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  • 1.
    Abreu-Vieira, Gustavo
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Thermal physiology and metabolism: Interplay between heat generation and energy homeostasis2015Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Mammal metabolism is intimately connected to the maintenance of body temperature. While metabolic pathways invariably produce heat as a by-product, the natural heat present in the environment also plays a role in defining the adaptive metabolism and general physiology of an organism. This thesis aims to discuss basic aspects of energy expenditure and their interactions with energy stores and body composition. In Paper I, we apply a new technique – high-resolution laser-Doppler imaging – to describe physiological regulatory features of adrenergically-stimulated blood flow in brown adipose tissue, and evaluate the validity of blood flow as a parameter to estimate nonshivering thermogenesis. Paper II focuses on the central regulation of body temperature. In the absence of bombesin receptor subtype-3, mice present an altered neurological body temperature setpoint, while peripheral thermogenic capacity remains intact. We conclude that brown adipose tissue malfunction is not the cause of the hypothermia observed in this mouse model. Paper III incorporates measurements of body temperature to the energy expenditure of different sources: basal metabolic rate, physical activity, thermic effect of food, and cold-induced thermogenesis. We describe basic aspects of dynamic insulation, energetic costs of circadian variation and hypothesize that physical activity may change the body temperature setpoint. Paper IV describes methodological issues related to glucose tolerance tests in obese mice. We conclude that the erroneous scaling of doses may affect the interpretation of metabolic health in mouse models, and suggest a new methodology. Paper V describes the outcomes caused by the expression of the human Cidea protein in adipose tissue of mice and suggests that this protein may clarify the link between adipose tissue expansion and healthy obesity. Paper VI explores the dissociation between thiazolidinedione-induced adipose tissue “browning” and reduced blood glycaemia. We demonstrate that although this pharmacological class tends to induce some level of brown adipose tissue recruitment, this phenomenon does not define its antidiabetic effects.

  • 2.
    Andersson, Per
    Stockholm University, Faculty of Social Sciences, Department of Psychology.
    Relevance of the Irrelevant: Using Task-Irrelevant Emotional Stimuli to Test the Load-Hypothesis through ERP’s2010Independent thesis Basic level (degree of Bachelor), 10 credits / 15 HE creditsStudent thesis
    Abstract [en]

    The role of attention and perceptual resources were studied in a one-back task and a letter-search task, both using the same stimuli. In the letter task, pictures were used as task-irrelevant and distracting emotional stimuli. The emotional processing of the pictures was measured through the Late Positive Potential (LPP), an event-related potential (ERP) recorded with EEG. LPP activity was significantly greater to emotional than neutral stimuli during the one-back task; this shows that emotional stimuli were processed during an easy task (low load). However, LPP activity dropped for all stimuli during the difficult perceptual task (high load). Selective processes of attention are discussed, in relation to Load Theory and the ability to ignore task-irrelevant, but emotionally significant, stimuli.

  • 3. Appelberg, Jonas
    et al.
    Janson, Christer
    Lindberg, Eva
    Pavlenko, Tatjana
    Stockholm University, Faculty of Social Sciences, Department of Statistics.
    Hedenstierna, Göran
    Lung aeration during sleep in patients with obstructive sleep apnoea2010In: Clinical Physiology and Functional Imaging, ISSN 1475-0961, E-ISSN 1475-097X, Vol. 30, no 4, p. 301-307Article in journal (Refereed)
    Abstract [en]

    P>Background: Previous studies have indicated that patients with obstructive sleep apnoea (OSA) have altered ventilation and lung volumes awake and the results suggest that this may be a determinant of severity of desaturations during sleep. However, little is known about regional lung aeration during sleep in patients with OSA. Methods: Twelve patients with OSA were included in the study. Computed tomography was used to study regional lung aeration during wakefulness and sleep. Lung aeration was calculated in ml gas/g lung tissue in four different regions of interest (ROI1-4), along the border of the lung from ventral to dorsal. Results: Lung aeration in the dorsal (dependent) lung region (ROI4) was lower during sleep compared to wakefulness 0 center dot 78 +/- 0 center dot 19 versus 0 center dot 88 +/- 0 center dot 19 (mean +/- SD) ml gas/g lung tissue (P = 0 center dot 005). Associations were found between awake expiratory reserve volume and change in lung aeration from wakefulness to sleep in ROI4 (r = -0 center dot 69; P = 0 center dot 012). In addition, the change in lung aeration in the dorsal region correlated to sleep time (r = 0 center dot 69; P = 0 center dot 014) but not to time in supine position. The difference in lung aeration between inspiration and expiration (i.e. ventilation), was larger in the ventral lung region when expressed as ml gas per g lung tissue. In two patients it was noted that, during on-going obstructive apnoea, lung aeration tended to be increased rather than decreased. Conclusions: Aeration in the dorsal lung region is reduced during sleep in patients with OSA. The decrease is related to lung volume awake and to sleep time.

  • 4.
    Barragan, Antonio
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. Karolinska Institutet, Sweden.
    Weidner, Jessica M.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. Karolinska Institutet, Sweden.
    Jin, Z.
    Korpi, E. R.
    Birnir, B.
    GABAergic signalling in the immune system2015In: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 213, no 4, p. 819-827Article, review/survey (Refereed)
    Abstract [en]

    The GABAergic system is the main inhibitory neurotransmitter system in the central nervous system (CNS) of vertebrates. Signalling of the transmitter c-aminobutyric acid (GABA) via GABA type A receptor channels or G-protein-coupled type B receptors is implicated in multiple CNS functions. Recent findings have implicated the GABAergic system in immune cell functions, inflammatory conditions and diseases in peripheral tissues. Interestingly, the specific effects may vary between immune cell types, with stage of activation and be altered by infectious agents. GABA/GABA-A receptor-mediated immunomodulatory functions have been unveiled in immune cells, being present in T lymphocytes and regulating the migration of Toxoplasma-infected dendritic cells. The GABAergic system may also play a role in the regulation of brain resident immune cells, the microglial cells. Activation of microglia appears to regulate the function of GABAergic neurotransmission in neighbouring neurones through changes induced by secretion of brain-derived neurotrophic factor. The neurotransmitter-driven immunomodulation is a new but rapidly growing field of science. Herein, we review the present knowledge of the GABA signalling in immune cells of the periphery and the CNS and raise questions for future research.

  • 5.
    Beramendi, Ana
    Stockholm University, Faculty of Science, Department of Zoology.
    Morphologican and functional studies on the Drosophila neuromuscular system during postembryonic stages2005Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The nervous system of the fruit fly Drosophila melanogaster has emerged as an excellent model for fundamental neuroscience as well as for biomedical research of human neurological diseases. In this thesis, two aspects of the neuromuscular system have been investigated: the role of the IkB-protein Cactus in the larval neuromuscular junction and the morphology of motor terminals throughout adult life.

    We found that cactus mutant larvae have poor locomotion, morphological abnormalities at the presynaptic site of motor terminals and impaired mechanical and electrophysiological properties, demonstrating that Cactus is clearly involved in the normal functioning of Drosophila neuromuscular system. In the adult, we show that cactus, dorsal and dif are expressed in the brain but are not redistributed between cytoplasm and nucleus in a circadian manner as expected from a previous finding in larval brain. Both Cactus and Dif immunoreactivity was strong in mushroom bodies and antennal lobes, suggesting a putative role in olfactory memory. In the rat, proteins of the same family are involved in the regulation of sleep but we found no indication of such regulation in flies subjected to 6 hrs of sleep deprivation.

    We found that neuromuscular junctions continue to change throughout adult life. Two types of long-term changes in the morphology of neuromuscular junctions are demonstrated here: a daily change in the size of synaptic boutons and long-term changes in bouton size developing over several weeks. By careful morphological studies of flight neuromuscular terminals in clock-gene mutants and wild type flies of different ages we demonstrate that the daily changes depend on the biological clock and disappear in the old fly. Moreover, we show that light is necessary for the motor neurons studied to reach maximum size of synaptic boutons. Lastly, we found that the two clock genes period and timeless are also necessary to control axonal branching.

    Transmission electron microscopy revealed several ultrastructural features distinct of the aging fly and indicative of reduced plasticity. We used a temperature-sensitive allele of shibire that rapidly and reversibly blocks vesicle recycling to investigate whether the morphological phenotype found in neuromuscular junctions of aging flies could be explained by impairment of endocytotic mechanisms. Our results show a clear reduction of the time required for complete paralysis and an increased recovery time in old flies, indicating that aging correlates with impaired endocytosis and membrane dynamics.

  • 6. Bhandage, A. K.
    et al.
    Hellgren, C.
    Jin, Z.
    Olafsson, Einar B.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Sundström-Poromaa, I.
    Birnir, B.
    Expression of GABA receptors subunits in peripheral blood mononuclear cells is gender dependent, altered in pregnancy and modified by mental health2015In: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 213, no 3, p. 575-585Article in journal (Refereed)
    Abstract [en]

    AimThe concept of nerve-driven immunity recognizes a link between the nervous and the immune system. -aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the brain, and receptors activated by GABA can be expressed by immune cells. Here, we examined whether the expression of GABA receptors and chloride transporters in human peripheral blood mononuclear cells (PBMCs) was influenced by gender, pregnancy or mental health. MethodsWe used RT-qPCR to determine the mRNA expression level in PBMCs from men (n=16), non-pregnant women (n=19), healthy pregnant women (n=27) and depressed pregnant women (n=15). ResultsThe 2 subunit had the most prominent expression level of the GABA-A receptor subunits in all samples. The and 2 subunits were up-regulated by pregnancy, whereas the epsilon subunit was more frequently expressed in healthy pregnant women than non-pregnant women who, in turn, commonly expressed the 6 and the 2 subunits. The 1 and epsilon subunits expression was altered by depression in pregnant women. The GABA-B1 receptor was up-regulated by depression in pregnant women, while the transporters NKCC1 and KCC4 were down-regulated by pregnancy. The changes recorded in the mRNA expression levels imply participation of GABA receptors in establishing and maintaining tolerance in pregnancy. Importantly, the correlation of mental health with the expression of specific receptor subunits reveals a connection between the immune cells and the brain. Biomarkers for mental health may be identified in PBMCs. ConclusionThe results demonstrate the impact gender, pregnancy and mental health have on the expression of GABA receptors and chloride transporters expressed in human PBMCs.

  • 7.
    Cannon, Barbara
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Nedergaard, Jan
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Nonshivering thermogenesis and its adequate measurement in metabolic studies2011In: Journal of Experimental Biology, ISSN 0022-0949, E-ISSN 1477-9145, Vol. 214, no Pt 2, p. 242-53Article in journal (Refereed)
    Abstract [en]

    Alterations in nonshivering thermogenesis are presently discussed as being both potentially causative of and able to counteract obesity. However, the necessity for mammals to defend their body temperature means that the ambient temperature profoundly affects the outcome and interpretation of metabolic experiments. An adequate understanding and assessment of nonshivering thermogenesis is therefore paramount for metabolic studies. Classical nonshivering thermogenesis is facultative, i.e. it is only activated when an animal acutely requires extra heat (switched on in minutes), and adaptive, i.e. it takes weeks for an increase in capacity to develop. Nonshivering thermogenesis is fully due to brown adipose tissue activity; adaptation corresponds to the recruitment of this tissue. Diet-induced thermogenesis is probably also facultative and adaptive and due to brown adipose tissue activity. Although all mammals respond to injected/infused norepinephrine (noradrenaline) with an increase in metabolism, in non-adapted mammals this increase mainly represents the response of organs not involved in nonshivering thermogenesis; only the increase after adaptation represents nonshivering thermogenesis. Thermogenesis (metabolism) should be expressed per animal, and not per body mass [not even to any power (0.75 or 0.66)]. A 'cold tolerance test' does not examine nonshivering thermogenesis capacity; rather it tests shivering capacity and endurance. For mice, normal animal house temperatures are markedly below thermoneutrality, and the mice therefore have a metabolic rate and food consumption about 1.5 times higher than their intrinsic requirements. Housing and examining mice at normal house temperatures carries a high risk of identifying false positives for intrinsic metabolic changes; in particular, mutations/treatments that affect the animal's insulation (fur, skin) may lead to such problems. Correspondingly, true alterations in intrinsic metabolic rate remain undetected when metabolism is examined at temperatures below thermoneutrality. Thus, experiments with animals kept and examined at thermoneutrality are likely to yield an improved possibility of identifying agents and genes important for human energy balance.

  • 8.
    Cannon, Barbara
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Physiology.
    Nedergaard, Jan
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Physiology.
    Thermogenesis challenges the adipostat hypothesis for body-weight control.2009In: Proceedings of the Nutrition Society, ISSN 0029-6651, E-ISSN 1475-2719, Vol. 68, no 4, p. 401-7Article in journal (Refereed)
    Abstract [en]

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

  • 9.
    Cavazzana, Annachiara
    et al.
    Stockholm University, Faculty of Social Sciences, Department of Psychology. TU Dresden, Germany.
    Poletti, Sophia C.
    Guducu, Cagdas
    Larsson, Maria
    Stockholm University, Faculty of Social Sciences, Department of Psychology, Perception and psychophysics.
    Hummel, Thomas
    Electro-olfactogram Responses Before and After Aversive Olfactory Conditioning in Humans2018In: Neuroscience, ISSN 0306-4522, E-ISSN 1873-7544, Vol. 373, p. 199-206Article in journal (Refereed)
    Abstract [en]

    The aim of the present study was to investigate whether repetitive aversive odor conditioning induced changes at the level of the peripheral olfactory system in humans. A total of 51 volunteers participated. A pair of indistinguishable odor enantiomers [(+)-rose oxide and (-)-rose oxide] were used as stimuli. During the pre-conditioning, participants' ability to discriminate between the two odors was assessed using a three-alternative, forced-choice discrimination test. In addition, electro-olfactograms ( EOG) from the olfactory epithelium were recorded. Participants underwent three conditioning sessions on consecutive days. The experimental group received an electrical stimulus to the forearm only following (+)-rose oxide presentation, whereas its enantiomer sibling was never paired with the aversive stimulus; the control group did not receive any electrical stimulation. During the post-conditioning session, their ability to discriminate the two enantiomers was assessed again using the discrimination test and EOG recordings were obtained similarly to the pre-conditioning session. Results showed significant differences in the peripheral electrophysiological responses between the conditioned and the unconditioned stimulus, demonstrating contextually induced changes at the level of the first neuron in the olfactory system.

  • 10.
    Chernogubova, Ekaterina
    Stockholm University, Faculty of Science, Wenner-Gren Institute for Experimental Biology.
    Adrenergic stimulation of glucose uptake in brown adipocytes2005Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The aim of this study was to investigate adrenergically stimulated glucose uptake in brown adipose tissue (BAT) with the focus on receptor subtypes and intracellular signalling pathways. As a model system, we used primary cultured brown adipocytes.

    Adrenergic stimulation of glucose uptake occurs via β3-AR in wild type cells and β1-/α1-ARs in β3-KO cells, includes activation of adenylyl cyclase and cAMP formation, activation of PKA, PI3K, PKC and AMPK (Paper I, II, III). Interestingly, UCP1 activity is not required for the AMPK function in brown adipocytes (Paper III). Long-term adrenergic stimulation of glucose uptake induces an increase in GLUT1 mRNA and protein levels stimulating GLUT1 translocation to the plasma membrane (Paper IV).

  • 11.
    Cumming, Robert James
    Stockholm University, Faculty of Science, Department of Astronomy.
    Kroppen i rymden2008In: Populär Astronomi, ISSN 1650-7177, Vol. 9, no 4Article in journal (Other (popular science, discussion, etc.))
    Abstract [sv]

    Dag Linnarsson, professor i fysiologi och expert på rymdmedicin, intervjuas.

  • 12.
    Dahlgren, Anna
    et al.
    Stockholm University, Faculty of Social Sciences, Department of Psychology. National Institute for Psychosocial Medicine.
    Åkerstedt, Torbjörn
    National Institute for Psychosocial Medicine.
    Kecklund, Göran
    National Institute for Psychosocial Medicine.
    Individual differences in the diurnal cortisol response to stress2004In: Chronobiology International, ISSN 0742-0528, E-ISSN 1525-6073, Vol. 21, no 6, p. 913-922Article in journal (Refereed)
    Abstract [en]

    The objectives of this study were to explore individual differences associated with diverse reactions in cortisol secretion under different stress levels. This study was part of a larger project concerning working hours and health. Thirty-four whitecollar workers participated under two different conditions; one work week with a high stress level (H) and one with a lower stress level (L) as measured through self-rated stress during workdays. Based on the morning cortisol concentration during a workday subjects were divided into two groups. One group consisted of subjects whose morning level of cortisol increased in response to the high-stress week, compared to their morning levels in the low-stress condition (Group 1). The other group consisted of subjects whose morning cortisol response was the opposite, with a lower level under the high stress condition (Group 2). Subjects wore actiwatches, completed a sleep diary, and rated their sleepiness and stress for one work week in each condition, i.e., high and low stress. Saliva samples for measures of cortisol were collected on a Wednesday. Group 2 reported higher workload, fatigue, and exhaustion during both weeks. Since there were no differences in perceived stress, neither within nor between groups, the data indicate that there are other factors influencing morning cortisol. The results suggest that one component modulating the cortisol response might be the level of exhaustion, probably related to work overload. Higher levels of stress in exhausted individuals might suppress morning cortisol levels.

  • 13.
    Dallner, Olof
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    β-adrenergic regulation of glucose transporters2008Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The transport of glucose across the plasma membrane is a fundamental mechanism to provide cells with its basic requirements for energy yielding processes. It is also vital for clearing glucose from blood into tissues, a process normally stimulated by the hormone insulin in mammals. The sympathetic nervous system, normally activated during stress, also regulates glucose transport. The sympathetic neurotransmitter noradrenaline, acts on the family of adrenergic receptors (ARs). An important subtype of the AR family is the β-AR, which is subdivided into the β1, β2, and β3-AR. Glucose is transported across the plasma membrane by the family of glucose transporters (GLUT1-12, and HMIT). In this thesis, I have investigated the β-AR regulation of GLUT1 and 4, and glucose uptake, in skeletal muscle cells and brown adipocytes in culture, model systems which correspond to metabolically active, sympathetically innervated and insulin-sensitive tissues.

    In brown adipocytes, activation of the β3-ARs induced the expression of GLUT1, resulting in a large increase of glucose uptake. In skeletal myotubes, we postulate there is a possible mechanism where β2-ARs can regulate the intrinsic activity of GLUT1.

    We found that insulin signaling, but not β-adrenergic signaling, mediated glucose uptake through class I phosphatidylinositol 3-kinase (PI3K). The β-adrenergic signaling to glucose uptake appeared to involve a PI3K related kinase (PIKK), in both skeletal myotubes and brown adipocytes. Furthermore, the increase of glucose uptake by β-ARs in brown adipocytes is partially mediated by AMP-activated protein kinase (AMPK).

    However, in an artificially constructed system, with cells expressing GLUT4 and β2-ARs, both insulin and β-adrenergic activation translocated GLUT4 and increased glucose uptake.

    These results show that β-adrenergic signaling increase glucose uptake by regulating glucose transporters through distinct pathways, in skeletal myotubes and brown adipocytes.

  • 14.
    de Jong, Jasper
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Who is Who in the Adipose Organ: A look at the Heterogeneity of Adipocyte Biology2017Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The increasing prevalence of obesity and related health complications, such as type 2 diabetes, cardiovascular disease and cancer, demands thorough investigation of the underlying processes. One of the key tissues investigated in this context is adipose tissue. It is becoming increasingly clear that adipose tissue is a very dynamic and heterogenic organ. This thesis provides an overview of various aspects of adipose biology that illustrate its heterogenic nature and describes my own scientific contributions to this field.

    We typically distinguish between thermogenic, energy-expending brown adipocytes and energy-storing white adipocytes that are located in anatomically distinct adipose depots. In addition, brite (or beige) adipocytes are functionally thermogenic, but are located among white adipocytes.

    Related to functional variation, adipocytes and adipose tissues display a wide range of morphological appearances. An additional property that illustrates the heterogeneity among adipose cells and depots is the variation of cellular responses to physiological cues, such as changes in diet or environmental temperature. Furthermore, the developmental origins of various adipose types display great heterogeneity, which may explain some of the functional and dynamic differences that are observed.

    In line with the complexity of developmental origins, molecular markers that were initially proposed to distinguish between brown, brite/beige and white adipose subtypes have added to the notion that the composition of the adipose organ is much more complex than has long been appreciated.

    My own work has contributed to the enhancement of our understanding of the heterogeneity of adipose subtypes. In particular, my findings related to marker gene expression patterns have led to increased appreciation of the complex nature of adipose gene expression patterns and the complications of translating results obtained in mice to humans. Some of my other contributions have increased the understanding of the differences and similarities in thermogenic adipose tissue functionality and dynamics. With cell culture studies, I have revealed new characteristics of pre-adipose cells from various depots that further add to the appreciation of the adipose heterogeneity.

    Overall, this thesis provides an overview of important characteristics of the adipose organ, illustrating its heterogenic nature. Realization of this heterogeneity is of importance in order to properly study the adipose organ to ultimately understand how the adipose organ can be therapeutically targeted to effectively treat adipose-related diseases.

  • 15.
    de Jong, Jasper
    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.
    In primary brown adipose cultures, fetal and newborn bovine sera differently affect triglyceride storage and thermocompetenceManuscript (preprint) (Other academic)
  • 16.
    de Jong, Jasper
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Fischer, Alexander
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. University Medical Center Hamburg-Eppendorf, Germany.
    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.
    Petrovic, Natasa
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Brown adipose tissue in physiologically humanized mice phenocopies human brown fatManuscript (preprint) (Other academic)
  • 17. Edgar, Daniel
    et al.
    Shabalina, Irina
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Physiology.
    Camara, Yolanda
    Wredenberg, Anna
    Calvaruso, Maria Antonietta
    Nijtmans, Leo
    Nedergaard, Jan
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Physiology.
    Cannon, Barbara
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Physiology.
    Larsson, Nils-Göran
    Trifunovic, Aleksandra
    Random point mutations with major effects on protein-coding genes are the driving force behind premature aging in mtDNA mutator mice.2009In: Cell metabolism, ISSN 1932-7420, Vol. 10, no 2, p. 131-8Article in journal (Refereed)
    Abstract [en]

    The mtDNA mutator mice have high levels of point mutations and linear deletions of mtDNA causing a progressive respiratory chain dysfunction and a premature aging phenotype. We have now performed molecular analyses to determine the mechanism whereby these mtDNA mutations impair respiratory chain function. We report that mitochondrial protein synthesis is unimpaired in mtDNA mutator mice consistent with the observed minor alterations of steady-state levels of mitochondrial transcripts. These findings refute recent claims that circular mtDNA molecules with large deletions are driving the premature aging phenotype. We further show that the stability of several respiratory chain complexes is severely impaired despite normal synthesis of the corresponding mtDNA-encoded subunits. Our findings reveal a mechanism for induction of aging phenotypes by demonstrating a causative role for amino acid substitutions in mtDNA-encoded respiratory chain subunits, which, in turn, leads to decreased stability of the respiratory chain complexes and respiratory chain deficiency.

  • 18.
    Ek, Caroline
    et al.
    Stockholm University, Faculty of Science, Department of Environmental Science and Analytical Chemistry.
    Garbaras, Andrius
    Yu, Zhenyang
    Oskarsson, Hanna
    Stockholm University, Faculty of Science, Department of Ecology, Environment and Plant Sciences.
    Eriksson Wiklund, Ann-Kristin
    Stockholm University, Faculty of Science, Department of Environmental Science and Analytical Chemistry.
    Kumblad, Linda
    Stockholm University, Faculty of Science, Department of Ecology, Environment and Plant Sciences.
    Gorokhova, Elena
    Stockholm University, Faculty of Science, Department of Environmental Science and Analytical Chemistry.
    Increase in stable isotope ratios driven by metabolic alterations in amphipods exposed to the beta-blocker propranolol2019In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 14, no 5, article id e0211304Article in journal (Refereed)
    Abstract [en]

    Anthropogenic pressures, such as contaminant exposure, may affect stable isotope ratios in biota. These changes are driven by alterations in the nutrient allocation and metabolic pathways induced by specific stressors. In a controlled microcosm study with the amphipod Gammarus spp., we studied effects of the beta-blocker propranolol on stable isotope signatures (delta N-15 and delta C-13), elemental composition (%C and %N), and growth (protein content and body size) as well as biomarkers of oxidative status (antioxidant capacity, ORAC; lipid peroxidation, TBARS) and neurological activity (acetylcholinesterase, AChE). Based on the known effects of propranolol exposure on cellular functions, i.e., its mode of action (MOA), we expected to observe a lower scope for growth, accompanied by a decrease in protein deposition, oxidative processes and AChE inhibition, with a resulting increase in the isotopic signatures. The observed responses in growth, biochemical and elemental variables supported most of these predictions. In particular, an increase in %N was observed in the propranolol exposures, whereas both protein allocation and body size declined. Moreover, both ORAC and TBARS levels decreased with increasing propranolol concentration, with the decrease being more pronounced for TBARS, which indicates the prevalence of the antioxidative processes. These changes resulted in a significant increase of the delta N-15 and delta C-13 values in the propranolol-exposed animals compared to the control. These findings suggest that MOA of beta-blockers may be used to predict sublethal effects in non-target species, including inhibited AChE activity, improved oxidative balance, and elevated stable isotope ratios. The latter also indicates that metabolism-driven responses to environmental contaminants can alter stable isotope signatures, which should be taken into account when interpreting trophic interactions in the food webs.

  • 19. Ekstedt, Mirjam
    et al.
    Nyberg, Gisela
    Ingre, Michael
    Stockholm University, Faculty of Social Sciences, Stress Research Institute.
    Ekblom, Örjan
    Marcus, Claude
    Sleep, physical activity and BMI in six to ten-year-old children measured by accelerometry: a cross-sectional study2013In: International Journal of Behavioral Nutrition and Physical Activity, ISSN 1479-5868, E-ISSN 1479-5868, Vol. 10, p. 82-Article in journal (Refereed)
    Abstract [en]

    Background: The aim of this study is to describe the relationship between objective measures of sleep, physical activity and BMI in Swedish pre-adolescents. The day-to-day association between physical activity and sleep quality as well as week-day and weekend pattern of sleep is also described. Method: We conducted a cross sectional study consisted of a cohort of 1.231 children aged six to ten years within the Stockholm county area. Sleep and physical activity were measured by accelerometry during seven consecutive days. Outcome measures are total sleep time, sleep efficiency, sleep start and sleep end; physical activity intensity divided into: sedentary (<1.5 METS), light (1.5 to 3 METS) and moderate-to-vigorous (> 3 METS); and Body Mass Index standard deviations score, BMIsds. Results: Total sleep time decreased with increasing age, and was shorter in boys than girls on both weekdays and weekends. Late bedtime but consistent wake-up time during weekends made total sleep time shorter on weekends than on weekdays. Day-to-day within-subject analysis revealed that moderate-to-vigorous intense physical activity promoted an increased sleep efficiency the following night (CI < 0.001 to 0.047), while total sleep time was not affected (CI -0.003 to 0.043). Neither sleep duration (CI -0.024 to 0.022) nor sleep efficiency (CI -0.019 to 0.028) affected mean physical activity level the subsequent day. The between-subject analysis indicates that the sleep of children characterized by high moderate-to-vigorous physical activity during the day was frequently interrupted (SE = -. 23, P < .01). A negative association between BMIsds and sleep duration was found (-. 10, p < .01). Conclusions: Short sleep duration was associated with high BMI in six to ten year old children. This study underscores the importance of consistent bedtimes throughout the week for promoting sleep duration in preadolescents. Furthermore, this study suggests that a large proportion of intensive physical activity during the day might promote good sleep quality.

  • 20.
    Feldmann, Helena M.
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute, Physiology.
    Golozoubova, Valeria
    Stockholm University, Faculty of Science, The Wenner-Gren Institute.
    Cannon, Barbara
    Stockholm University, Faculty of Science, The Wenner-Gren Institute, Physiology.
    Nedergaard, Jan
    Stockholm University, Faculty of Science, The Wenner-Gren Institute, Physiology.
    UCP1 ablation induces obesity and abolishes diet-induced thermogenesis in mice exempt from thermal stress by living at thermoneutrality.2009In: Cell metabolism, ISSN 1932-7420, Vol. 9, no 2, p. 203-9Article in journal (Refereed)
    Abstract [en]

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

  • 21.
    Fischer, Alexander W.
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. University Medical Center Hamburg-Eppendorf, Germany.
    Csikasz, Robert I.
    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.
    No insulating effect of obesity2016In: American Journal of Physiology. Endocrinology and Metabolism, ISSN 0193-1849, E-ISSN 1522-1555, Vol. 311, no 1, p. e202-e213Article in journal (Refereed)
    Abstract [en]

    The development of obesity may be aggravated if obesity itself insulates against heat loss and thus diminishes the amount of food burnt for body temperature control. This would be particularly important under normal laboratory conditions where mice experience a chronic cold stress (at approximate to 20 degrees C). We used Scholander plots (energy expenditure plotted against ambient temperature) to examine the insulation (thermal conductance) of mice, defined as the inverse of the slope of the Scholander curve at subthermoneutral temperatures. We verified the method by demonstrating that shaved mice possessed only half the insulation of non-shaved mice. We examined a series of obesity models [mice fed high-fat diets and kept at different temperatures, classical diet-induced obese mice, ob/ob mice, and obesity-prone (C57BL/6) vs. obesity-resistant (129S)mice]. We found that neither acclimation temperature nor any kind or degree of obesity affected the thermal insulation of the mice when analyzed at the whole mouse level or as energy expenditure per lean weight. Calculation per body weight erroneously implied increased insulation in obese mice. We conclude that, in contrast to what would be expected, obesity of any kind does not increase thermal insulation in mice, and therefore, it does not in itself aggravate the development of obesity. It may be discussed as to what degree of effect excess adipose tissue has on insulation in humans and especially whether significant metabolic effects are associated with insulation in humans.

  • 22.
    Fischer, Alexander W.
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. University Medical Center Hamburg-Eppendorf, Germany.
    Schlein, Christian
    Cannon, Barbara
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Heeren, Joerg
    Nedergaard, Jan
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Intact innervation is essential for diet-induced recruitment of brown adipose tissue2019In: American Journal of Physiology. Endocrinology and Metabolism, ISSN 0193-1849, E-ISSN 1522-1555, Vol. 316, no 3, p. E487-E503Article in journal (Refereed)
    Abstract [en]

    The possibility that recruitment and activation of brown adipose tissue (BAT) thermogenesis could be beneficial for curtailing obesity development in humans prompts a need for a better understanding of the control of these processes [that are often referred to collectively as diet-induced thermogenesis (DIT)]. Dietary conditions are associated with large changes in blood-borne factors that could be responsible for BAT recruitment, but BAT is also innervated by the sympathetic nervous system. To examine the significance of the innervation for DIT recruitment, we surgically denervated the largest BAT depot, i.e., the interscapular BAT depot in mice and exposed the mice at thermoneutrality to a high-fat diet versus a chow diet. Denervation led to an alteration in feeding pattern but did not lead to enhanced obesity, but obesity was achieved with a lower food intake, as denervation increased metabolic efficiency. Conclusively. denervation totally abolished the diet-induced increase in total UCP1 protein levels observed in the intact mice, whereas basal UCP1 expression was not dependent on innervation. The denervation of interscapular BAT did not discernably hyper-recruit other BAT depots, and no UCP1 protein could be detected in the principally browning-competent inguinal white adipose tissue depot under any of the examined conditions. We conclude that intact innervation is essential for diet-induced thermogenesis and that circulating factors cannot by themselves initiate recruitment of brown adipose tissue under obesogenic conditions. Therefore, the processes that link food intake and energy storage to activation of the nervous system are those of significance for the further understanding of diet-induced thermogenesis.

  • 23. Fuxe, K.
    et al.
    Canals, M.
    Torvinen, M.
    Marcellino, D.
    Terasmaa, A.
    Genedani, S.
    Leo, G.
    Guidolin, D.
    Diaz-Cabiale, Z.
    Rivera, A.
    Lundström, L.
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Langel, Ülo
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Narvaez, J.
    Tanganelli, S.
    Lluis, C.
    Ferré, S.
    Woods, A.
    Franco, R.
    Agnati, L. F.
    Intramembrane receptor-receptor interactions: a novel principle in molecular medicine2007In: Journal of neural transmission, ISSN 0300-9564, E-ISSN 1435-1463, Vol. 114, no 1, p. 49-75Article in journal (Refereed)
    Abstract [en]

    In 1980/81 Agnati and Fuxe introduced the concept of intramembrane receptor-receptor interactions and presented the first experimental observations for their existence in crude membrane preparations. The second step was their introduction of the receptor mosaic hypothesis of the engram in 1982. The third step was their proposal that the existence of intramembrane receptor-receptor interactions made possible the integration of synaptic (WT) and extrasynaptic (VT) signals. With the discovery of the intramembrane receptor-receptor interactions with the likely formation of receptor aggregates of multiple receptors, so called receptor mosaics, the entire decoding process becomes a branched process already at the receptor level in the surface membrane. Recent developments indicate the relevance of cooperativity in intramembrane receptor-receptor interactions namely the presence of regulated cooperativity via receptor-receptor interactions in receptor mosaics (RM) built up of the same type of receptor (homo-oligomers) or of subtypes of the same receptor (RM type1). The receptor-receptor interactions will to a large extent determine the various conformational states of the receptors and their operation will be dependent on the receptor composition (stoichiometry), the spatial organization (topography) and order of receptor activation in the RM. The biochemical and functional integrative implications of the receptor-receptor interactions are outlined and long-lived heteromeric receptor complexes with frozen RM in various nerve cell systems may play an essential role in learning, memory and retrieval processes. Intramembrane receptor-receptor interactions in the brain have given rise to novel strategies for treatment of Parkinson's disease (A2A and mGluR5 receptor antagonists), schizophrenia (A2A and mGluR5 agonists) and depression (galanin receptor antagonists). The A2A/D2, A2A/D3 and A2A/mGluR5 heteromers and heteromeric complexes with their possible participation in different types of RM are described in detail, especially in the cortico-striatal glutamate synapse and its extrasynaptic components, together with a postulated existence of A2A/D4 heteromers. Finally, the impact of intramembrane receptor-receptor interactions in molecular medicine is discussed outside the brain with focus on the endocrine, the cardiovascular and the immune systems.

  • 24. Gburcik, Valentina
    et al.
    Cawthorn, William P.
    Nedergaard, Jan
    Timmons, James A.
    Cannon, Barbara
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Physiology.
    An essential role for Tbx15 in the differentiation of brown and "brite" but not white adipocytes2012In: American Journal of Physiology. Endocrinology and Metabolism, ISSN 0193-1849, E-ISSN 1522-1555, Vol. 303, no 8, p. e1053-E1060Article in journal (Refereed)
    Abstract [en]

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

  • 25. Gnjidic, Danijela
    et al.
    Johnell, Kristina
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Clinical implications from drug-drug and drug-disease interactions in older people2013In: Clinical and experimental pharmacology & physiology, ISSN 0305-1870, E-ISSN 1440-1681, Vol. 40, no 5, p. 320-325Article, review/survey (Refereed)
    Abstract [en]

    This clinical review summarizes the evidence in relation to clinical outcomes from drugdrug and drugdisease interactions in older people. Exposure to drugdrug interactions is associated with increased risk of hospitalization-related outcomes in older people. Drugdisease interactions have been linked with adverse drug interactions and adverse drug events in studies of older people. Although the prevalence of drugdrug and drugdisease interactions is common in older people, there are very limited empirical data on important clinical outcomes from drugdrug and drugdisease interactions. Clinical implications of interactions between drugs and geriatric syndromes such as frailty, falls, cognitive impairment, immobility and urinary incontinence should also be considered in older people.

  • 26. Holmér, Ingvar
    Physiology of swimming man1974Doctoral thesis, comprehensive summary (Other academic)
  • 27.
    Jacobsen, Kristin
    et al.
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Adlerz, Linda
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Multhaup, Gerd
    Institute for chemistry and biochemistry, Free University of Berlin.
    Iverfeldt, Kerstin
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Insulin-like growth factor-1 (IGF-1)-induced processing of amyloid-β precursor protein (APP) and APP-like protein 2 is mediated by different metalloproteinases2010In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 285, no 14, p. 10223-10231Article in journal (Refereed)
    Abstract [en]

    α-Secretase cleavage of the amyloid precursor protein (APP) is of great interest since it prevents the formation of the Alzheimer-linked amyloid-β peptide. APP belongs to a conserved gene family including the two paralogues APP-like protein (APLP) 1 and 2. Insulin-like growth factor-1 (IGF-1) stimulates the shedding of all three proteins. IGF-1-induced shedding of both APP and APLP1 is dependent on phosphatidylinositol 3-kinase (PI3-K), whereas sAPLP2 secretion is independent of this signaling pathway. Here, we used human neuroblastoma SH-SY5Y cells to investigate the involvement of protein kinase C (PKC) in the proteolytic processing of endogenously expressed members of the APP family. Processing was induced by IGF-1 or retinoic acid, another known stimulator of APP a-secretase shedding. Our results show that stimulation of APP and APLP1 processing involves multiple signaling pathways, whereas APLP2 processing is mainly dependent on PKC. Next, we wanted to investigate if the difference in the regulation of APLP2 shedding compared to APP shedding could be due to involvement of different processing enzymes. We focused on the two major a-secretase candidates ADAM10 and TACE, which both are members of the ADAM (a disintegrin and metalloprotease) family. Shedding was analyzed in the presence of the ADAM10 inhibitor GI254023X, or after transfection with siRNA targeted against TACE. The results clearly demonstrate that different α-secretases are involved in IGF-1-induced processing. APP is mainly cleaved by ADAM10, whereas APLP2 processing is mediated by TACE. Finally, we also show that IGF-1 induces PKC-dependent phosphorylation of TACE.

  • 28.
    Jakobsson, Andreas
    Stockholm University, Faculty of Science, Wenner-Gren Institute for Experimental Biology.
    Elovl3 and very long chain fatty acids; role in metabolism2005Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Fatty acids (FA) are important in several aspects of cellular function, for example as structural molecules and metabolic substrates. The bulk of FA up to 16 carbons (palmitic acid) in length are synthesised by a cytosolic enzyme complex called fatty acid synthase (FAS), while FA can be further elongated into very long-chain fatty acids (VLCFA) by membrane-bound enzymes in the endoplasmatic reticulum (ER). Individual enzymes perform the four different steps of the elongation cycle to extend VLCFA, where condensation enzymes (first step) are suggested to be rate-limiting as well as in control of substrate specificity. Six mammalian condensation enzymes, encoded by Elovl (Elogation of very long chain fatty acids) genes in mouse, have presently been identified which suggests multiple elongation pathways.

    In this report, I present data from studies performed mainly in brown adipose tissue and skin on the role of ELOVL3 in metabolic and structure-related processes. This enzyme is suggested to be involved in the synthesis of saturated and monounsaturated VLCFA, which are incorporated into different classes of lipids. Acyl-specific structural functions of sphingolipids, essential for proper membrane integrity, constitute a requirement for endogenous synthesis of VLCFA. We have demonstrated complementary functions between yeast and murine elongation enzymes in the synthesis of sphingolipids with corresponding alterations in cell viability. This indicates a conserved function for elongation enzymes in eukaryotic cells, which implicates cellular growth and maintenance of membrane structures.

    Investigations of the lipid composition in Elovl3-ablated mice, generated by homologous recombination, support a role for ELOVL3 in the synthesis of neutral lipids, such as triglycerides and sterol-esters. The phenotype of these mice includes impaired skin barrier function and altered VLCFA elongation activity in liver and brown adipose tissue, which is consistent with the tissue-specific expression pattern of this gene.

    Regulation of Elovl3 mRNA expression in brown adipocytes was found to differ from what was seen for other Elovl gene family members, which suggests divergent functional roles within the family of elongases. Elovl3 expression correlated with a high oxidative state, therefore, the function of this enzyme may be to replenish specific lipids under conditions of intense FA turnover. In addition, channeling of metabolic substrates is altered in brown adipocytes lacking ELOVL3, indicating important functions of specific VLCFA in nutritional homeostasis and substrate utilization.

  • 29. Jeruszka-Bielak, Marta
    et al.
    Kollajtis-Dolowy, Anna
    Santoro, Aurelia
    Ostan, Rita
    Berendsen, Agnes A. M.
    Jennings, Amy
    Meunier, Nathalie
    Marseglia, Anna
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Caumon, Elodie
    Gillings, Rachel
    de Groot, Lisette C. P. G. M.
    Franceschi, Claudio
    Hieke, Sophie
    Pietruszka, Barbara
    Are Nutrition-Related Knowledge and Attitudes Reflected in Lifestyle and Health Among Elderly People? A Study Across Five European Countries2018In: Frontiers in Physiology, ISSN 1664-042X, E-ISSN 1664-042X, Vol. 9, article id 994Article in journal (Refereed)
    Abstract [en]

    Background: Nutrition-related knowledge (NRK) and nutrition-related attitudes (NRAs) are necessary for dietary changes toward healthier dietary patterns. In turn, healthier dietary patterns can be beneficial in maintaining health of older adults. Therefore, the aim of this cross-sectional study was to investigate whether NRK and NRAs were associated with lifestyle and health features among older adults (65+ years) from five European countries (France, Italy, Poland, the Netherlands and United Kingdom). Methods: Within the European project NU-AGE, 1,144 healthy elderly volunteers (65-79 years) were randomly assigned to two groups: intervention (NU-AGE diet) or control. After 1-year of follow-up, both NRK and NRAs were assessed during exit interviews, in combination with a number of lifestyle and health variables (e.g., physical activity, smoking, alcohol use, BMI, self-assessed health status). Multivariable linear regression models were used in data analysis. Results: In the NU-AGE study sample, good NRK was associated with lower BMI and higher physical activity. More positive NRAs were related to lower BMI and self-reported very good or good appetite. Moreover, both NRK and NRAs were associated with some socio-economic determinants, like financial situation, age, education, living area (for NRK), and country (for NRAs). Participants in the intervention group showed a better NRK (beta = 0 367 [95% CI 0.117; 0.617], p = 0.004) and more positive NRAs beta = 0.838 [95% CI 0.318, 1.358], p = 0.002) than those in the control group. Higher self-evaluated knowledge was also significantly related to more positive NRAs (p < 0.001). The most popular sources of nutrition information were food labels, books and magazines on health, the dietitian and the doctor's office, although their importance varied significantly among countries, and, to a lesser extent, between women and men and between intervention and control group. Conclusion: Higher NRK and NRA scores were associated with lower BMI and higher physical activity level. Therefore, a good nutrition-related knowledge and positive nutrition-related attitudes can strongly and positively influence the health status and quality of life among the older population. These results offer a great opportunity for policy makers to implement educational programs in order to counteract the epidemic of obesity and to improve the health span of European population.

  • 30. Kasimova, Marina A.
    et al.
    Lindahl, Erik
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab). KTH Royal Institute of Technology, Sweden.
    Delemotte, Lucie
    Determining the molecular basis of voltage sensitivity in membrane proteins2018In: The Journal of General Physiology, ISSN 0022-1295, E-ISSN 1540-7748, Vol. 150, no 10, p. 1444-1458Article in journal (Refereed)
    Abstract [en]

    Voltage-sensitive membrane proteins are united by their ability to transform changes in membrane potential into mechanical work. They are responsible for a spectrum of physiological processes in living organisms, including electrical signaling and cell-cycle progression. Although the mechanism of voltage-sensing has been well characterized for some membrane proteins, including voltage-gated ion channels, even the location of the voltage-sensing elements remains unknown for others. Moreover, the detection of these elements by using experimental techniques is challenging because of the diversity of membrane proteins. Here, we provide a computational approach to predict voltage-sensing elements in any membrane protein, independent of its structure or function. It relies on an estimation of the propensity of a protein to respond to changes in membrane potential. We first show that this property correlates well with voltage sensitivity by applying our approach to a set of voltage-sensitive and voltage-insensitive membrane proteins. We further show that it correctly identifies authentic voltage-sensitive residues in the voltage-sensor domain of voltage-gated ion channels. Finally, we investigate six membrane proteins for which the voltage-sensing elements have not yet been characterized and identify residues and ions that might be involved in the response to voltage. The suggested approach is fast and simple and enables a characterization of voltage sensitivity that goes beyond mere identification of charges. We anticipate that its application before mutagenesis experiments will significantly reduce the number of potential voltage-sensitive elements to be tested.

  • 31. 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, ISSN 1472-6823, 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.

  • 32. Marraffa, Alexandre
    et al.
    Lekander, Mats
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska Institutet, Sweden.
    Solsjö, Peter
    Olsson, Mats J.
    Lasselin, Julie
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska Institutet, Sweden; University Hospital Essen, Germany.
    Axelsson, John
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska Institutet, Sweden.
    Yawning, a thermoregulatory mechanism during fever? A study of yawning frequency and its predictors during experimentally induced sickness2017In: Physiology and Behavior, ISSN 0031-9384, E-ISSN 1873-507X, Vol. 182, p. 27-33Article in journal (Refereed)
    Abstract [en]

    Yawning has been proposed to serve both physiological and social functions, the latter likely to have developed later in its evolution. A central hypothesis is that yawning cools the brain but whether yawning is a thermoregulatory mechanism that is activated during hyperthermia (i.e., thermoregulatory failure) or is activated in any instance of brain temperature increase (e.g., also during fever) is unclear and experimental assessments of yawning during fever are lacking. In this study, we determined the effect of experimentally induced fever on yawning frequency. We also explored alternative predictors of yawning during sickness (sleepiness, autonomic nervous system indexes and sickness symptoms). Twenty-two healthy human subjects participated in a randomized, placebo-controlled, cross-over study, where the subjects received an injection of the bacterial endotoxin lipopolysaccharide (LPS) at a dose of 2 ng/kg body weight in one condition and placebo in the other. Yawning was scored from video recordings from 30 min before to 4 h after the injection. Body temperature was measured frequently, alongside with heart rate, blood pressure, nausea and overall sickness symptoms. Yawning frequency was found to significantly increase over time during experimentally induced sickness, but not in the placebo condition. In particular, yawning frequency was increased during the rising phase of body temperature induced by LPS administration, although no significant correlation was found between body temperature increase and yawning frequency. In addition, exploratory analyses showed that a higher yawning frequency was associated with less increase in sickness symptoms and nausea intensity. While the current study adds to previous research showing significant increase in yawning frequency during hyperthermia, further studies are needed if we are to properly characterize the brain cooling role of yawning in humans. The investigation of other functions, such as being a vasovagal inhibitory, may shed stronger light on the functions of yawning.

  • 33. Martins, Andressa Juliane
    et al.
    Vasconcelos, Suleima Pedroza
    Skene, Debra Jean
    Lowden, Arne
    Stockholm University, Faculty of Social Sciences, Stress Research Institute.
    de Castro Moreno, Claudia Roberta
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. University of São Paulo, Brazil.
    Effects of physical activity at work and life-style on sleep in workers from an Amazonian Extractivist Reserve2016In: Sleep Science, ISSN 1984-0659, E-ISSN 1984-0063, Vol. 9, no 4, p. 289-294Article in journal (Refereed)
    Abstract [en]

    Physical activity has been recommended as a strategy for improving sleep. Nevertheless, physical effort at work might not be not the ideal type of activity to promote sleep quality. The aim of this study was to evaluate the effects of type of job (low vs. high physical effort) and life-style on sleep of workers from an Amazonian Extractivist Reserve, Brazil. A cross-sectional study of 148 low physical activity (factory workers) and 340 high physical activity (rubber tappers) was conducted between September and November 2011. The workers filled out questionnaires collecting data on demographics (sex, age, occupation, marital status and children), health (reported morbidities, sleep disturbances, musculoskeletal pain and body mass index) and life-style (smoking, alcohol use and practice of leisure-time physical activity). Logistic regression models were applied with the presence of sleep disturbances as the primary outcome variable. The prevalence of sleep disturbances among factory workers and rubber tappers was 15.5% and 27.9%, respectively. The following independent variables of the analysis were selected based on a univariate model (p<0.20): sex, age, marital status, work type, smoking, morbidities and musculoskeletal pain. The predictors for sleep disturbances were type of job (high physical effort); sex (female); age (>40 years), and having musculoskeletal pain (≥5 symptoms). Rubber tapper work, owing to greater physical effort, pain and musculoskeletal fatigue, was associated with sleep disturbances. Being female and older than 40 years were also predictors of poor sleep. In short, these findings suggest that demanding physical exertion at work may not improve sleep quality.

  • 34.
    Mattsson, Charlotte L.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Role of caveolin-1 in brown adipose tissue2010Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Caveolae are 50-100 nm invaginations in the plasma membrane. Caveolae and the protein caveolin-1 (Cav1) have been shown to be important in many signaling pathways in different cell types; however, in some cell types caveolae and Cav1 do not seem to affect the investigated signaling pathways. In my thesis, I have investigated the role of caveolin-1 (Cav1) in metabolism and b3-adrenergic, LPA-, EGF- and PDGF-receptor signaling in brown adipocytes.

    Brown adipose tissue is responsible for nonshivering thermogenesis. Recent studies have shown that not only infants but also adult man can have brown adipose tissue and that the presence is negatively correlated with both obesity and age. By understanding how signaling for proliferation and differentiation in brown adipocytes is regulated, it could be possible in the future to activate brown adipose tissue to combat obesity and the metabolic syndrome.

    In brown adipocytes, both epidermal growth factor (EGF) and platelet-derived growth factor (PDGF) were able to induce proliferation, which was dependent on Erk1/2 activation. However, EGF and PDGF utilized different pathways to activate Erk1/2, with EGF signaling partially occurring via a Src-pathway (not involving PI3K/PKC) and PDGF via a PI3K/PKC/Src-pathway. Furthermore, LPA receptors were able to activate Erk1/2 via two pathways, one Gi/PKC/Src-pathway and one PI3K-pathway. For these receptors, Cav1-ablation did not affect the agonist-induced Erk1/2 activation. Cav1 was, however, required for proper b3-adrenergic receptor (b3-AR) signaling to cAMP and for adenylyl cyclase activity.

    In Cav1-ablated mice, the adrenergic receptors are desensitized. However, this desensitization could be overcome physiologically, and the Cav1-ablated mice were therefore able to survive in prolonged cold by nonshivering thermogenesis.

    In conclusion, ablation of Cav1 affected certain signaling pathways in brown adipocytes, while other pathways were not affected or could be physiologically rescued.

  • 35.
    Moreno, Claudia R. C.
    et al.
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. University of São Paulo, Brazil.
    Lowden, Arne
    Stockholm University, Faculty of Social Sciences, Stress Research Institute.
    Vasconcelos, Suleima
    Marqueze, Elaine C.
    Musculoskeletal pain and insomnia among workers with different occupations and working hours2016In: Chronobiology International, ISSN 0742-0528, E-ISSN 1525-6073, Vol. 33, no 6, p. 749-753Article in journal (Refereed)
    Abstract [en]

    Several studies have shown a bidirectional relationship between insomnia and pain. The aim of this study was to evaluate whether working hours and type of occupation are associated with insomnia, pain and insomnia plus pain. Insomnia and musculoskeletal pain symptoms were measured in airline pilots, rural workers and factory workers using validated indexes. Rural and night work were predictors for the outcomes (insomnia and pain). However, musculoskeletal pain was found to be a predictor of insomnia but not vice versa. The current findings suggest that working hours and type of occupation play a role in the sleep-pain relationship.

  • 36.
    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.

  • 37.
    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.

  • 38.
    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)
  • 39.
    Olsen, Jessica M.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    β-Adrenergic Signalling Through mTOR2017Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Adrenergic signalling is part of the sympathetic nervous system and is activated upon stimulation by the catecholamines epinephrine and norepinephrine. This regulates heart rate, energy mobilization, digestion and helps to divert blood flow to important organs. Insulin is released to regulate metabolism of carbohydrates, fats and proteins, mainly by taking up glucose from the blood. The insulin and the catecholamine hormone systems are normally working as opposing metabolic regulators and are therefore thought to antagonize each other.

    One of the major regulators involved in insulin signalling is the mechanistic target of rapamycin (mTOR). There are two different complexes of mTOR; mTORC1 and mTORC2, and they are essential in the control of cell growth, metabolism and energy homeostasis. Since mTOR is one of the major signalling nodes for anabolic actions of insulin it was thought that catecholamines might oppose this action by inhibiting the complexes. However, lately there are studies demonstrating that this may not be the case. mTOR is for instance part of the adrenergic signalling pathway resulting in hypertrophy of cardiac and skeletal muscle cells and inhibition of smooth muscle relaxation and helps to regulate browning in white adipose tissue and thermogenesis in brown adipose tissue (BAT).

    In this thesis I show that β-adrenergic signalling leading to glucose uptake occurs independently of insulin in skeletal muscle and BAT, and does not activate either Akt or mTORC1, but that the master regulator of this pathway is mTORC2. Further, my co-workers and I demonstrates that β-adrenergic stimulation in skeletal muscle and BAT utilizes different glucose transporters. In skeletal muscle, GLUT4 is translocated to the plasma membrane upon stimulation. However, in BAT, β-adrenergic stimulation results in glucose uptake through translocation of GLUT1. Importantly, in both skeletal muscle and BAT, the role of mTORC2 in β-adrenergic stimulated glucose uptake is to regulate GLUT-translocation.

  • 40.
    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.

  • 41.
    Olsen, Jessica M.
    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. Monash Institute of Pharmaceutical Sciences, Australia.
    Dallner, Olof S.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. The Rockefeller University, USA.
    Sandström, Anna L.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Pisani, Didier F.
    Jean-Claude, Chambard
    Amri, Ez-Zoubir
    Hutchinson, Dana S.
    Bengtsson, Tore
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Glucose uptake in brown fat cells is dependent on mTOR complex 2-promoted GLUT1 translocation2014In: Journal of Cell Biology, ISSN 0021-9525, E-ISSN 1540-8140, Vol. 207, no 3, article id 365Article in journal (Refereed)
    Abstract [en]

    Brown adipose tissue is the primary site for thermogenesis and can consume, in addition to free fatty acids, a very high amount of glucose from the blood, which can both acutely and chronically affect glucose homeostasis. Here, we show that mechanistic target of rapamycin (mTOR) complex 2 has a novel role in β3-adrenoceptor-stimulated glucose uptake in brown adipose tissue. We show that β3-adrenoceptors stimulate glucose uptake in brown adipose tissue via a signaling pathway that is comprised of two different parts: one part dependent on cAMP-mediated increases in GLUT1 transcription and de novo synthesis of GLUT1 and another part dependent on mTOR complex 2-stimulated translocation of newly synthesized GLUT1 to the plasma membrane, leading to increased glucose uptake. Both parts are essential for β3-adrenoceptor-stimulated glucose uptake. Importantly, the effect of β3-adrenoceptor on mTOR complex 2 is independent of the classical insulin-phosphoinositide 3-kinase-Akt pathway, highlighting a novel mechanism of mTOR complex 2 activation.

  • 42.
    Olsen, Jessica M.
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Åslund, Alice
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Sandström, Anna
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Bengtsson, Jessica
    Akt is not required for β3-adrenergically induced glucose uptake in brown adipose tissueManuscript (preprint) (Other academic)
  • 43. Papp, Marian E.
    et al.
    Lindfors, Petra
    Stockholm University, Faculty of Social Sciences, Department of Psychology, Work and organizational psychology.
    Nygren-Bonnier, Malin
    Gullstrand, Lennart
    Wändell, Per E.
    Effects of high-intensity hatha yoga on cardiovascular fitness, adipocytokines, and apolipoproteins in healthy students: a randomized controlled study2016In: Journal of Alternative and Complementary Medicine, ISSN 1075-5535, E-ISSN 1557-7708, Vol. 22, no 1, p. 81-87Article in journal (Refereed)
    Abstract [en]

    Background: Yoga exercises are often used as a form of body and mind exercise to increase performance. However, knowledge about the physiologic effects of performing high-intensity Hatha yoga exercises over a longer time period remains limited.

    Objective: To investigate the effects of high-intensity yoga (HIY) on cardiovascular fitness (maximal oxygen consumption, estimated from the Cooper running test), ratings of perceived exertion (RPE), heart rate (HR), heart rate recovery (HRR), blood pressure (BP), adipocytokines, apolipoprotein A1 (ApoA1), apolipoprotein B (ApoB), and glycosylated hemoglobin (HbA1c) in healthy students.

    Methods: The 44 participants (38 women and 6 men; median age, 25 years [range, 20–39 years]) were randomly assigned to an HIY or a control group. The HIY program was held for 6 weeks (60 minutes once a week). Cardiovascular fitness, RPE, HR, HRR, BP, adipocytokines, HbA1c, ApoA1, and ApoB were measured at baseline and after 6 weeks in both groups.

    Results: HIY had no significant effects on cardiovascular fitness (mean dose: 390 minutes [range, 210–800 minutes]), HR, HRR, BP, or any of the blood parameters. However, ApoA1 (1.47 ± 0.17 to 1.55 ± 0.16 g/L; p = 0.03) and adiponectin (8.32 ± 3.32 to 9.68 ± 3.83 mg/L; p = 0.003) levels increased significantly in the HIY group after 6 weeks.

    Conclusions: Six weeks of HIY did not significantly improve cardiovascular fitness. However, ApoA1 and adiponectin levels increased significantly in the HIY group. This finding suggests that HIY may have positive effects on blood lipids and an anti-inflammatory effect.

  • 44.
    Pauter, Anna Maria
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Metabolic Significance of Systemic DHA Deficiency2016Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Fatty acid composition in the body displays a high level of heterogeneity and can rapidly respond to changes in diet regime or to starvation. Homeostasis of the level of certain fatty acids is an important factor for maintenance of structural integrity as well as for proper signaling within the organism. Hence, changes in fatty acid composition have been proposed as an important factor during the pathogenesis of many diseases.Concentration of polyunsaturated fatty acid (PUFA) within the body is modulated by the interplay between dietary intake, endogenous de novo synthesis or mobilization of fatty acids from tissue reservoirs. Endogenous synthesis of PUFA is regulated on different genetic levels as well as the level of substrate availability. Studies have reported a variation in PUFA biosynthesis between different developmental stages, age, gender, during pregnancy, lactation and under conditions of certain disorders. A member of the enzymatic machinery involved in PUFA synthesis is the elongase Elongation of very long-chain fatty acids 2 (ELOVL2) that controls the elongation of PUFA with 22 carbons to produce 24 carbons precursors for the production of the omega-3 PUFA, docosahexaenoic acid (DHA, 22:6n3) and the omega-6 PUFA, docosapentaenoic (DPAn6, 22:5n6). Deletion of Elovl2 in a mouse model (Elovl2KO) leads to systemic DHA deficiency at different physiological and early lifestages, and is related to certain metabolic dysfunctions. Mitochondria of Elovl2KO mice display structural and functional impairment. Compared to wild type littermates, Elovl2KO mice do not gain as much weight after high-fat diet treatment and do not develop hepatic steatosis, despite having a higher level of the positive regulator of denovo lipogenesis, nuclear transcription factor SREBP1c. Resistance to high fat diet induced-obesity in Elovl2KO mice is abolished by DHA supplementation together with high sucrose content in the background diet. In conclusion, deletion of Elovl2 in mice leads to systemic DHA deficiency that has pleiotropic effect on mouse energy metabolism.

  • 45.
    Petersen, Helena
    et al.
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska Institutet, Sweden.
    Kecklund, Göran
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska Institutet, Sweden.
    D'Onofrio, Paolo
    Stockholm University, Faculty of Social Sciences, Stress Research Institute.
    Axelsson, John
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska Institutet, Sweden.
    Åkerstedt, Torbjörn
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska Institutet, Sweden.
    Thank god it's Friday - sleep improved2017In: Journal of Sleep Research, ISSN 0962-1105, E-ISSN 1365-2869, Vol. 26, no 5, p. 567-571Article in journal (Refereed)
    Abstract [en]

    The weekend is usually seen as a window of recovery. Thus, sleep before a day off may be less impaired than that before a workday. However, very few polysomnographical studies have investigated this hypothesis. Therefore, the aim of the present study was to compare sleep before a workday with that before a weekend. Seventeen teachers participated. Sleep was recorded with polysomnography on one weekday night during the workweek, and on a workday (Friday) followed by a day off. Sleep diaries and actigraphs were also used. Weekend sleep showed delayed bedtime and time of rising, a longer total sleep time (45 min), increased N3 and N1, and decreased N2 and REM. Sleep spindles were reduced. The results remained after truncation to the shortest common sleep duration (5 h). The increase in N3 from weekday sleep to Friday night sleep was positively correlated with N1 change (r = 0.853, P <= 0.001), and negatively correlated with N2 change (r = -0.614, P <= 0.001). Subjective ratings showed that weekend sleep was associated with less awakening problems and lower subjective arousal during the day. The authors concluded that weekend sleep was longer, and showed increased N3 and N1. The authors suggest that the N3 increase before the day off is a result of lower stress, while the N1 increase may be an effect of sleep spindle suppression via the increase of N3 (which would suppress sleep spindles), thus reducing N2 and enhancing N1.

  • 46.
    Runesson, Johan
    et al.
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Langel, Ülo
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Receptor subtype selective galanin analogous for better understanding of the role of galanin in cancer progression2010Conference paper (Other academic)
    Abstract [en]

    Galanin and galanin receptors have been found in several tumors. Galanin signaling has been studied in more detail in small cell lung carcinoma, where signaling via the GalR2 decreases the tumor growth. Galanin has also been included in a clinical therapy for pancreatic tumor together with a somatostatin agonist and serotonin. However, galanin signals via three receptors subtype with a broad expression pattern. We have therefore, developed several subtype selective galanin analogous that should reduce the side effects caused by galanin treatment. Therefore, we hope that the successful design of galanin receptor subtype selective ligands increase the interest for galanin and cancer progression.

  • 47.
    Sato, Masaaki
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. Monash University, Australia.
    Dehvari, Nodi
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Öberg, Anette I.
    Dallner, Olof S.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. The Rockefeller University, USA.
    Sandström, Anna L.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Olsen, Jessica M.
    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.
    Summers, Roger J.
    Hutchinson, Dana S.
    Bengtsson, Tore
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Improving type 2 diabetes through a distinct adrenergic signaling pathway involving mTORC2 that mediates glucose uptake in skeletal muscle2014In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 63, no 12, p. 4115-4129Article in journal (Refereed)
    Abstract [en]

    There is an increasing worldwide epidemic of type 2 diabetes that poses major health problems. We have identified a novel physiological system that increases glucose uptake in skeletal muscle but not in white adipocytes. Activation of this system improves glucose tolerance in Goto-Kakizaki rats or mice fed a high-fat diet, which are established models for type 2 diabetes. The pathway involves activation of β2-adrenoceptors that increase cAMP levels and activate cAMP-dependent protein kinase, which phosphorylates mammalian target of rapamycin complex 2 (mTORC2) at S2481. The active mTORC2 causes translocation of GLUT4 to the plasma membrane and glucose uptake without the involvement of Akt or AS160. Stimulation of glucose uptake into skeletal muscle after activation of the sympathetic nervous system is likely to be of high physiological relevance because mTORC2 activation was observed at the cellular, tissue, and whole-animal level in rodent and human systems. This signaling pathway provides new opportunities for the treatment of type 2 diabetes.

  • 48. Schnell, Robert
    Studies on ribosome interacting proteins2003Doctoral thesis, comprehensive summary (Other academic)
  • 49.
    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.

  • 50. Steinz, Maarten M.
    et al.
    Persson, Malin
    Aresh, Bejan
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Olsson, Karl
    Cheng, Arthur J.
    Ahlstrand, Emma
    Lilja, Mats
    Lundberg, Tommy R.
    Rullman, Eric
    Ängeby Möller, Kristina
    Sandor, Katalin
    Ajeganova, Sofia
    Yamada, Takashi
    Beard, Nicole
    Karlsson, Björn C. G.
    Tavi, Pasi
    Kenne, Ellinor
    Svensson, Camilla
    Rassier, Dilson E.
    Karlsson, Roger
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Friedman, Ran
    Gustafsson, Thomas
    Lanner, Johanna T.
    Oxidative hotspots on actin promote skeletal muscle weakness in rheumatoid arthritis2019In: JCI Insight, ISSN 2379-3708, Vol. 4, no 9, article id e126347Article in journal (Refereed)
    Abstract [en]

    Skeletal muscle weakness in patients suffering from rheumatoid arthritis (RA) adds to their impaired working abilities and reduced quality of life. However, little molecular insight is available on muscle weakness associated with RA. Oxidative stress has been implicated in the disease pathogenesis of RA. Here, we show that oxidative posttranslational modifications of the contractile machinery targeted to actin result in impaired actin polymerization and reduced force production. Using mass spectrometry, we identified the actin residues targeted by oxidative 3-nitrotyrosine (3-NT) or malondialdehyde (MDA) adduct modifications in weakened skeletal muscle from mice with arthritis and patients afflicted by RA. The residues were primarily located in 3 distinct regions positioned at matching surface areas of the skeletal muscle actin molecule from arthritic mice and patients with RA. Moreover, molecular dynamics simulations revealed that these areas, here coined hotspots, are important for the stability of the actin molecule and its capacity to generate filaments and interact with myosin. Together, these data demonstrate how oxidative modifications on actin promote muscle weakness in RA patients and may provide novel leads for targeted therapeutic treatment to improve muscle function.

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