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  • 51.
    Isidor, Marie S.
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Winther, Sally
    Markussen, Lasse K.
    Basse, Astrid L.
    Quistorff, Bjørn
    Nedergaard, Jan
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Emanuelli, Brice
    Hansen, Jacob B.
    Pyruvate kinase M2 represses thermogenic gene expression in brown adipocytes2020In: FEBS Letters, ISSN 0014-5793, E-ISSN 1873-3468, Vol. 594, no 7, p. 1218-1225Article in journal (Refereed)
    Abstract [en]

    Utilizing the thermogenic capacity of brown adipose tissue is a potential anti-obesity strategy; therefore, the mechanisms controlling expression of thermogenesis-related genes are of interest. Pyruvate kinase (PK) catalyzes the last step of glycolysis and exists as four isoenzymes: PK, liver, PK, red blood cell, PK, muscle (PKM1 and PKM2). PKM2 has both glycolytic and nuclear functions. Here, we report that PKM2 is enriched in brown adipose compared with white adipose tissue. Specific knockdown of PKM2 in mature brown adipocytes demonstrates that silencing of PKM2 does not lead to a decrease in PK activity, but causes a robust upregulation of thermogenic uncoupling protein 1 (Ucp1) and fibroblast growth factor 21 (Fgf21) gene expression. This increase is not mediated by any of the known mechanisms for PKM2-regulated gene expression, thus implying the existence of a novel mechanism for PKM2-dependent effects on gene expression.

  • 52.
    Kalinovich, Anastasia V.
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    de Jong, Jasper M. A.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Cannon, Barbara
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Nedergaard, Jan
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    UCP1 in adipose tissues: two steps to full browning2017In: Biochimie, ISSN 0300-9084, E-ISSN 1638-6183, Vol. 134, p. 127-137Article in journal (Refereed)
    Abstract [en]

    The possibility that brown adipose tissue thermogenesis can be recruited in order to combat the development of obesity has led to a high interest in the identification of "browning agents", i.e. agents that increase the amount and activity of UCP1 in brown and brite/beige adipose tissues. However, functional analysis of the browning process yields confusingly different results when the analysis is performed in one of two alternative steps. Thus, in one of the steps, using cold acclimation as a potent model browning agent, we find that if the browning process is followed in mice initially housed at 21 °C (the most common procedure), there is only weak molecular evidence for increases in UCP1 gene expression or UCP1 protein abundance in classical brown adipose tissue; however, in brite/beige adipose depots, there are large increases, apparently associating functional browning with events only in the brite/beige tissues. Contrastingly, in another step, if the process is followed starting with mice initially housed at 30 °C (thermoneutrality for mice, thus similar to normal human conditions), large increases in UCP1 gene expression and UCP1 protein abundance are observed in the classical brown adipose tissue depots; there is then practically no observable UCP1 gene expression in brite/beige tissues. This apparent conundrum can be resolved when it is realized that the classical brown adipose tissue at 21 °C is already essentially fully differentiated and thus expands extensively through proliferation upon further browning induction, rather than by further enhancing cellular differentiation. When the limiting factor for thermogenesis, i.e. the total amount of UCP1 protein per depot, is analyzed, classical brown adipose tissue is by far the predominant site for the browning process, irrespective of which of the two steps is analyzed. There are to date no published data demonstrating that alternative browning agents would selectively promote brite/beige tissues versus classical brown tissue to a higher degree than does cold acclimation. Thus, to restrict investigations to examine adipose tissue depots where only a limited part of the adaptation process occurs (i.e. the brite/beige tissues) and to use initial conditions different from the thermoneutrality normally experienced by adult humans may seriously hamper the identification of therapeutically valid browning agents. The data presented here have therefore important implications for the analysis of the potential of browning agents and the nature of human brown adipose tissue.

  • 53. Keller, Pernille
    et al.
    Gburcik, Valentina
    Petrovic, Natasa
    Stockholm University, Faculty of Science, The Wenner-Gren Institute, Physiology.
    Gallagher, Iain J.
    Nedergaard, Jan
    Stockholm University, Faculty of Science, The Wenner-Gren Institute, Physiology.
    Cannon, Barbara
    Stockholm University, Faculty of Science, The Wenner-Gren Institute, Physiology.
    Timmons, James A.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute, Physiology.
    Gene-chip studies of adipogenesis-regulated microRNAs in mouse primary adipocytes and human obesity2011In: BMC Endocrine Disorders, E-ISSN 1472-6823, Vol. 11, p. 7-Article in journal (Refereed)
    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.

  • 54.
    Kramarova, Tatiana V.
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Shabalina, Irina G.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Andersson, Ulf
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Westerberg, Rolf
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Carlberg, Inger
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Houstek, Josef
    Nedergaard, Jan
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Cannon, Barbara
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Mitochondrial ATP synthase levels in brown adipose tissue are governed by the c-Fo subunit P1 isoform2008In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 22, no 1, p. 55-63Article in journal (Refereed)
    Abstract [en]

    Despite the significance of mitochondrial ATP synthase for mammalian metabolism, the regulation of the amount of ATP synthase in mammalian systems is not understood. As brown adipose tissue mitochondria contain very low amounts of ATP synthase, relative to respiratory chain components, they constitute a physiological system that allows for examination of the control of ATP synthase assembly. To examine the role of the expression of the P1-isoform of the c-F-o subunit in the biogenesis of ATP synthase, we made transgenic mice that express the P1-c subunit isoform under the promoter of the brown adipose tissue-specific protein UCP1. In the resulting UCP1p1 transgenic mice, total P1-c subunit mRNA levels were increased; mRNA levels of other F1F(o)-ATPase subunits were unchanged. In isolated brown-fat mitochondria, protein levels of the total c-Fo subunit were increased. Remarkably, protein levels of ATP synthase subunits that are part of the F-1-ATPase complex were also increased, as was the entire Complex V. Increased ATPase and ATP synthase activities demonstrated an increased functional activity of the F1Fo-ATPase. Thus, the levels of the c-F-o subunit P1-isoform are crucial for defining the final content of the ATP synthase in brown adipose tissue. The level of c-F-o subunit may be a determining factor for F1Fo-ATPase assembly in all higher eukaryotes.-Kramarova, T. V., Shabalina, I. G., Andersson, U., Westerberg, R., Carlberg, I., Houstek, J., Nedergaard, J., Cannon, B. Mitochondrial ATP synthase levels in brown adipose tissue are governed by the c-F-o subunit P1 isoform.

  • 55. Kramarova, Tatiana V
    et al.
    Shabalina, Irina G
    Andersson, Ulf
    Westerberg, Rolf
    Carlberg, Inger
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Houstek, Josef
    Nedergaard, Jan
    Cannon, Barbara
    Mitochondrial ATP synthase levels in brown adipose tissue are governed by the c-Fo subunit P1 isoform.2007In: FASEB J, ISSN 1530-6860Article in journal (Refereed)
  • 56.
    Luijten, Ineke
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Brooks, Katie
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Boulet, Nathalie
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Shabalina, Irina
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Jaiprakash, Ankita
    Carlsson, Bo
    Fischer, Alexander
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Cannon, Barbara
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Nedergaard, Jan
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Glucocorticoid-induced obesity develops independently of UCP1Manuscript (preprint) (Other academic)
    Abstract [en]

    An excess of glucocorticoids is associated with the development of obesity, as is evident from the accumulation of visceral fat in patients suffering from Cushing’s Syndrome. Activated brown adipose tissue (BAT) reduces metabolic efficiency; correspondingly an inactivation of BAT has been proposed to cause glucocorticoid-induced obesity. Here we determine the extent to which changes in BAT function as a result of glucocorticoid treatment contribute to the simultaneous development of obesity. In mice housed at 21 °C and treated with corticosterone for 2 weeks (CORT), we unexpectedly found no change in total BAT uncoupling protein 1 (UCP1) protein levels or in non-shivering thermogenic capacity. In mice housed at thermoneutrality, a humanized condition, we did observe a reduction in total UCP1 protein levels in BAT in response to CORT, which was reflected in reduced brown adipocyte cellular and mitochondrial UCP1-dependent respiration. However, glucocorticoid-induced obesity developed to the same extent in animals housed at 21 °C and 30 °C, while total BAT UCP1 protein levels differed 100-fold between the two groups. In wild-type and UCP1 knock-out mice housed at 30 °C and treated with CORT, obesity also developed to the same extent. Thus, contrary to what has previously been suggested, our results show that the development of glucocorticoid-induced obesity is unrelated to the presence of UCP1.

  • 57.
    Luijten, Ineke
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Feldmann, Helena
    von Essen, Gabriella
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Cannon, Barbara
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Nedergaard, Jan
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    In the absence of UCP1-mediated diet-induced thermogenesis, obesity is augmented even in the obesity-resistant 129S mouse strainManuscript (preprint) (Other academic)
    Abstract [en]

    The attractive tenet that recruitment and activation of brown adipose tissue (BAT) and Uncoupling Protein 1 (UCP1) could counteract the development of obesity and its comorbidities in humans has been experimentally corroborated mainly by experiments demonstrating that UCP1-ablated mice on a C57Bl/6 background (housed exempt from thermal stress) become more obese when fed a high-fat diet. However, concerns may be raised that this outcome of UCP1 ablation is restricted to this very special inbred and particularly obesity-prone mouse strain. We have therefore examined to which degree UCP1 ablation has similar metabolic effects in a mouse strain known tobe obesity resistant: the 129S strain. For this, male 129S2/sv or 129SV/Pas mice and corresponding UCP1-KO mice were fed chow, or a high-fat or a cafeteria diet for 4 weeks. The absence of UCP1 augmented obesity (weight gain, body fat mass, % body fat, fat depot size) in high-fat diet- and cafeteria-fed mice, with a similar or lower food intake, indicating that, when present, UCP1 indeed decreases metabolic efficiency. The increased obesity was due to a decrease in energy expenditure. The consumption of a high-fat or cafeteria diet increased total BAT UCP1 protein levels in wild-type mice, and correspondingly, high-fat diet and cafeteria diet-fed mice demonstrated increased norepinephrine-induced oxygen consumption. There was a positive correlation between body fat and total BAT UCP1 protein content. No evidence for diet-induced adrenergic thermogenesis was found in UCP1-ablated mice. Thus, the obesity-reducing effect of UCP1 is not restricted to a particular, and perhaps not representative, mouse strain. 

  • 58.
    Luijten, Ineke H. N.
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Brooks, Katie
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Boulet, Nathalie
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Shabalina, Irina G.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Jaiprakash, Ankita
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Carlsson, Bo
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Fischer, Alexander W.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. University Medical Center Hamburg Eppendor, Germany.
    Cannon, Barbara
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Nedergaard, Jan
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Glucocorticoid-Induced Obesity Develops Independently of UCP12019In: Cell Reports, E-ISSN 2211-1247, Vol. 27, no 6, p. 1686-1698Article in journal (Refereed)
    Abstract [en]

    An excess of glucocorticoids leads to the development of obesity in both mice and humans, but the mechanism for this is unknown. Here, we determine the extent to which decreased BAT thermogenic capacity (as a result of glucocorticoid treatment) contributes to the development of obesity. Contrary to previous suggestions, we show that only in mice housed at thermoneutrality (30 degrees C) does corticosterone treatment reduce total BAT UCP1 protein. This reduction is reflected in reduced brown adipocyte cellular and mitochondrial UCP1-dependent respiration. However, glucocorticoid-induced obesity develops to the same extent in animals housed at 21 degrees C and 30 degrees C, whereas total BAT UCP1 protein levels differ 100-fold between the two groups. In corticosterone-treated wild-type and UCP1 knockout mice housed at 30 degrees C, obesity also develops to the same extent. Thus, our results demonstrate that the development of glucocorticoid-induced obesity is not caused by a decreased UCP1-dependent thermogenic capacity.

  • 59.
    Luijten, Ineke H. N.
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Cannon, Barbara
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Nedergaard, Jan
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Glucocorticoids and Brown Adipose Tissue: Do glucocorticoids really inhibit thermogenesis?2019In: Molecular Aspects of Medicine, ISSN 0098-2997, E-ISSN 1872-9452, Vol. 68, p. 42-59Article, review/survey (Refereed)
    Abstract [en]

    A reduction in the thermogenic activity of brown adipose tissue (BAT) is presently discussed as a possible determinant for the development of obesity in humans. One group of endogenous factors that could potentially affect BAT activity is the glucocorticoids (e.g. cortisol). We analyse here studies examining the effects of alterations in glucocorticoid signaling on BAT recruitment and thermogenic capacity. We find that irrespective of which manipulation of glucocorticoid signaling is examined, a seemingly homogeneous picture of lowered thermogenic capacity due to glucocorticoid stimulation is apparently obtained: e.g. lowered uncoupling protein 1 (UCP1) protein levels per mg protein, and an increased lipid accumulation in BAT. However, further analyses generally indicate that these effects result from a dilution effect rather than a true decrease in total capacity; the tissue may thus be said to be in a state of pseudo-atrophy. However, under conditions of very low physiological stimulation of BAT, glucocorticoids may truly inhibit Ucp1 gene expression and consequently lower total UCP1 protein levels, but the metabolic effects of this reduction are probably minor. It is thus unlikely that glucocorticoids affect organismal metabolism and induce the development of obesity through alterations of BAT activity.

  • 60.
    Luijten, Ineke H. N.
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Feldmann, Helena M.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    von Essen, Gabriella
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Cannon, Barbara
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Nedergaard, Jan
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    In the absence of UCP1-mediated diet-induced thermogenesis, obesity is augmented even in the obesity-resistant 129S mouse strain2019In: American Journal of Physiology. Endocrinology and Metabolism, ISSN 0193-1849, E-ISSN 1522-1555, Vol. 316, no 5, p. E729-E740Article in journal (Refereed)
    Abstract [en]

    The attractive tenet that recruitment and activation of brown adipose tissue (BAT) and uncoupling protein 1 (UCP1) could counteract the development of obesity and its comorbidities in humans has been experimentally corroborated mainly by experiments demonstrating that UCP1-ablated mice on a C57B1/6 background (exempt from thermal stress) become more obese when fed a high-fat diet. However, concerns may be raised that this outcome of UCP1 ablation is restricted to this very special inbred and particularly obesity-prone mouse strain. Therefore, we have examined to which degree UCP1 ablation has similar metabolic effects in a mouse strain known to be obesity resistant: the 129S strain. For this, male 129S2/sv or 129SV/Pas mice and corresponding UCP1-knockout mice were fed chow or a high-fat or a cafeteria diet for 4 w.k. The absence of UCP1 augmented obesity (weight gain, body fat mass, %body fat, fat depot size) in high-fat diet- and cafeteria-fed mice, with a similar or lower food intake, indicating that, when present, UCP1 indeed decreases metabolic efficiency. The increased obesity was due to a decrease in energy expenditure. The consumption of a high-fat or cafeteria diet increased total BAT UCP1 protein levels in wild-type mice, and correspondingly. high-fat diet and cafeteria diet-fed mice demonstrated increased norepinephrine-induced oxygen consumption. There was a positive correlation between body fat and total BAT UCP1 protein content. No evidence for diet-induced adrenergic thermogenesis was found in UCP1-ablated mice. Thus, the obesity-reducing effect of UCP1 is not restricted to a particular, and perhaps not representative, mouse strain.

  • 61.
    Luijten, Ineke
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Jaiprakash, Ankita
    Hettinga, Laura
    Gao, Yun
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Cannon, Barbara
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Nedergaard, Jan
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Ucp1 transcription is regulated by glucocorticoid receptor binding at Ucp1 regulatory regionsManuscript (preprint) (Other academic)
    Abstract [en]

    Glucocorticoids suppress Ucp1gene expression in brown adipocytes (BA) and brite/beige adipocytes (WA) in a cell-autonomous manner. The intracellular mechanism through which this suppression is mediated is not known. In in vitrodifferentiated primary cultures of murine brown and brite pre-adipocytes, the presence of dexamethasone (DEX) significantly reduced adrenergically-induced Ucp1mRNA levels, but upregulated the expression of other adrenergically-regulated genes. Additionally, DEX treatment increased NE-induced cAMP accumulation in BA. We thus conclude that the glucocorticoid-induced downregulation of Ucp1transcription occurs independently of a glucocorticoid-induced upregulation of the adrenergic signaling pathway. Using chromatin immunoprecipitation in combination with DNA sequencing in brown adipose tissue isolated from C57Bl/6 and BALB/c mice, we identified 6 glucocorticoid receptor binding sites in Ucp1active enhancer regions marked by H3K27ac. Luciferase reporter gene assays in the BA WT1 cell line indicated that the liganded GR binds to a regulatory region 0-4 kb upstream of the Ucp1transcription start site and thereby suppresses transcription. Thus, our study has identified a direct regulation of Ucp1transcription by the glucocorticoid receptor that occurs independently of the effects of glucocorticoids on adrenergic signaling. 

  • 62. 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
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Physiology.
    Nedergaard, Jan
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Physiology.
    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.2010In: PloS one, ISSN 1932-6203, Vol. 5, no 6, p. e11391-Article in journal (Refereed)
    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.

  • 63.
    Mattsson, Charlotte L.
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Andersson, Emma R.
    Department of Cell and Molecular Biology, Karolinska Institute, SE-171 77 Stockholm, Sweden.
    Nedergaard, Jan
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Differential involvement of caveolin-1 in brown adipocyte signaling: impaired b3-adrenergic but unaffected LPA, PDGF and EGF receptorManuscript (preprint) (Other academic)
  • 64.
    Mattsson, Charlotte L
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Physiology.
    Andersson, Emma R
    Nedergaard, Jan
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Differential involvement of caveolin-1 in brown adipocyte signaling: impaired beta3-adrenergic, but unaffected LPA, PDGF and EGF receptor signaling.2010In: Biochimica et Biophysica Acta, ISSN 0006-3002, E-ISSN 1878-2434, Vol. 1803, no 8, p. 983-9Article in journal (Refereed)
    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

  • 65.
    Mattsson, Charlotte L.
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Csikasz, Robert I.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Shabalina, Irina G.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Nedergaard, Jan
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Cannon, Barbara
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Caveolin-1-ablated mice survive cold by nonshivering thermogenesis, despite desensitized adrenergic receptorsManuscript (preprint) (Other academic)
  • 66.
    Mattsson, Charlotte L
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Physiology.
    Csikasz, Robert I
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Physiology.
    Shabalina, Irina G
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Physiology.
    Nedergaard, Jan
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Physiology.
    Cannon, Barbara
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Physiology.
    Caveolin-1-ablated mice survive in cold by nonshivering thermogenesis despite desensitized adrenergic responsiveness2010In: American Journal of Physiology. Endocrinology and Metabolism, ISSN 0193-1849, E-ISSN 1522-1555, Vol. 299, no 3, p. E374-83Article in journal (Refereed)
    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.

  • 67.
    Nabben, Miranda
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Shabalina, Irina G.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Moonen-Kornips, Esther
    van Beurden, Denis
    Cannon, Barbara
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Schrauwen, Patrick
    Nedergaard, Jan
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Hoeks, Joris
    Uncoupled respiration, ROS production, acute lipotoxicity and oxidative damage in isolated skeletal muscle mitochondria from UCP3-ablated mice2011In: Biochimica et Biophysica Acta - Bioenergetics, ISSN 0005-2728, E-ISSN 1879-2650, Vol. 1807, no 9, p. 1095-1105Article in journal (Refereed)
    Abstract [en]

    The function of uncoupling protein 3 (UCP3) is still not established. Mitochondrial uncoupling, control of ROS production, protection against lipotoxicity and protection against oxidative stress are functions classically discussed. To establish a role for UCP3 in these functions, we have here used UCP3 (-/-) mice, backcrossed for 10 generations on a C57Bl/6 background. In isolated skeletal muscle mitochondria, we examined uncoupled respiration, both unstimulated and in the presence of fatty acids. We did not observe any difference between mitochondria from wildtype and UCP3 (-/-) mice. We measured H(2)O(2) production rate and respiration rate under reactive oxygen species-generating conditions (succinate without rotenone) but found no effect of UCP3. We tested two models of acute lipotoxicity fatty add-induced oxidative inhibition and fatty acid-induced swelling-but did not observe any protective effect of UCP3. We examined oxidative stress by quantifying 4-hydroxynonenal protein adducts and protein carbonyls in the mitochondria-but did not observe any protective effect of UCP3. We conclude that under the experimental conditions tested here, we find no evidence for the function of UCP3 being basal or induced uncoupling, regulation of ROS production, protection against acute lipotoxicity or protection against oxidative damage.

  • 68.
    Nedergaard, Jan
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Control of fatty acid utilization in brown adipose tissue1980Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    In order to keep warm in cold surroundings, mammals have developed a mechanism for non-shivering thermogenesis. The major part of this heat production takes place in brown adipose tissue. The heat results from combustion of fatty acids. In experiments performed with isolated brown fat cells and mitochondria from hamsters and rats, the control of fatty acid utilization in the tissue has been investigated. Optimal conditions for fatty acid export from and for fatty acid combustion in brown fat cells have been established, and the effects of norepinephrine and insulin on the cells measured. Catecholamine sensitivity has been reintroduced into cells from cold-adapted animals. Factors which control peroxisomal β-oxidation and mitochondrial pyruvate carboxylation have been investigated. A hypothesis is suggested, according to which catecholamine- elicited increase in plasma membrane Na permeability leads to increased cytosolic Ca++ through the action of the mitochondrial Na+ /Ca++ exchange; such an increased cytosolic Ca++ concentration may have regulatory functions; eg. it may, by stimulation of the mitochondrial glycerol -3-phosphate dehydrogenase, direct fatty acids towards combustion (and not towards re-esterification) during thermogenesis. The heat production of norepinephrine-stimulated isolated brown fat cells has been directly measured; it is established that the capacity for heat production (about 0.3 W per gram wet weight) would be sufficient to counteract the heat loss of mammals in cold surroundings.

  • 69.
    Nedergaard, Jan
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Bengtsson, Tore
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Cannon, Barbara
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    New Powers of Brown Fat: Fighting the Metabolic Syndrome2011In: Cell Metabolism, ISSN 1550-4131, E-ISSN 1932-7420, Vol. 13, no 3, p. 238-240Article in journal (Refereed)
    Abstract [en]

    An understanding of the full powers of brown adipose tissue (BAT) is only successively being accumulated. In a paper in Nature Medicine, Bartelt et al. (2011) add further impressive aspects to the potential powers of BAT in the combat against the metabolic syndrome by demonstrating its vast capacity for triglyceride clearance and glucose disposal.

  • 70.
    Nedergaard, Jan
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute, Physiology.
    Bengtsson, Tore
    Stockholm University, Faculty of Science, The Wenner-Gren Institute, Physiology.
    Cannon, Barbara
    Stockholm University, Faculty of Science, The Wenner-Gren Institute, Physiology.
    Three years with adult human brown adipose tissue2010In: Annals of the New York Academy of Sciences, ISSN 0077-8923, E-ISSN 1749-6632, Vol. 1212, p. E20-E36Article in journal (Refereed)
    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.

  • 71.
    Nedergaard, Jan
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Cannon, Barbara
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Brown adipose tissue: development and function2011In: Fetal and neonatal physiology / [ed] Richard A Polin, William W Fox and Steven H Abman, Philadelphia, PA: Saunders Elsevier, 2011, 4th ed., p. 470-482Chapter in book (Refereed)
  • 72.
    Nedergaard, Jan
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Cannon, Barbara
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Diet-Induced Thermogenesis: Principles and Pitfalls2022In: Brown Adipose Tissue: Methods and Protocols / [ed] David A. Guertin, Christian Wolfrum, New York: Humana Press, 2022, p. 177-202Chapter in book (Refereed)
    Abstract [en]

    Concerning diet-induced thermogenesis, methodological issues relate mainly to the interpretation of measurements, rather than to the technical methodology as such. In the following, we point to a series of issues where the analysis often suggests the occurrence of UCP1-related diet-induced thermogenesis but where the observations are often the consequences of a process that has induced leanness rather than being the cause of them. We particularly emphasize the necessity of focusing on the total organism when interpreting biochemical and molecular data, where the concept of total tissue values rather than relative data better reflects physiologically important alterations. We stress the importance of performing experiments at thermoneutrality in order to obtain clinically relevant data and stress that true thermogenic agents may be overlooked if this is not done. 

  • 73.
    Nedergaard, Jan
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Cannon, Barbara
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    How brown is brown fat?: It depends where you look2013In: Nature Medicine, ISSN 1078-8956, E-ISSN 1546-170X, Vol. 19, no 5, p. 540-541Article in journal (Other academic)
    Abstract [en]

    Although it is now accepted that adult humans possess active brown adipose tissue, it has been questioned whether this is genuine classical brown adipose tissue. Two new studies provide evidence that humans, both as babies and adults, do have classical brown tissue and also indicate that there is heterogeneity in the composition of brown fat depots in humans, as in mice (

  • 74.
    Nedergaard, Jan
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Cannon, Barbara
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    The Browning of White Adipose Tissue: Some Burning Issues2014In: Cell Metabolism, ISSN 1550-4131, E-ISSN 1932-7420, Vol. 20, no 3, p. 396-407Article, review/survey (Refereed)
    Abstract [en]

    Igniting thermogenesis within white adipose tissue (i.e., promoting expression and activity of the uncoupling protein UCP1) has attracted much interest. Numerous browning agents'' have now been described (gene ablations, transgenes, foodcomponents, drugs, environments, etc.). The implied action of browning agents is that they increase UCP1 through this heat production, leading to slimming. Here, we particularly point to the possibility that cause and effect may on occasion be the reverse: browning agents may disrupt, for example, the fur, leading to increased heat loss, increased thermogenic demand to counteract this heat loss, and thus, through sympathetic nervous system activation, to enhanced UCP1 expression in white (and brown) adipose tissues.

  • 75.
    Nedergaard, Jan
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Cannon, Barbara
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    The changed metabolic world with human brown adipose tissue: therapeutic visions2010In: Cell metabolism, ISSN 1932-7420, Vol. 11, no 4, p. 268-272Article in journal (Refereed)
    Abstract [en]

    That adult humans possess active brown adipose tissue potentially leads to a paradigm shift in the understanding of human metabolism and of obesity. Adaptive adrenergic thermogenesis in humans represents brown adipose tissue activity, the absence of which may contribute to middle-age obesity.

  • 76.
    Nedergaard, Jan
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Cannon, Barbara
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    UCP1 mRNA does not produce heat2013In: Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids, ISSN 1388-1981, E-ISSN 1879-2618, Vol. 1831, no 5, p. 943-949Article in journal (Refereed)
    Abstract [en]

    Because of the possible role of brown adipose tissue and UCP1 in metabolic regulation, even in adult humans, there is presently considerable interest in quantifying, from in-vitro data, the thermogenic capacities of brown and brite/beige adipose tissues. An important issue is therefore to establish which parameters are the most adequate for this. A particularly important issue is the relevance of UCP1 mRNA levels as estimates of the degree of recruitment and of the thermogenic capacity resulting from differences in physiological conditions and from experimental manipulations. By solely following UCP1 mRNA levels in brown adipose tissue, the conclusion would be made that the tissue's highest activation occurs after only 6 h in the cold and then successively decreases to being only some 50% elevated after 1 month in the cold. However, measurement of total UCP1 protein levels per depot (mouse) reveals that the maximal thermogenic capacity estimated in this way is reached first after 1 month but represents an approx. 10-fold increase in thermogenic capacity. Since this in-vitro measure correlates quantitatively and temporally with the acquisition of nonshivering thermogenesis, this must be considered the most physiologically relevant parameter. Similarly, observations that cold acclimation barely increases UCP1 mRNA levels in classical brown adipose tissue but leads to a 200-fold increase in UCP1 mRNA levels in brite/beige adipose tissue depots may overemphasise the physiological significance of these depots, as the high fold-increases are due to very low initial levels, and the UCP1 mRNA levels reached are at least an order of magnitude lower than in brown adipose tissue; furthermore, based on total UCP1 protein amounts, the brite/beige depots attain only about 10% of the thermogenic capacity of the classical brown adipose tissue depots. Consequently, inadequate conclusions may be reached if UCP1 mRNA levels are used as a proxy for the metabolic significance of recruited versus non-recruited brown adipose tissue and for estimating the metabolic significance of brown versus brite/beige adipose tissues. This article is part of a Special Issue entitled Brown and White Fat: From Signaling to Disease.

  • 77.
    Nedergaard, Jan
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Fischer, Alexander W.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Cannon, Barbara
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Leptin as an Antitorpor Hormone: An Explanation for the Increased Metabolic Efficiency and Cold Sensitivity of ob/ob Mice?2023In: Physiological and Biochemical Zoology, ISSN 1522-2152, E-ISSN 1537-5293, Vol. 96, no 1, p. 30-39Article in journal (Refereed)
    Abstract [en]

    Leptin is recognized as an anorexigenic hormone. In its absence (e.g., in ob/ob mutant mice), mice become obese, primarily as a result of hyperphagia. A recurrent question is whether, additionally, leptin is thermogenic and thus also an antiobesity hormone in this way. We have earlier reviewed available data and have concluded that most articles implying a thermogenic effect of leptin have based this on a misconstrued division by body weight. Here, we have collected evidence that the remaining observations that imply that leptin is a thermogenic hormone are better understood as implying that leptin is an antitorpor hormone. Leptin levels increase in proportion to the body's energy reserves (i.e., stored lipids in the adipose tissue), and leptin thus serves as an indicator of energy availability. In the absence of leptin, ob/ob mice are exceedingly prone to enter daily torpor, since the absence of leptin causes them to perceive a lack of body energy reserves that, in combination with restricted or no food, induces them to enter the torpid state to save energy. This antitorpor effect of leptin probably explains the following earlier observations. First, ob/ob mice have the ability to gain weight even when pair fed with leptin-treated ob/ob mice. This is understood as follows: In the leptin-treated ob/ob mice, food intake is reduced. Untreated pair-fed mice enter daily torpor, and this markedly lowers total daily energy expenditure; the resulting surplus food energy is then accumulated as fat in these mice. However, ob/ob mice fed ad lib. do not enter torpor, so under normal conditions this mechanism does not contribute to the obesity found in the ob/ob mice. Second, neonatal ob/ob mice have the ability to become obese despite eating the same amount as wild-type mice: this is understood as these mice similarly entering daily torpor. Third, ob/ob mice on the C57BL/6J background have a lower metabolic rate: these mice were examined in the absence of food, and torpor was thus probably induced. Fourth, ob/ob mice have apparent high cold sensitivity: these mice experienced cold in the absence of food and would immediately enter deep torpor. It is suggested that this novel explanation of how the antitorpor effects of leptin affect mouse energy metabolism can open new avenues for leptin research.

  • 78.
    Nedergaard, Jan
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute.
    Shabalina, Irina
    Stockholm University, Faculty of Science, The Wenner-Gren Institute.
    Mild uncoupling to counteract ROS production: Physiologically relevant or not?2012In: Biochimica et Biophysica Acta - Bioenergetics, ISSN 0005-2728, E-ISSN 1879-2650, Vol. 1817, no Suppl., p. S96-S97Article in journal (Refereed)
  • 79.
    Nedergaard, Jan
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    von Essen, Gabriella
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Cannon, Barbara
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Brown adipose tissue: can it keep us slim? A discussion of the evidence for and against the existence of diet-induced thermogenesis in mice and men2023In: Philosophical Transactions of the Royal Society of London. Biological Sciences, ISSN 0962-8436, E-ISSN 1471-2970, Vol. 378, no 1888, article id 20220220Article, review/survey (Refereed)
    Abstract [en]

    The issue under discussion here is whether a decrease in the degree of UCP1 activity (and brown adipose tissue activity in general) could be a cause of obesity in humans. This possibility principally requires the existence of the phenomenon of diet-induced thermogenesis. Obesity could be a consequence of a reduced functionality of diet-induced thermogenesis. Experiments in mice indicate that diet-induced thermogenesis exists and is dependent on the presence of UCP1 and thus of brown adipose tissue activity. Accordingly, many (but not all) experiments indicate that in the absence of UCP1, mice become obese. Whether similar mechanisms exist in humans is still unknown. A series of studies have indicated a correlation between obesity and low brown adipose tissue activity, but it may be so that the obesity itself may influence the estimates of brown adipose tissue activity (generally glucose uptake), partly explaining the relationship. Estimates of brown adipose tissue catabolizing activity would seem to indicate that it may possess a capacity sufficient to help maintain body weight, and obesity would thus be aggravated in its absence.

  • 80.
    Nedergaard, Jan
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Wang, Yanling
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Cannon, Barbara
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Cell proliferation and apoptosis inhibition: essential processes for recruitment of the full thermogenic capacity-of-brown-adipose-tissue2019In: Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids, ISSN 1388-1981, E-ISSN 1879-2618, Vol. 1864, no 1, p. 51-58Article, review/survey (Refereed)
    Abstract [en]

    In mice living under normal animal house conditions, the brown adipocytes in classical brown adipose tissue depots are already essentially fully differentiated: UCP1 mRNA and UCP1 protein levels are practically saturated. This means that any further recruitment in response to cold exposure or any other browning agent - does not result in significant augmentation of these parameters. This may easily be construed to indicate that classical brown adipose tissue cannot be further recruited. However, this is far from the case: the capacity for further recruitment instead lies in the ability of the tissue to increase the number of brown-fat cells, a remarkable and highly controlled physiological recruitment process. We have compiled here the available data concerning the unique ability of norepinephrine to increase cell proliferation and inhibit apoptosis in brown adipocytes. Adrenergically stimulated cell proliferation is fully mediated via beta(1)-adrenoceptors and occurs through activation of stem cells in the tissue; intracellular mediation of the signal involves CAMP and protein kinase A activation, but activation of Erk1/2 is not part of the pathway. Apoptosis inhibition in brown adipocytes is induced by both beta- and alpha(1)-adrenergic receptors and here the intracellular pathway includes Erk1/2 activation. This unique ability of norepinephrine to increase cell number in an apparently mitogenically dormant tissue provides possibilities to augment the metabolic capacity of brown adipose tissue, also for therapeutic purposes.

  • 81.
    Olsen, Jessica M.
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. Karolinska University Hospital Solna, Sweden.
    Csikasz, Robert I.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. Karolinska University Hospital Solna, Sweden.
    Dehvari, Nodi
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Lu, Li
    Sandström, Anna
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Öberg, Anette I.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Nedergaard, Jan
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Stone-Elander, Sharon
    Bengtsson, Tore
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    β3-Adrenergically induced glucose uptake in brown adipose tissue is independent of UCP1 presence or activity: Mediation through the mTOR pathway2017In: Molecular Metabolism, ISSN 2212-8778, Vol. 6, no 6, p. 611-619Article in journal (Refereed)
    Abstract [en]

    Objective

    Today, the presence and activity of brown adipose tissue (BAT) in adult humans is generally equated with the induced accumulation of [2-18F]2-fluoro-2-deoxy-d-glucose([18F]FDG) in adipose tissues, as investigated by positron emission tomography (PET) scanning. In reality, PET-FDG is currently the only method available for in vivoquantification of BAT activity in adult humans. The underlying assumption is that the glucose uptake reflects the thermogenic activity of the tissue.

    Methods

    To examine this basic assumption, we here followed [18F]FDG uptake by PET and by tissue [3H]-2-deoxy-d-glucose uptake in wildtype and UCP1(−/−) mice, i.e. in mice that do or do not possess the unique thermogenic and calorie-consuming ability of BAT.

    Results

    Unexpectedly, we found that β3-adrenergically induced (by CL-316,243) glucose uptake was UCP1-independent. Thus, whereas PET-FDG scans adequately reflect glucose uptake, this acute glucose uptake is not secondary to thermogenesis but is governed by an independent cellular signalling, here demonstrated to be mediated via the previously described KU-0063794-sensitive mTOR pathway.

    Conclusions

    Thus, PET-FDG scans do not exclusively reveal active BAT deposits but rather any tissue possessing an adrenergically-mediated glucose uptake pathway. In contrast, we found that the marked glucose uptake-ameliorating effect of prolonged β3-adrenergictreatment was UCP1 dependent. Thus, therapeutically, UCP1 activity is required for any anti-diabetic effect of BAT activation.

  • 82.
    Otton, Rosemari
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. Cruzeiro do Sul University, Brazil.
    Petrovic, Natasa
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Cannon, Barbara
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Nedergaard, Jan
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    On the Validity of Adipogenic Cell Lines as Model Systems for Browning Processes: In Authentic Brown, Brite/Beige, and White Preadipocytes, There is No Cell-Autonomous Thermogenic Recruitment by Green Tea Compounds2021In: Frontiers in Nutrition, E-ISSN 2296-861X, Vol. 8, article id 715859Article in journal (Refereed)
    Abstract [en]

    The potential ability of nutritional compounds to induce or enhance the browning of adipocytes has attracted large interest as a workable means of combatting the obesity epidemic. Green tea compounds are discussed as such inducers of an enhanced thermogenic capacity and activity. However, the cell-autonomous effects of green tea compounds on adipocytes have until now only been demonstrated in adipogenic cell lines (3T3-L1 and 3T3-F442A), i.e., cells of undefined tissue lineage. In this study, we examine the ability of green tea compounds to cell-autonomously induce thermogenic recruitment in authentic brown and brite/beige adipocytes in vitro. In primary brown adipocytes, the green tea compounds suppressed basal UCP1 gene expression, and there was no positive interaction between the compounds and adrenergic stimulation. In white adipocytes, green tea compounds decreased both basal and norepinephrine-induced UCP1 mRNA levels, and this was associated with the suppression of cell differentiation, indicated by reduced lipogenic gene expression and lipid accumulation. A lack of interaction between rosiglitazone and green tea compounds suggests that the green tea compounds do not directly interact with the PPARγ pathway. We conclude that there is a negative effect of the green tea compounds on basal UCP1 gene expression, in both brown and white primary adipocytes, in contrast to the positive effects earlier reported from studies in adipogenic cell lines. We posit that the epigenetic status of the adipogenic cell lines is fundamentally different from that of genuine brown and white adipocytes, reflected, e.g., in several-thousand-fold differences in UCP1 gene expression levels. Thus, results obtained with adipogenic cell lines cannot unreservedly be extrapolated as being relevant for authentic effects in brown and white adipocytes. We suggest that this conclusion can be of general concern for studies attempting to establish physiologically relevant cell-autonomous effects.

  • 83.
    Petrovic, Natasa
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Physiology.
    Walden, Tomas B
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Physiology.
    Shabalina, Irina G
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Physiology.
    Timmons, James A
    Cannon, Barbara
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Physiology.
    Nedergaard, Jan
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Physiology.
    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.2010In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 285, no 10, p. 7153-7164Article in journal (Refereed)
    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.

  • 84.
    Sabanov, Victor
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Nedergaard, Jan
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Ca2+-independent effects of BAPTA and EGTA on single-channel Cl- currents in brown adipocytes2007In: Biochimica et Biophysica Acta - Biomembranes, ISSN 0005-2736, E-ISSN 1879-2642, Vol. 1768, no 11, p. 2714-2725Article in journal (Refereed)
    Abstract [en]

    The Cl channels of brown adipocytes electrophysiologically resemble outwardly rectifying Cl channels (ORCC). To study tentative Ca2+ regulation of these channels, we attempted to control Ca2+ levels at the cytoplasmic side of the inside-out membrane patches with Ca2+-chelating agents. However, we found that the commonly used Ca2+-chelators EGTA and BAPTA by themselves influenced the Cl channel currents, unrelated to their calcium chelating effects. Consequently, in this report we delineate effects of Ca2+-chelators (acting from the cytoplasmic side) on the single Cl channel currents in patch-clamp experiments. Using fixed (1–2 mM) concentrations of chelators, two types of Cl channels were identified, as discriminated by their reaction to the Ca2+-chelators and by their conductance: true-blockage channels (31 pS) and quasi-blockage channels (52 pS). In true-blockage channels, EGTA and BAPTA inhibited channel activity in a classical flickery type manner. In quasi-blockage channels, chelators significantly shortened the duration of individual openings, as in a flickering block, but the overall channel activity tended to increase. This dual effect of mean open time decrease accompanied by a tendency of open probability to increase we termed a quasi-blockage. Despite the complications due to the chelators as such, we could detect a moderate inhibitory effect of Ca2+. The anionic classical Cl channel blockers DIDS and SITS could mimic the true/quasi blockage of EGTA and BAPTA. It was concluded that at least in this experimental system, standard techniques for Ca2+ level control in themselves could fundamentally affect the behaviour of Cl channels.

  • 85. Sahlin, Kent
    et al.
    Shabalina, Irina G
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Physiology.
    Mattsson, C Mikael
    Bakkman, Linda
    Fernström, Maria
    Rozhdestvenskaya, Zinaida
    Enqvist, Jonas K
    Nedergaard, Jan
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Physiology.
    Ekblom, Björn
    Tonkonogi, Michail
    Ultraendurance exercise increases the production of reactive oxygen species in isolated mitochondria from human skeletal muscle2010In: Journal of applied physiology, ISSN 8750-7587, E-ISSN 1522-1601, Vol. 108, no 4, p. 780-7Article in journal (Refereed)
    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.

  • 86.
    Shabalina, Irina
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Edgar, Daniel
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Gibanova, Natalia
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Kalinovich, Anastasia
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Petrovic, Natasa
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Vyssokikh, Mikhail Yu.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Cannon, Barbara
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Nedergaard, Jan
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Enhanced ROS Production in Mitochondria from Prematurely Aging mtDNA Mutator Mice2024In: Biochemistry (Moscow), ISSN 0006-2979, E-ISSN 1608-3040, Vol. 89, no 2, p. 279-298Article in journal (Refereed)
    Abstract [en]

    An increase in mitochondrial DNA (mtDNA) mutations and an ensuing increase in mitochondrial reactive oxygen species (ROS) production have been suggested to be a cause of the aging process (the mitochondrial hypothesis of aging). In agreement with this, mtDNA-mutator mice accumulate a large amount of mtDNA mutations, giving rise to defective mitochondria and an accelerated aging phenotype. However, incongruously, the rates of ROS production in mtDNA mutator mitochondria have generally earlier been reported to be lower - not higher - than in wildtype, thus apparently invalidating the mitochondrial hypothesis of aging. We have here re-examined ROS production rates in mtDNA-mutator mice mitochondria. Using traditional conditions for measuring ROS (succinate in the absence of rotenone), we indeed found lower ROS in the mtDNA-mutator mitochondria compared to wildtype. This ROS mainly results from reverse electron flow driven by the membrane potential, but the membrane potential reached in the isolated mtDNA-mutator mitochondria was 33 mV lower than that in wildtype mitochondria, due to the feedback inhibition of succinate oxidation by oxaloacetate, and to a lower oxidative capacity in the mtDNA-mutator mice, explaining the lower ROS production. In contrast, in normal forward electron flow systems (pyruvate (or glutamate) + malate or palmitoyl-CoA + carnitine), mitochondrial ROS production was higher in the mtDNA-mutator mitochondria. Particularly, even during active oxidative phosphorylation (as would be ongoing physiologically), higher ROS rates were seen in the mtDNA-mutator mitochondria than in wildtype. Thus, when examined under physiological conditions, mitochondrial ROS production rates are indeed increased in mtDNA-mutator mitochondria. While this does not prove the validity of the mitochondrial hypothesis of aging, it may no longer be said to be negated in this respect. This paper is dedicated to the memory of Professor Vladimir P. Skulachev.

  • 87.
    Shabalina, Irina G
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Physiology.
    Hoeks, Joris
    Kramarova, Tatiana V
    Schrauwen, Patrick
    Cannon, Barbara
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Physiology.
    Nedergaard, Jan
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Physiology.
    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.2010In: Biochimica et Biophysica Acta, ISSN 0006-3002, E-ISSN 1878-2434, Vol. 1797, no 6-7, p. 968-80Article in journal (Refereed)
    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.

  • 88.
    Shabalina, Irina G.
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Kalinovich, Anastasia V.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Cannon, Barbara
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Nedergaard, Jan
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Metabolically inert perfluorinated fatty acids directly activate uncoupling protein 1 in brown-fat mitochondria2016In: Archives of Toxicology, ISSN 0340-5761, E-ISSN 1432-0738, Vol. 90, no 5, p. 1117-1128Article in journal (Refereed)
    Abstract [en]

    The metabolically inert perfluorinated fatty acids perfluorooctane sulfonate (PFOS) and perfluorooctanoate (PFOA) can display fatty acid-like activity in biological systems. The uncoupling protein 1 (UCP1) in brown adipose tissue is physiologically (re)activated by fatty acids, including octanoate. This leads to bioenergetically uncoupled energy dissipation (heat production, thermogenesis). We have examined here the possibility that PFOA/PFOS can directly (re)activate UCP1 in isolated mouse brown-fat mitochondria. In wild-type brown-fat mitochondria, PFOS and PFOA overcame GDP-inhibited thermogenesis, leading to increased oxygen consumption and dissipated membrane potential. The absence of this effect in brown-fat mitochondria from UCP1-ablated mice indicated that it occurred through activation of UCP1. A competitive type of inhibition by increased GDP concentrations indicated interaction with the same mechanistic site as that utilized by fatty acids. No effect was observed in heart mitochondria, i.e., in mitochondria without UCP1. The stimulatory effect of PFOA/PFOS was not secondary to non-specific mitochondrial membrane permeabilization or to ROS production. Thus, metabolic effects of perfluorinated fatty acids could include direct brown adipose tissue (UCP1) activation. The possibility that this may lead to unwarranted extra heat production and thus extra utilization of food resources, leading to decreased fitness in mammalian wildlife, is discussed, as well as possible negative effects in humans. However, a possibility to utilize PFOA-/PFOS-like substances for activating UCP1 therapeutically in obesity-prone humans may also be envisaged.

  • 89.
    Shabalina, Irina G.
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Kramarova, Tatiana V.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Mattsson, Charlotte L.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Petrovic, Natasa
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Qazi, Mousumi Rahman
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Csikasz, Robert I.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Chang, Shu-Ching
    Butenhoff, John
    DePierre, Joseph W.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Cannon, Barbara
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Nedergaard, Jan
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    The Environmental Pollutants Perfluorooctane Sulfonate and Perfluorooctanoic Acid Upregulate Uncoupling Protein 1 (UCP1) in Brown-Fat Mitochondria Through a UCP1-Dependent Reduction in Food Intake2015In: Toxicological Sciences, ISSN 1096-6080, E-ISSN 1096-0929, Vol. 146, no 2, p. 334-343Article in journal (Refereed)
    Abstract [en]

    The environmental pollutants perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA) cause a dramatic reduction in the size of the major adipose tissue depots and a general body weight decrease when they are added to the food of mice. We demonstrate here that this is mainly due to a reduction in food intake; this reduction was not due to food aversion. Remarkably and unexpectedly, a large part of the effect of PFOA/PFOS on food intake was dependent on the presence of the uncoupling protein 1 (UCP1) in the mice. Correspondingly, PFOA/PFOS treatment induced recruitment of brown adipose tissue mitochondria: increased oxidative capacity and increased UCP1-mediated oxygen consumption (thermogenesis). In mice pair-fed to the food intake during PFOA/PFOS treatment in wildtype mice, brown-fat mitochondrial recruitment was also induced. We conclude that we have uncovered the existence of a regulatory component of food intake that is dependent upon brown adipose tissue thermogenic activity. The possible environmental consequences of this novel PFOA/PFOS effect (a possible decreased fitness) are noted, as well as the perspectives of this finding on the general understanding of control of food intake control and its possible extension to combatting obesity.

  • 90.
    Shabalina, Irina G.
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Landreh, Luise
    Edgar, Daniel
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. Karolinska Institutet, Sweden.
    Hou, Mi
    Gibanova, Natalia
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Atanassova, Nina
    Petrovic, Natasa
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Hultenby, Kjell
    Söder, Olle
    Nedergaard, Jan
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Svechnikov, Konstantin
    Leydig cell steroidogenesis unexpectedly escapes mitochondrial dysfunction in prematurely aging mice2015In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 29, no 8, p. 3274-3286Article in journal (Refereed)
    Abstract [en]

    Point mutations and deletions of mitochondrial DNA (mtDNA) accumulate in tissues during aging in animals and humans and are the basis for mitochondrial diseases. Testosterone synthesis occurs in the mitochondria of Leydig cells. Mitochondrial dysfunction (as induced here experimentally in mtDNA mutator mice that carry a proofreading-deficient form of mtDNA polymerase gamma, leading to mitochondrial dysfunction in all cells types so far studied) would therefore be expected to lead to low testosterone levels. Although mtDNA mutator mice showed a dramatic reduction in testicle weight (only 15% remaining) and similar decreases in number of spermatozoa, testosterone levels in mt DNA mutator mice were unexpectedly fully unchanged. Leydig cell did not escape mitochondrial damage (only 20% of complex I and complex IV remaining) and did show high levels of reactive oxygen species (ROS) production (>5-fold increased), and permeabilized cells demonstrated absence of normal mitochondrial function. Nevertheless, within intact cells, mitochondrial membrane potential remained high, and testosterone production was maintained. This implies development of a compensatory mechanism. A rescuing mechanism involving electronsfrom the pentose phosphate pathway transferred via a 3-fold up-regulated cytochrome b5 to cytochrome c, allowing for mitochondrial energization, is suggested. Thus, the Leydig cells escape mitochondrial dysfunction via a unique rescue pathway. Such a pathway, bypassing respiratory chain dysfunction, may be of relevance with regard to mitochondrial disease therapy and to managing ageing in general.

  • 91.
    Shabalina, Irina G.
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Nedergaard, Jan
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Mitochondrial ('mild') uncoupling and ROS production: physiologically relevant or not?2011In: Biochemical Society Transactions, ISSN 0300-5127, E-ISSN 1470-8752, Vol. 39, p. 1305-1309Article in journal (Refereed)
    Abstract [en]

    During the last decade, the possibility that 'mild' uncoupling could be protective against oxidative damage by diminishing ROS (reactive oxygen species) production has attracted much interest. In the present paper, we briefly examine the evidence for this possibility. It is only ROS production from succinate under reverse electron-flow conditions that is sensitive to membrane potential fluctuations, and so only this type of ROS production could be affected; however, the conditions under which succinate-supported ROS production is observed include succinate concentrations that are supraphysiological. Any decrease in membrane potential, even 'mild uncoupling', must necessarily lead to large increases in respiration, i.e. it must be markedly thermogenic. Mitochondria within cells are normally ATP-producing and thus already have a diminished membrane potential, and treatment of cells, organs or animals with small amounts of artificial uncoupler does not seem to have beneficial effects that are explainable via reduced ROS production. Although it has been suggested that members of the uncoupling protein family (UCP1, UCP2 and UCP3) may mediate a mild uncoupling, present evidence does not unequivocally support such an effect, e.g. the absence of the truly uncoupling protein UCP1 is not associated with increased oxidative damage. Thus present evidence does not support mild uncoupling as a physiologically relevant alleviator of oxidative damage.

  • 92.
    Shabalina, Irina G
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Physiology.
    Ost, Mario
    Petrovic, Natasa
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Physiology.
    Vrbacky, Marek
    Nedergaard, Jan
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Physiology.
    Cannon, Barbara
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Physiology.
    Uncoupling protein-1 is not leaky.2010In: Biochimica et Biophysica Acta, ISSN 0006-3002, E-ISSN 1878-2434, Vol. 1797, no 6-7, p. 773-84Article in journal (Refereed)
    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.

  • 93.
    Shabalina, Irina G.
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Petrovic, Natasa
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    de Jong, Jasper M. A.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Kalinovich, Anastasia
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Cannon, Barbara
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Nedergaard, Jan
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    UCP1 in Brite/Beige Adipose Tissue Mitochondria Is Functionally Thermogenic2013In: Cell Reports, E-ISSN 2211-1247, Vol. 5, no 5, p. 1196-1203Article in journal (Refereed)
    Abstract [en]

    The phenomenon of white fat browning, in which certain white adipose tissue depots significantly increase gene expression for the uncoupling protein UCP1 and thus supposedly acquire thermogenic, fat-burning properties, has attracted considerable attention. Because the mRNA increases are from very low initial levels, the metabolic relevance of the change is unclear: is the UCP1 protein thermogenically competent in these brite/beige-fat mitochondria? We found that, in mitochondria isolated from the inguinal white adipose depot of cold-acclimated mice, UCP1 protein levels almost reached those in brown-fat mitochondria. The UCP1 was thermogenically functional, in that these mitochondria exhibited UCP1-dependent thermogenesis with lipid or carbohydrate substrates with canonical guanosine diphosphate (GDP) sensitivity and loss of thermogenesis in UCP1 knockout (KO) mice. Obesogenic mouse strains had a lower thermogenic potential than obesity-resistant strains. The thermogenic density (UCP1-dependent oxygen consumption per g tissue) of inguinal white adipose tissue was maximally one-fifth of interscapular brown adipose tissue, and the total quantitative contribution of all inguinal mitochondria was maximally one-third of all interscapular brown-fat mitochondria, indicating that the classical brown adipose tissue depots would still predominate in thermogenesis.

  • 94.
    Shabalina, Irina G.
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Vrbacky, Marek
    Pecinova, Alena
    Kalinovich, Anastasia V.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Drahota, Zdenek
    Houstek, Josef
    Mracek, Tomas
    Cannon, Barbara
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Nedergaard, Jan
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    ROS production in brown adipose tissue mitochondria: The question of UCP1-dependence2014In: Biochimica et Biophysica Acta - Bioenergetics, ISSN 0005-2728, E-ISSN 1879-2650, Vol. 1837, no 12, p. 2017-2030Article in journal (Refereed)
    Abstract [en]

    Whether active UCP1 can reduce ROS production in brown-fat mitochondria is presently not settled. The issue is of principal significance, as it can be seen as a proof- or disproof-of-principle concerning the ability of any protein to diminish ROS production through membrane depolarization. We therefore undertook a comprehensive investigation of the significance of UCP1 for ROS production, by comparing the ROS production in brown-fat mitochondria isolated from wildtype mice (that display membrane depolarization) or from UCP1(-/-) mice (with a high membrane potential). We tested the significance of UCP1 for glycerol-3-phosphate-supported ROS production by three methods (fluorescent dihydroethidium and the ESR probe PHH for superoxide, and fluorescent Amplex Red for hydrogen peroxide), and followed ROS production also with succinate, acyl-CoA or pyruvate as substrate. We studied the effects of the reverse electron flow inhibitor rotenone, the UCP1 activity inhibitor GDP, and the uncoupler FCCP. We also examined the effect of a physiologically induced increase in UCP1 amount. We noted GDP effects that were not UCP1-related. We conclude that only ROS production supported by exogenously added succinate was affected by the presence of active UCP1; ROS production supported by any other tested substrate (including endogenously generated succinate) was unaffected. This conclusion indicates that UCP1 is not involved in control of ROS production in brown-fat mitochondria. Extrapolation of these data to other tissues would imply that membrane depolarization may not necessarily decrease physiologically relevant ROS production.

  • 95.
    Shabalina, Irina G.
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Vyssokikh, Mikhail Yu.
    Gibanova, Natalia
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Csikasz, Robert I.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Edgar, Daniel
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Hallden-Waldemarson, Anne
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Rozhdestvenskaya, Zinaida
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Bakeeva, Lora E.
    Vays, Valeria B.
    Pustovidko, Antonina V.
    Skulachev, Maxim V.
    Cannon, Barbara
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Skulachev, Vladimir P.
    Nedergaard, Jan
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Improved health-span and lifespan in mtDNA mutator mice treated with the mitochondrially targeted antioxidant SkQ12017In: Aging, ISSN 1945-4589, E-ISSN 1945-4589, Vol. 9, no 2, p. 315-339Article in journal (Refereed)
    Abstract [en]

    MtDNA mutator mice exhibit marked features of premature aging. We find that these mice treated from age of approximate to 100 days with the mitochondria-targeted antioxidant SkQ1 showed a delayed appearance of traits of aging such as kyphosis, alopecia, lowering of body temperature, body weight loss, as well as ameliorated heart, kidney and liver pathologies. These effects of SkQ1 are suggested to be related to an alleviation of the effects of an enhanced reactive oxygen species (ROS) level in mtDNA mutator mice: the increased mitochondrial ROS released due to mitochondrial mutations probably interact with polyunsaturated fatty acids in cardiolipin, releasing malondialdehyde and 4-hydroxynonenal that form protein adducts and thus diminishes mitochondrial functions. SkQ1 counteracts this as it scavenges mitochondrial ROS. As the results, the normal mitochondrial ultrastructure is preserved in liver and heart; the phosphorylation capacity of skeletal muscle mitochondria as well as the thermogenic capacity of brown adipose tissue is also improved. The SkQ1-treated mice live significantly longer (335 versus 290 days). These data may be relevant in relation to treatment of mitochondrial diseases particularly and the process of aging in general.

  • 96. Shinoda, Kosaku
    et al.
    Luijten, Ineke H. N.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. University of California, USA.
    Hasegawa, Yutaka
    Hong, Haemin
    Sonne, Si B.
    Kim, Miae
    Xue, Ruidan
    Chondronikola, Maria
    Cypess, Aaron M.
    Tseng, Yu-Hua
    Nedergaard, Jan
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Sidossis, Labros S.
    Kajimura, Shingo
    Genetic and functional characterization of clonally derived adult human brown adipocytes2015In: Nature Medicine, ISSN 1078-8956, E-ISSN 1546-170X, Vol. 21, no 4, p. 389-394Article in journal (Refereed)
    Abstract [en]

    Brown adipose tissue (BAT) acts in mammals as a natural defense system against hypothermia, and its activation to a state of increased energy expenditure is believed to protect against the development of obesity. Even though the existence of BAT in adult humans has been widely appreciated(1-8), its cellular origin and molecular identity remain elusive largely because of high cellular heterogeneity within various adipose tissue depots. To understand the nature of adult human brown adipocytes at single cell resolution, we isolated clonally derived adipocytes from stromal vascular fractions of adult human BAT from two individuals and globally analyzed their molecular signatures. We used RNA sequencing followed by unbiased genome-wide expression analyses and found that a population of uncoupling protein 1 (UCP1)-positive human adipocytes possessed molecular signatures resembling those of a recruitable form of thermogenic adipocytes (that is, beige adipocytes). In addition, we identified molecular markers that were highly enriched in UCP1-positive human adipocytes, a set that included potassium channel K3 (KCNK3) and mitochondrial tumor suppressor 1 (MTUS1). Further, we functionally characterized these two markers using a loss-of-function approach and found that KCNK3 and MTUS1 were required for beige adipocyte differentiation and thermogenic function. The results of this study present new opportunities for human BAT research, such as facilitating cell-based disease modeling and unbiased screens for thermogenic regulators.

  • 97. Siersbaek, Majken S.
    et al.
    Loft, Anne
    Aagaard, Mads M.
    Nielsen, Ronni
    Schmidt, Soren F.
    Petrovic, Natasa
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Nedergaard, Jan
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Mandrup, Susanne
    Genome-Wide Profiling of Peroxisome Proliferator-Activated Receptor gamma in Primary Epididymal, Inguinal, and Brown Adipocytes Reveals Depot-Selective Binding Correlated with Gene Expression2012In: Molecular and Cellular Biology, ISSN 0270-7306, E-ISSN 1098-5549, Vol. 32, no 17, p. 3452-3463Article in journal (Refereed)
    Abstract [en]

    Peroxisome proliferator-activated receptor gamma (PPAR gamma) is a master regulator of adipocyte differentiation and function. We and others have previously mapped PPAR gamma binding at a genome-wide level in murine and human adipocyte cell lines and in primary human adipocytes. However, little is known about how binding patterns of PPAR gamma differ between brown and white adipocytes and among different types of white adipocytes. Here we have employed chromatin immunoprecipitation combined with deep sequencing to map and compare PPAR gamma binding in in vitro differentiated primary mouse adipocytes isolated from epididymal, inguinal, and brown adipose tissues. While these PPAR gamma binding profiles are overall similar, there are clear depot-selective binding sites. Most PPAR gamma binding sites previously mapped in 3T3-L1 adipocytes can also be detected in primary adipocytes, but there are a large number of PPAR gamma binding sites that are specific to the primary cells, and these tend to be located in closed chromatin regions in 3T3-L1 adipocytes. The depot-selective binding of PPAR gamma is associated with highly depot-specific gene expression. This indicates that PPAR gamma plays a role in the induction of genes characteristic of different adipocyte lineages and that preadipocytes from different depots are differentially preprogrammed to permit PPAR gamma lineage-specific recruitment even when differentiated in vitro.

  • 98. Timmons, James A
    et al.
    Wennmalm, Kristian
    Larsson, Ola
    Walden, Tomas B
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Lassmann, Timo
    Petrovic, Natasa
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Hamilton, D Lee
    Gimeno, Ruth E
    Wahlestedt, Claes
    Baar, Keith
    Nedergaard, Jan
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Cannon, Barbara
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Myogenic gene expression signature establishes that brown and white adipocytes originate from distinct cell lineages.2007In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 104, no 11, p. 4401-4406Article in journal (Refereed)
    Abstract [en]

    Attainment of a brown adipocyte cell phenotype in white adipocytes, with their abundant mitochondria and increased energy expenditure potential, is a legitimate strategy for combating obesity. The unique transcriptional regulators of the primary brown adipocyte phenotype are unknown, limiting our ability to promote brown adipogenesis over white. In the present work, we used microarray analysis strategies to study primary preadipocytes, and we made the striking discovery that brown preadipocytes demonstrate a myogenic transcriptional signature, whereas both brown and white primary preadipocytes demonstrate signatures distinct from those found in immortalized adipogenic models. We found a plausible SIRT1-related transcriptional signature during brown adipocyte differentiation that may contribute to silencing the myogenic signature. In contrast to brown preadipocytes or skeletal muscle cells, white preadipocytes express Tcf21, a transcription factor that has been shown to suppress myogenesis and nuclear receptor activity. In addition, we identified a number of developmental genes that are differentially expressed between brown and white preadipocytes and that have recently been implicated in human obesity. The interlinkage between the myocyte and the brown preadipocyte confirms the distinct origin for brown versus white adipose tissue and also represents a plausible explanation as to why brown adipocytes ultimately specialize in lipid catabolism rather than storage, much like oxidative skeletal muscle tissue.

  • 99.
    von Essen, Gabriella
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Englund, Petter
    Cannon, Barbara
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Nedergaard, Jan
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    At thermoneutrality, medium-chain fatty acids totally protect against diet-induced obesity in a UCP1-independent mannerManuscript (preprint) (Other academic)
  • 100.
    von Essen, Gabriella
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Lindsund, Erik
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Cannon, Barbara
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Nedergaard, Jan
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Adaptive Facultative Diet-induced Thermogenesis in Wild-type but not in UCP1-ablated MiceManuscript (preprint) (Other academic)
123 51 - 100 of 119
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