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  • 101.
    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 mice2017In: American Journal of Physiology. Endocrinology and Metabolism, ISSN 0193-1849, E-ISSN 1522-1555, Vol. 313, no 5, p. E515-E527Article in journal (Refereed)
    Abstract [en]

    The significance of diet-induced thermogenesis (DIT) for metabolic control is still debated. Although obesogenic diets recruit UCP1 and adrenergically inducible thermogenesis, and although the absence of UCP1 may promote the development of obesity, no actual UCP1-related thermogenesis identifiable as diet-induced thermogenesis has to date been unambiguously demonstrated. Examining mice living at thermoneutrality, we have identified a process of facultative (directly elicited by acute eating), adaptive (magnitude develops over weeks on an obesogenic diet), and fully UCP1-dependent thermogenesis. We found no evidence for UCP1-independent diet-induced thermogenesis. The thermogenesis was proportional to the total amount of UCP1 protein in brown adipose tissue and was not dependent on any contribution of UCP1 in brite/beige adipose tissue, since no UCP1 protein was found there under these conditions. Total UCP1 protein amount developed proportionally to total body fat content. The physiological messenger linking obesity level and acute eating to increased thermogenesis is not known. Thus UCP1-dependent diet-induced thermogenesis limits obesity development during exposure to obesogenic diets but does not prevent obesity as such.

  • 102.
    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.
    Maldonado, Elaina
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Zouhar, Petr
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. Institute of Physiology of the Czech Academy of Sciences, Czech Republic.
    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.
    Highly recruited brown adipose tissue does not in itself protect against obesity2023In: Molecular Metabolism, ISSN 2212-8778, Vol. 76, article id 101782Article in journal (Refereed)
    Abstract [en]

    Objective: The possibility to counteract the development of obesity in humans by recruiting brown or brite/beige adipose tissue (and thus UCP1) has attracted much attention. Here we examine if a diet that can activate diet-induced thermogenesis can exploit pre-enhanced amounts of UCP1 to counteract the development of diet-induced obesity.Methods: To investigate the anti-obesity significance of highly augmented amounts of UCP1 for control of body energy reserves, we physiologically increased total UCP1 amounts by recruitment of brown and brite/beige tissues in mice. We then examined the influence of the augmented UCP1 levels on metabolic parameters when the mice were exposed to a high-fat/high-sucrose diet under thermoneutral conditions.Results: The total UCP1 levels achieved were about 50-fold higher in recruited than in non-recruited mice. Contrary to underlying expectations, in the mice with highly recruited UCP1 and exposed to a high-fat/high-sucrose diet the thermogenic capacity of this UCP1 was completely inactivate. The mice even transiently (in an adipostat-like manner) demonstrated a higher metabolic efficiency and fat gain than did non-recruited mice. This was accomplished without altering energy expenditure or food absorption efficiency. The metabolic efficiency here was indistinguishable from that of mice totally devoid of UCP1.Conclusions: Although UCP1 protein may be available, it is not inevitably utilized for diet-induced thermogenesis. Thus, although attempts to recruit UCP1 in humans may become successful as such, it is only if constant activation of the UCP1 is also achieved that amelioration of obesity development could be attained.& COPY; 2023 The Authors. Published by Elsevier GmbH. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

  • 103.
    von Essen, Gabriella
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Maldonado, Elaina
    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.
    Highly recruited brown adipose tissue does not in itself protect against obesityManuscript (preprint) (Other academic)
  • 104.
    Walden, Tomas B.
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Department of Physiology. Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Petrovic, Natasa
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Nedergaard, Jan
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    PPARa is not involved in the regulation of muscle-associated genesin brown adipose tissue.Manuscript (preprint) (Other academic)
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  • 105.
    Walden, Tomas B
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Department of Physiology. Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Timmons, James A
    Keller, Pernille
    Nedergaard, Jan
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Department of Physiology. Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Cannon, Barbara
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Department of Physiology. Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Distinct expression of muscle-specific microRNAs (myomirs) in brown adipocytes.2009In: Journal of Cellular Physiology, ISSN 0021-9541, E-ISSN 1097-4652, Vol. 218, no 2, p. 444-449Article in journal (Refereed)
    Abstract [en]

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

  • 106.
    Waldén, Tomas B.
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Hansen, Ida R.
    Timmons, James A.
    Cannon, Barbara
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Nedergaard, Jan
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Molecular signatures of brown, white and brite adipose tissues.Manuscript (preprint) (Other academic)
    Download full text (pdf)
    FULLTEXT01
  • 107.
    Waldén, Tomas B.
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute.
    Hansen, Ida R.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute.
    Timmons, James A.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute. The Royal Veterinary College, United Kingdom.
    Cannon, Barbara
    Stockholm University, Faculty of Science, The Wenner-Gren Institute. The Royal Veterinary College, United Kingdom.
    Nedergaard, Jan
    Stockholm University, Faculty of Science, The Wenner-Gren Institute.
    Recruited vs. nonrecruited molecular signatures of brown, “brite,” and white adipose tissues2012In: American Journal of Physiology. Endocrinology and Metabolism, ISSN 0193-1849, E-ISSN 1522-1555, Vol. 302, no 1, p. E19-E31Article in journal (Refereed)
    Abstract [en]

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

  • 108.
    Waldén, Tomas B
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Petrovic, Natasa
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Nedergaard, Jan
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    PPARalpha does not suppress muscle-associated gene expression in brown adipocytes but does influence expression of factors that fingerprint the brown adipocyte.2010In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 397, no 2, p. 146-51Article in journal (Refereed)
    Abstract [en]

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

  • 109.
    Wang, Yanling
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Fälting, Johanna M.
    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.
    Holmström, Therese E.
    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 brown adipocytes, adrenergically induced beta(1)-/beta(3)-(G(s))-, alpha(2)-(G(i))- and alpha(1)-(G(q))-signalling to Erk1/2 activation is not mediated via EGF receptor transactivation2013In: Experimental Cell Research, ISSN 0014-4827, E-ISSN 1090-2422, Vol. 319, no 17, p. 2718-2727Article in journal (Refereed)
    Abstract [en]

    Brown adipose tissue is unusual in that the neurotransmitter norepinephrine influences cell destiny in ways generally associated with effects of classical growth factors: regulation of cell proliferation, of apoptosis, and progression of differentiation. The norepinephrine effects are mediated through G-protein-coupled receptors; further mediation of such stimulation to e.g. Erk1/2 activation is in cell biology in general accepted to occur through transactivation of the EGF receptor (by external or internal pathways). We have examined here the significance of such transactivation in brown adipocytes. Stimulation of mature brown adipocytes with cirazoline (alpha(1)-adrenoceptor coupled via G(q)), clonidine (alpha(2) via G(i)) or CL316243 (beta(3) via G(s)) or via beta(1)-receptors significantly activated Erk1/2. Pretreatment with the EGF receptor kinase inhibitor AG1478 had, remarkably, no significant effect on Erk1/2 activation induced by any of these adrenergic agonists (although it fully abolished EGF-induced Erk1/2 activation), demonstrating absence of EGF receptor-mediated transactivation. Results with brown preadipocytes (cells in more proliferative states) were not qualitatively different. Joint stimulation of all adrenoceptors with norepinephrine did not result in synergism on Erk1/2 activation. AG1478 action on EGF-stimulated Erk1/2 phosphorylation showed a sharp concentration response relationship (IC50 0.3 mu M); a minor apparent effect of AG1478 on norepinephrine-stimulated Erk1/2 phosphorylation showed nonspecific kinetics, implying caution in interpretation of partial effects of AG1478 as reported in other systems. Transactivation of the EGF receptor is clearly not a universal prerequisite for coupling of G-protein coupled receptors to Erk1/2 signalling cascades.

  • 110.
    Wang, Yanling
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Fälting, Johanna M.
    Mattsson, Charlotte L.
    Holmström, Therése E.
    Nedergaard, Jan
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    In brown adipocytes, adrenergically induced β1-/β3-(Gs)-, α2-(Gi)- and α1-(Gq)-mediated Erk1/2 activation is not mediated via EGF receptor transactivationArticle in journal (Other academic)
    Abstract [en]

    Brown adipose tissue is unusual in utilising the neurotransmitter norepineph- rine to influence cell destiny in ways generally associated with classical growth factors: regulation of cell proliferation, apoptosis, progression of differentiation. These effects are thus mediated through G-protein-coupled receptors; mediation of such stimulation to e.g. Erk1/2 activation is generally accepted to occur through transactivation of the EGF receptor (by external or internal pathways). We have examined here the significance of such transac- tivation in brown adipocytes. Stimulation of mature brown adipocytes with cirazoline (α1-adrenoceptor coupled via Gq), clonidine (α2 via Gi) or CL316243 (β3 via Gs) significantly activated Erk1/2. Pretreatment with the EGF receptor kinase inhibitor AG1478 had, remarkably, no significant effect on Erk1/2 activation induced by any of the adrenergic agonists (although it fully abolished EGF-induced Erk1/2 activation), demonstrating absence of transactivation. Results with brown adipocytes in more proliferative states were not qualitatively different. Joint stimulation of all adrenoceptors with norepinephrine did not result in synergism on Erk1/2 activation or in occur- rence of transactivation. AG1478 action on EGF-stimulated Erk1/2 phos- phorylation showed a sharp concentration-response relationship with an IC50 of approx. 0.3 μM; a minor effect of AG1478 on norepinephrine- stimulated Erk1/2 phosphorylation was clearly nonspecific, occurring suc- cessively and only partially over 3 decades of AG1478 concentrations; cau- tion may therefore be required in interpretation of effects of AG1478 at higher concentrations. Transactivation of the EGF receptor is clearly not a universal prerequisite for coupling of G-protein coupled receptors to Erk1/2 signaling cascades. 

  • 111.
    Wang, Yanling
    et al.
    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.
    Identifying novel genes involved in cAMP- induced cell proliferation of brown preadi- pocytesManuscript (preprint) (Other academic)
    Abstract [en]

    Norepinephrine, through the second messenger cAMP, stimulates cell prolif- eration in a variety of cell types including brown preadipocytes. However, the cell signalling pathway mediating the cAMP mitogenic effect is poorly established, especially in physiologically relevant systems. A change in tran- scriptional profile due to the activation of specific transcription factors is an important part of intracellular signalling activated by various extracellular stimulants. In the present study, we have used brown preadipocytes as a model system to investigate novel genes that are involved in cAMP-induced cell growth. Based on data from a genome-wide microarray study, 18 genes upregulated by NE in brown preadipocyte were selected for further study. These genes were later confirmed with RT-qPCR to be upregulated by both norepinephrine and forskolin, indicating that they are truly under the positive regulation of cAMP. We therefore suggest that these genes, namely: Ado- ra2b, Arhgap8, Fgf18, Gpr133, Prr5, Tmem37, Twist2 and Ube2s, may be candidates involved in cAMP-stimulated cell proliferation. 

  • 112.
    Wang, Yanling
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Sato, Masaaki
    Bengtsson, Tore
    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.
    cAMP-stimulated cell proliferation in brown preadipocytes is mediated by protein kinase A, but is independent of ERK1/2, PI3K and mTORManuscript (preprint) (Other academic)
    Abstract [en]

    The physiological agonist norepinephrine (NE) promotes cell proliferation of brown preadipocytes during the process of tissue recruitment. In a primary culture system, cAMP was shown to mediate these adrenergic effects in the presence of serum. In the present study, we have demonstrated that in con- trast to other systems where the cAMP mitogenic effect requires the syner- gistic action of growth factors, especially insulin/IGF, the cAMP effect in brown preadipocytes is independent of serum and insulin. Furthermore, we showed that the increase in total DNA resulted from forskolin stimulation of cell proliferation, in addition to the anti-apoptosis effect reported previously. Protein kinase A, rather than Epac, mediated the cAMP mitogenic effect. In a further attempt to elucidate the cell signalling pathways involved in this process, we found that both mTOR complexes and the ERK 1/2 family of MAPK, two cell proliferation hallmarks, are indeed activated by cAMP. However, mTOR inhibition with rapamycin only caused partial inhibition of cell proliferation, and Ku-0063794, another inhibitor of mTOR, showed no inhibitory effect on cAMP-stimulated cell proliferation. The involvement of ERK1/2 was tested with pharmacological inhibitors of ERK1/2. PD98059 brought about a significant inhibitory effect, whereas U0126 did not have any inhibitory effect on cAMP-stimulated cell proliferation, even though ERK1/2 phosphorylation was equally well abolished by both inhibitors. Taken together, these results suggest that in brown preadipocytes under se- rum-free conditions, PKA, rather than Epac, mediated the cAMP mitogenic effect through activation of a pathway sensitive to PD98059 but inde- pendently of PI3K, mTOR complexes and the ERK1/2 family of MAPK. 

  • 113.
    Wang, Yanling
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Sato, Masaaki
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Guo, Yuan
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Bengtsson, Tore
    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.
    Protein kinase A-mediated cell proliferation in brown preadipocytes is independent of Erk1/2, PI3K and mTOR2014In: Experimental Cell Research, ISSN 0014-4827, E-ISSN 1090-2422, Vol. 328, no 1, p. 143-155Article in journal (Refereed)
    Abstract [en]

    The physiological agonist norepinephrine promotes cell proliferation of brown preadipocytes during the process of tissue recruitment. In a primary culture system, CAMP mediates these adrenergic effects. In the present study, we demonstrated that, in contrast to other systems where the mitogenic effect of cAMP requires the synergistic action of (serum) growth factors, especially insulin/IGF, the cAMP effect in brown preadipocytes was independent of serum and insulin. Protein kinase A, rather than Epac, mediated the cAMP mitogenic effect. The Erk 1/2 family of MAPK, the PI3K system and the mTOR complexes were all activated by cAMP, but these activations were not necessary for cAMP-induced cell proliferation; a protein kinase C isoform may be involved in mediating cAMP-activated cell proliferation. We conclude that the generally acknowledged cellular mediators for induction of cell proliferation are not involved in this process in the brown preadipocyte system; this conclusion may be of relevance both for examination of mechanisms for induction of brown adipose tissue recruitment but also for understanding the mechanism behind e.g. certain endocrine neoplasias.

  • 114.
    Wikström, Jakob D.
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. Boston University, USA.
    Mahdaviani, Kiana
    Liesa, Marc
    Sereda, Samuel B.
    Si, Yaguang
    Las, Guy
    Twig, Gilad
    Petrovic, Natasa
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Zingaretti, Cristina
    Graham, Adam
    Cinti, Saverio
    Corkey, Barbara E.
    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.
    Shirihai, Orian S.
    Hormone-induced mitochondrial fission is utilized by brown adipocytes as an amplification pathway for energy expenditure2014In: EMBO Journal, ISSN 0261-4189, E-ISSN 1460-2075, Vol. 33, no 5, p. 418-436Article in journal (Refereed)
    Abstract [en]

    Adrenergic stimulation of brown adipocytes (BA) induces mitochondrial uncoupling, thereby increasing energy expenditure by shifting nutrient oxidation towards thermogenesis. Here we describe that mitochondrial dynamics is a physiological regulator of adrenergically-induced changes in energy expenditure. The sympathetic neurotransmitter Norepinephrine (NE) induced complete and rapid mitochondrial fragmentation in BA, characterized by Drp1 phosphorylation and Opa1 cleavage. Mechanistically, NE-mediated Drp1 phosphorylation was dependent on Protein Kinase-A (PKA) activity, whereas Opa1 cleavage required mitochondrial depolarization mediated by FFAs released as a result of lipolysis. This change in mitochondrial architecture was observed both in primary cultures and brown adipose tissue from cold-exposed mice. Mitochondrial uncoupling induced by NE in brown adipocytes was reduced by inhibition of mitochondrial fission through transient Drp1 DN overexpression. Furthermore, forced mitochondrial fragmentation in BA through Mfn2 knock down increased the capacity of exogenous FFAs to increase energy expenditure. These results suggest that, in addition to its ability to stimulate lipolysis, NE induces energy expenditure in BA by promoting mitochondrial fragmentation. Together these data reveal that adrenergically-induced changes to mitochondrial dynamics are required for BA thermogenic activation and for the control of energy expenditure.

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

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

  • 116. Zenius Jespersen, Naja
    et al.
    Juhlin Larsen, Therese
    Peijs, Lone
    Daugaard, Søren
    Homøe, Preben
    Loft, Annika
    de Jong, Jasper
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Mathur, Neha
    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.
    Klarlund Pedersen, Bente
    Møller, Kirsten
    Scheele, Camilla
    A classical brown adipose tissue mRNA signature partly overlaps with brite in the supraclavicular region of adult humans2013In: Cell Metabolism, ISSN 1550-4131, E-ISSN 1932-7420, Vol. 17, no 5, p. 798-805Article in journal (Refereed)
    Abstract [en]

    Human brown adipose tissue (BAT) has been detected in adults but was recently suggested to be of brite/beige origin. We collected BAT from the supraclavicular region in 21 patients undergoing surgery for suspected cancer in the neck area and assessed the gene expression of established murine markers for brown, brite/beige, and white adipocytes. We demonstrate that a classical brown expression signature, including upregulation of miR-206, miR-133b, LHX8, and ZIC1 and downregulation of HOXC8 and HOXC9, coexists with an upregulation of two newly established brite/beige markers, TBX1 and TMEM26. A similar mRNA expression profile was observed when comparing isolated human adipocytes from BAT and white adipose tissue (WAT) depots, differentiated in vitro. In conclusion, our data suggest that human BAT might consist of both classical brown and recruitable brite adipocytes, an observation important for future considerations on how to induce human BAT.

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

    Classically, adult humans have been considered not to possess active brown adipose tissue (BAT). However, positron-emission-tomography has shown fluorodeoxyglucose uptake that is distributed in such a way (e.g., in the neck) that it would seem to be BAT. Until now this has not been supported by direct evidence that these areas truly represented BAT, that is, the presence of the BAT-unique uncoupling protein-1 (UCP1). Samples of adipose tissue from the neck of 35 patients undergoing surgery for thyroid diseases were obtained and analyzed. In 1/3 of the subjects (the younger and leaner), distinct islands composed of UCP1 immunoreactive brown adipocytes could clearly be discerned, accounting for up to 1/3 of all adipocytes. The brown-adipose islands were richly sympathetically innervated (indicating acute central control); adjacent white adipose areas were not. The capillary density was high, implying a high capacity for oxygen delivery. Cells with features of brown adipocyte precursors were found in pericapillary areas. These data demonstrate that human adults indeed possess BAT and thus imply possibilities of future therapeutic strategies for the treatment of obesity, including maintenance of brown adipocytes and stimulation of the growth of preexisting brown precursors.

  • 118. Zouhar, Petr
    et al.
    Janovska, Petra
    Stanic, Sara
    Bardova, Kristina
    Funda, Jiri
    Haberlova, Blanka
    Andersen, Birgitte
    Rossmeisl, Martin
    Cannon, Barbara
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Kopecky, Jan
    Nedergaard, Jan
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    A pyrexic effect of FGF21 independent of energy expenditure and UCP12021In: Molecular Metabolism, ISSN 2212-8778, Vol. 53, article id 101324Article in journal (Refereed)
    Abstract [en]

    Objective: Administration of FGF21 to mice reduces body weight and increases body temperature. The increase in body temperature is generally interpreted as hyperthermia, i.e. a condition secondary to the increase in energy expenditure (heat production). Here, we examine an alternative hypothesis: that FGF21 has a direct pyrexic effect, i.e. FGF21 increases body temperature independently of any effect on energy expenditure.

    Methods: We studied the effects of FGF21 treatment on body temperature and energy expenditure in high-fat-diet-fed and chow-fed mice exposed acutely to various ambient temperatures, in high-fat diet-fed mice housed at 30 °C (i.e. at thermoneutrality), and in mice lacking uncoupling protein 1 (UCP1).

    Results: In every model studied, FGF21 increased body temperature, but energy expenditure was increased only in some models. The effect of FGF21 on body temperature was more (not less, as expected in hyperthermia) pronounced at lower ambient temperatures. Effects on body temperature and energy expenditure were temporally distinct (daytime versus nighttime). FGF21 enhanced UCP1 protein content in brown adipose tissue (BAT); there was no measurable UCP1 protein in inguinal brite/beige adipose tissue. FGF21 increased energy expenditure through adrenergic stimulation of BAT. In mice lacking UCP1, FGF21 did not increase energy expenditure but increased body temperature by reducing heat loss, e.g. a reduced tail surface temperature.

    Conclusion: The effect of FGF21 on body temperature is independent of UCP1 and can be achieved in the absence of any change in energy expenditure. Since elevated body temperature is a primary effect of FGF21 and can be achieved without increasing energy expenditure, only limited body weight-lowering effects of FGF21 may be expected.

  • 119.
    Zouhar, Petr
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. Institute of Physiology CAS, the Czech Republic.
    Rakipovski, Gunaj
    Bokhari, Muhammad Hamza
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Busby, Oliver
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Paulsson, Johan F.
    Conde-Frieboes, Kilian W.
    Fels, Johannes J.
    Raun, Kirsten
    Andersen, Birgitte
    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-independent glucose-lowering effect of leptin in type 1 diabetes: only in conditions of hypoleptinemia2020In: American Journal of Physiology. Endocrinology and Metabolism, ISSN 0193-1849, E-ISSN 1522-1555, Vol. 318, no 1, p. E72-E86Article in journal (Refereed)
    Abstract [en]

    The possibility to use leptin therapeutically for lowering glucose levels in patients with type 1 diabetes has attracted interest. However, earlier animal models of type 1 diabetes are severely catabolic with very low endogenous leptin levels, unlike most patients with diabetes. Here, we aim to test glucose-lowering effects of leptin in novel, more human-like murine models. We examined the glucose-lowering potential of leptin in diabetic models of two types: streptozotocin-treated mice and mice treated with the insulin receptor antagonist S961. To prevent hypoleptinemia, we used combinations of thermoneutral temperature and high-fat feeding. Leptin fully normalized hyperglycemia in standard chow-fed streptozotocin-treated diabetic mice. However, more humanized physiological conditions (high-fat diets or thermoneutral temperatures) that increased adiposity- and thus also leptin level-sin the diabetic mice abrogated the effects of leptin, i.e., the mice developed leptin resistance also in this respect. The glucose-lowering effect of leptin was not dependent on the presence of the uncoupling protein-1 and was not associated with alterations in plasma insulin, insulin-like growth factor 1, food intake or corticosterone but fully correlated with decreased plasma glucagon levels and gluconeogenesis. An important implication of these observations is that the therapeutic potential of leptin as an additional treatment in patients with type 1 diabetes is probably limited. This is because such patients are treated with insulin and do not display low leptin levels. Thus, the potential for a glucose-lowering effect of leptin would already have been attained with standard insulin therapy, and further effects on blood glucose level through additional leptin cannot be anticipated.

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