dedicated studies show that the true prevalence is 30-100%, depending on cohort. Warm temperature during the investigation-as well as adrenergic antagonists-inhibit tissue activity. There is probably no sexual dimorphism in the prevalence of brown adipose tissue. Outdoor temperature may affect the amount of brown adipose tissue, and the amount is negatively correlated with age and obesity. The presence of brown adipose tissue is associated with cold-induced nonshivering thermogenesis, and the tissue may be a major organ for glucose disposal. The decline in brown adipose tissue amount with increasing age may account for or aggravate middle-age obesity. Maintained activation of brown adipose tissue throughout life may thus protect against obesity and diabetes.

  • 21.
    Petrovic, Natasa
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för fysiologi.
    Walden, Tomas B
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för fysiologi.
    Shabalina, Irina G
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för fysiologi.
    Timmons, James A
    Cannon, Barbara
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för fysiologi.
    Nedergaard, Jan
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för fysiologi.
    Chronic Perixosome Proliferator-activated Receptor gamma (PPARgamma) activation of epididymally derived white adipocyte cultures reveals a population of thermogenically competent, UCP1-containing adipocytes molecularly distinct from classical brown adipocytes.2010Inngår i: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 285, nr 10, 7153-7164 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The recent insight that brown adipocytes and muscle cells share a common origin and in this respect are distinct from white adipocytes has spurred questions concerning the origin and molecular characteristics of the UCP1-expressing cells observed in classical white adipose tissue depots under certain physiological or pharmacological conditions. Examining precursors from the purest white adipose tissue depot (epididymal), we report here that chronic treatment with the PPARgamma agonist rosiglitazone promotes not only the expression of PGC-1alpha and mitochondriogenesis in these cells but also a norepinephrine-augmentable UCP1 gene expression in a significant subset of the cells, providing these cells with a genuine thermogenic capacity. However, although functional thermogenic genes are expressed, the cells are devoid of transcripts for the novel transcription factors now associated with classical brown adipocytes (Zic1, Lhx8, Meox2 and characteristically PRDM16) or for myocyte-associated genes (myogenin and myomirs (muscle-specific microRNAs)) and retain white-fat characteristics such as Hoxc9 expression. Co-culture experiments verify that the UCP1-expressing cells are not proliferating classical brown adipocytes (adipomyocytes) and these cells therefore constitute a subset of adipocytes (''brite'' adipocytes) with a developmental origin and molecular characteristics distinguishing them as a separate class of cells.

  • 22. Rakicevic, Ljiljana
    et al.
    Petrovic, Natasa
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för fysiologi.
    Radojkovic, Dragica
    Kojic, Snezana
    THE EXPRESSION OF MUSCLE ANKYRIN REPEAT PROTEINS IN BROWN ADIPOSE TISSUE2011Inngår i: ARCHIVES OF BIOLOGICAL SCIENCES, ISSN 0354-4664, Vol. 63, nr 4, 915-920 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    MARP family members CARP, Ankrd2 and DARP are expressed in the striated muscle, while DARP protein is also detected in brown adipose tissue (BAT). Taking into account recent findings concerning the common origin of muscle and brown fat, expression of CARP and Ankrd2 in mouse BAT was investigated. We demonstrated Ankrd2 expression in both inactive and thermogenically active BAT, while CARP expression was not detected. Our findings suggest that the expression of Ankrd2 in BAT could be a part of the myogenic transcriptional signature, further supporting the evidence that muscle and brown adipose cells arise from the same myoblastic precursor.

  • 23. Sahlin, Kent
    et al.
    Shabalina, Irina G
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för fysiologi.
    Mattsson, C Mikael
    Bakkman, Linda
    Fernström, Maria
    Rozhdestvenskaya, Zinaida
    Enqvist, Jonas K
    Nedergaard, Jan
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för fysiologi.
    Ekblom, Björn
    Tonkonogi, Michail
    Ultraendurance exercise increases the production of reactive oxygen species in isolated mitochondria from human skeletal muscle2010Inngår i: Journal of applied physiology, ISSN 8750-7587, E-ISSN 1522-1601, Vol. 108, nr 4, 780-7 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Exercise-induced oxidative stress is important for the muscular adaptation to training but may also cause muscle damage. We hypothesized that prolonged exercise would increase mitochondrial production of reactive oxygen species (ROS) measured in vitro and that this correlates with oxidative damage. Eight male athletes (24-32 yr) performed ultraendurance exercise (kayaking/running/cycling) with an average work intensity of 55% V(O(2peak)) for 24 h. Muscle biopsies were taken from vastus lateralis before exercise, immediately after exercise, and after 28 h of recovery. The production of H(2)O(2) was measured fluorometrically in isolated mitochondria with the Amplex red and peroxidase system. Succinate-supported mitochondrial H(2)O(2) production was significantly increased after exercise (73% higher, P = 0.025) but restored to the initial level at recovery. Plasma level of free fatty acids (FFA) increased fourfold and exceeded 1.2 mmol/l during the last 6 h of exercise. Plasma FFA at the end of exercise was significantly correlated to mitochondrial ROS production (r = 0.74, P < 0.05). Mitochondrial content of 4-hydroxy-nonenal-adducts (a marker of oxidative damage) was increased only after recovery and was not correlated with mitochondrial ROS production. Total thiol group level and glutathione peroxidase activity were elevated after recovery. In conclusion, ultraendurance exercise increases ROS production in isolated mitochondria, but this is reversed after 28 h recovery. Mitochondrial ROS production was not correlated with oxidative damage of mitochondrial proteins, which was increased at recovery but not immediately after exercise.

  • 24.
    Sato, Masaaki
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för fysiologi.
    Hutchinson, Dana S.
    Halls, Michelle L.
    Furness, Sebastian G. B.
    Bengtsson, Tore
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för fysiologi.
    Evans, Bronwyn A.
    Summers, Roger J.
    Interaction with Caveolin-1 Modulates G Protein Coupling of Mouse beta(3)-Adrenoceptor2012Inngår i: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 287, nr 24, 20674-20688 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Caveolins act as scaffold proteins in multiprotein complexes and have been implicated in signaling by G protein-coupled receptors. Studies using knock-out mice suggest that beta(3)-adrenoceptor (beta(3)-AR) signaling is dependent on caveolin-1; however, it is not known whether caveolin-1 is associated with the beta(3)-AR or solely with downstream signaling proteins. We have addressed this question by examining the impact of membrane rafts and caveolin-1 on the differential signaling of mouse beta(3a)- and beta(3b)-AR isoforms that diverge at the distal C terminus. Only the beta(3b)-AR promotes pertussis toxin (PTX)-sensitive cAMP accumulation. When cells expressing the beta(3a)-AR were treated with filipin III to disrupt membrane rafts or transfected with caveolin-1 siRNA, the cyclic AMP response to the beta(3)-AR agonist CL316243 became PTX-sensitive, suggesting G alpha(i/o) coupling. The beta(3a)-AR C terminus, S (P-384) under bar PLNR (P-389) under bar DG (Y-392) under bar EGARP (P-398) under bar PT, resembles a caveolin interaction motif. Mutant beta(3a)-ARs (F389A/Y392A/F398A or P384S/F389A) promoted PTX-sensitive cAMP responses, and in situ proximity assays demonstrated an association between caveolin-1 and the wild type beta(3a)-AR but not the mutant receptors. In membrane preparations, the beta(3b)-AR activated G alpha(o) and mediated PTX-sensitive cAMP responses, whereas the beta(3a)-AR did not activate G alpha(i/o) proteins. The endogenous beta(3a)-AR displayed G alpha(i/o) coupling in brown adipocytes from caveolin-1 knock-out mice or in wild type adipocytes treated with filipin III. Our studies indicate that interaction of the beta(3a)-AR with caveolin inhibits coupling to G alpha(i/o) proteins and suggest that signaling is modulated by a raft-enriched complex containing the beta(3a)-AR, caveolin-1, G alpha(s), and adenylyl cyclase.

  • 25.
    Shabalina, Irina G
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för fysiologi.
    Hoeks, Joris
    Kramarova, Tatiana V
    Schrauwen, Patrick
    Cannon, Barbara
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för fysiologi.
    Nedergaard, Jan
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för fysiologi.
    Cold tolerance of UCP1-ablated mice: A skeletal muscle mitochondria switch toward lipid oxidation with marked UCP3 up-regulation not associated with increased basal, fatty acid- or ROS-induced uncoupling or enhanced GDP effects.2010Inngår i: Biochimica et Biophysica Acta, ISSN 0006-3002, E-ISSN 1878-2434, Vol. 1797, nr 6-7, 968-80 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Mice lacking the thermogenic mitochondrial membrane protein UCP1 (uncoupling protein 1) - and thus all heat production from brown adipose tissue - can still adapt to a cold environment (4 degrees C) if successively transferred to the cold. The mechanism behind this adaptation has not been clarified. To examine possible adaptive processes in the skeletal muscle, we isolated mitochondria from the hind limb muscles of cold-acclimated wild-type and UCP1(-/-) mice and examined their bioenergetic chracteristics. We observed a switch in metabolism, from carbohydrate towards lipid catabolism, and an increased total mitochondrial complement, with an increased total ATP production capacity. The UCP1(-/-) muscle mitochondria did not display a changed state-4 respiration rate (no uncoupling) and were less sensitive to the uncoupling effect of fatty acids than the wild-type mitochondria. The content of UCP3 was increased 3-4 fold, but despite this, endogenous superoxide could not invoke a higher proton leak, and the small inhibitory effect of GDP was unaltered, indicating that it was not mediated by UCP3. Double mutant mice (UCP1(-/-) plus superoxide dismutase 2-overexpression) were not more cold sensitive than UCP1(-/-), bringing into question an involvement of reactive oxygen species (ROS) in activation of any alternative thermogenic mechanism. We conclude that there is no evidence for an involvement of UCP3 in basal, fatty-acid- or superoxide-stimulated oxygen consumption or in GDP sensitivity. The adaptations observed did not imply any direct alternative process for nonshivering thermogenesis but the adaptations observed would be congruent with adaptation to chronically enhanced muscle activity caused by incessant shivering in these mice.

  • 26.
    Shabalina, Irina G
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för fysiologi.
    Ost, Mario
    Petrovic, Natasa
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för fysiologi.
    Vrbacky, Marek
    Nedergaard, Jan
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för fysiologi.
    Cannon, Barbara
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för fysiologi.
    Uncoupling protein-1 is not leaky.2010Inngår i: Biochimica et Biophysica Acta, ISSN 0006-3002, E-ISSN 1878-2434, Vol. 1797, nr 6-7, 773-84 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The activity of uncoupling protein-1 (UCP1) is rate-limiting for nonshivering thermogenesis and diet-induced thermogenesis. Characteristically, this activity is inhibited by GDP experimentally and presumably mainly by cytosolic ATP within brown-fat cells. The issue as to whether UCP1 has a residual proton conductance even when fully saturated with GDP/ATP (as has recently been suggested) has not only scientific but also applied interest, since a residual proton conductance would make overexpressed UCP1 weight-reducing even without physiological/pharmacological activation. To examine this question, we have here established optimal conditions for studying the bioenergetics of wild-type and UCP1(-/-) brown-fat mitochondria, analysing UCP1-mediated differences in parallel preparations of brown-fat mitochondria from both genotypes. Comparing different substrates, we find that pyruvate (or palmitoyl-l-carnitine) shows the largest relative coupling by GDP. Comparing albumin concentrations, we find the range 0.1-0.6% optimal; higher concentrations are inhibitory. Comparing basic medium composition, we find 125mM sucrose optimal; an ionic medium (50-100mM KCl) functions for wild-type but is detrimental for UCP1(-/-) mitochondria. Using optimal conditions, we find no evidence for a residual proton conductance (not a higher post-GDP respiration, a lower membrane potential or an altered proton leak at highest common potential) with either pyruvate or glycerol-3-phosphate as substrates, nor by a 3-4-fold alteration of the amount of UCP1. We could demonstrate that certain experimental conditions, due to respiratoty inhibition, could lead to the suggestion that UCP1 possesses a residual proton conductance but find that under optimal conditions our experiments concur with implications from physiological observations that in the presence of inhibitory nucleotides, UCP1 is not leaky.

  • 27. Virtue, Sam
    et al.
    Feldmann, Helena
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för fysiologi.
    Christian, Mark
    Tan, Chong Yew
    Masoodi, Mojgan
    Dale, Martin
    Lelliott, Chris
    Burling, Keith
    Campbell, Mark
    Eguchi, Naomi
    Voshol, Peter
    Sethi, Jaswinder K.
    Parker, Malcolm
    Urade, Yoshihiro
    Griffin, Julian L.
    Cannon, Barbara
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för fysiologi.
    Vidal-Puig, Antonio
    A New Role for Lipocalin Prostaglandin D Synthase in the Regulation of Brown Adipose Tissue Substrate Utilization2012Inngår i: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 61, nr 12, 3139-3147 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    In this study, we define a new role for lipocalin prostaglandin D synthase (L-PGDS) in the control of metabolic fuel utilization by brown adipose tissue (BAT). We demonstrate that L-PGDS expression in BAT is positively correlated with BAT activity, upregulated by peroxisome proliferator activated receptor gamma coactivator 1 alpha or 1 beta and repressed by receptor-interacting protein 140. Under cold-acclimated conditions, mice lacking L-PGDS had elevated reliance on carbohydrate to provide fuel for thermogenesis and had increased expression of genes regulating glycolysis mid de novo lipogenesis in BAT. These transcriptional differences were associated with increased lipid content in BAT and a BAT lipid composition enriched with de novo synthesized lipids. Consistent with the concept that lack of L-PGDS increases glucose utilization, mice lacking L-PGDS had improved glucose tolerance after high-fat, feeding. The improved glucose tolerance appeared to be independent of changes in insulin sensitivity, as insulin levels during the glucose tolerance test and insulin, leptin, and adiponectin levels were unchanged. Moreover, L-PGDS knock-out mice exhibited increased expression of genes involved in thermogenesis and increased norepinephrine-stimulated glucose uptake to BAT, suggesting that sympathetically mediated changes in glucose uptake may have improved glucose tolerance. Taken together, these results suggest that L-PGDS plays an important role in the regulation of glucose utilization in vivo. Diabetes 61:3139-3147, 2012

  • 28.
    Walden, Tomas B
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för fysiologi.
    Hansen, Ida R
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för fysiologi.
    Timmons, James A
    Cannon, Barbara
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för fysiologi.
    Nedergaard, Jan
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för fysiologi.
    Recruited vs. nonrecruited molecular signatures of brown, “brite,” and white adipose tissues2011Inngår i: American Journal of Physiology. Endocrinology and Metabolism, ISSN 0193-1849, E-ISSN 1522-1555, Vol. 302, nr 1, E19-E31 s.Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 29.
    Walden, Tomas B.
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för fysiologi. Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut.
    Petrovic, Natasa
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut.
    Nedergaard, Jan
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut.
    PPARa is not involved in the regulation of muscle-associated genesin brown adipose tissue.Manuskript (preprint) (Annet vitenskapelig)
  • 30.
    Walden, Tomas B
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för fysiologi. Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut.
    Timmons, James A
    Keller, Pernille
    Nedergaard, Jan
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för fysiologi. Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut.
    Cannon, Barbara
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för fysiologi. Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut.
    Distinct expression of muscle-specific microRNAs (myomirs) in brown adipocytes.2009Inngår i: Journal of Cellular Physiology, ISSN 0021-9541, E-ISSN 1097-4652, Vol. 218, nr 2, 444-449 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    MicroRNAs, a novel class of post-transcriptional gene regulators, have been demonstrated to be involved in several cellular processes regulating the expression of protein-coding genes. Here we examine murine white and brown primary cell cultures for differential expression of miRNAs. The adipogenesis-related miRNA miR-143 was highly expressed in mature white adipocytes but was low in mature brown adipocytes. Three classical "myogenic" miRNAs miR-1, miR-133a and miR-206 were absent from white adipocytes but were specifically expressed both in brown pre- and mature adipocytes, reinforcing the concept that brown adipocytes and myocytes derive from a common cell lineage that specifies energy-dissipating cells. Augmentation of adipocyte differentiation status with norepinephrine or rosiglitazone did not affect the expression of the above miRNAs, the expression levels of which were thus innately regulated. However, expression of the miRNA miR-455 was enhanced during brown adipocyte differentiation, similarly to the expression pattern of the brown adipocyte differentiation marker UCP1. In conclusion, miRNAs are differentially expressed in white and brown adipocytes and may be important in defining the common precursor cell for myocytes and brown adipocytes and thus have distinct roles in energy-storing versus energy-dissipating cells.

  • 31. Whittle, Andrew J.
    et al.
    Carobbio, Stefania
    Martins, Luis
    Slawik, Marc
    Hondares, Elayne
    Jesus Vazquez, Maria
    Morgan, Donald
    Csikasz, Robert I.
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för fysiologi.
    Gallego, Rosalia
    Rodriguez-Cuenca, Sergio
    Dale, Martin
    Virtue, Samuel
    Villarroya, Francesc
    Cannon, Barbara
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för fysiologi.
    Rahmouni, Kamal
    Lopez, Miguel
    Vidal-Puig, Antonio
    BMP8B Increases Brown Adipose Tissue Thermogenesis through Both Central and Peripheral Actions2012Inngår i: Cell, ISSN 0092-8674, E-ISSN 1097-4172, Vol. 149, nr 4, 871-885 s.Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 32. Xue, Yuan
    et al.
    Petrovic, Natasa
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för fysiologi.
    Cao, Renhai
    Larsson, Ola
    Lim, Sharon
    Chen, Shaohua
    Feldmann, Helena M
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för fysiologi.
    Liang, Zicai
    Zhu, Zhenping
    Nedergaard, Jan
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för fysiologi.
    Cannon, Barbara
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för fysiologi.
    Cao, Yihai
    Hypoxia-independent angiogenesis in adipose tissues during cold acclimation.2009Inngår i: Cell Metabolism, ISSN 1550-4131, E-ISSN 1932-7420, Vol. 9, nr 1, 99-109 s.Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 33.
    Zadravec, Damir
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för fysiologi.
    Tvrdik, Petr
    Guillou, Hervé
    Haslam, Richard
    Kobayashi, Tsutomu
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut.
    Napier, Johnathan A
    Capecchi, Mario R
    Jacobsson, Anders
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för fysiologi.
    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 mice2011Inngår i: Journal of Lipid Research, ISSN 0022-2275, E-ISSN 1539-7262, Vol. 52, nr 2, 245-255 s.Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 34. Zingaretti, Maria Cristina
    et al.
    Crosta, Francesca
    Vitali, Alessandra
    Guerrieri, Mario
    Frontini, Andrea
    Cannon, Barbara
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för fysiologi.
    Nedergaard, Jan
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för fysiologi.
    Cinti, Saverio
    The presence of UCP1 demonstrates that metabolically active adipose tissue in the neck of adult humans truly represents brown adipose tissue.2009Inngår i: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 23, nr 9, 3113-20 s.Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 35.
    Öberg, Anette I.
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för fysiologi.
    Dehvari, Nodi
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för fysiologi.
    Bengtsson, Tore
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för fysiologi.
    beta-Adrenergic Inhibition of Contractility in L6 Skeletal Muscle Cells2011Inngår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 6, nr 7, e22304- s.Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 36.
    Öberg, Anette I.
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för fysiologi.
    Yassin, Kamal
    Csikasz, Robert I.
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för fysiologi.
    Dehvari, Nodi
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för fysiologi.
    Shabalina, Irina G.
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för fysiologi.
    Hutchinson, Dana S.
    Wilcke, Mona
    Östenson, Claes-Göran
    Bengtsson, Tore
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för fysiologi.
    Shikonin Increases Glucose Uptake in Skeletal Muscle Cells and Improves Plasma Glucose Levels in Diabetic Goto-Kakizaki Rats2011Inngår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 6, nr 7, e22510- s.Artikkel i tidsskrift (Fagfellevurdert)
    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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