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  • 1.
    Abreu-Vieira, Gustavo
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Bengtsson, Tore
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Petrovic, Natasa
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Nedergaard, Jan
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    On adequate procedures for glucose tolerance tests in obese animals: Measurement of glucose tolerance in obesityManuskript (preprint) (Annet vitenskapelig)
    Abstract [en]

    Routine procedures for glucose tolerance test in rodents utilize an amount of injected glucose that is proportional to total body weight (normally 2 mg per g body weight). Obese mice consist of much more chemically inert lipid than lean mice but have only marginal increases in lean body mass (the only compartment where glucose is distributed). Present procedures thus inevitably lead to a diagnosis of impaired glucose tolerance and enhanced insulin levels in obesity. Routine procedures should use fixed glucose amounts per lean body mass (or per mouse).

  • 2.
    Abreu-Vieira, Gustavo
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Fischer, Alexander W.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut. University of Hamburg, Germany.
    Mattsson, Charlotte
    de Jong, Jasper M. A.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Shabalina, Irina G.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Ryden, Mikael
    Laurencikiene, Jurga
    Arner, Peter
    Cannon, Barbara
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Nedergaard, Jan
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Petrovic, Natasa
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Cidea improves the metabolic profile through expansion of adipose tissue2015Inngår i: Nature Communications, E-ISSN 2041-1723, Vol. 6, artikkel-id 7433Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    In humans, Cidea (cell death-inducing DNA fragmentation factor alpha-like effector A) is highly but variably expressed in white fat, and expression correlates with metabolic health. Here we generate transgenic mice expressing human Cidea in adipose tissues (aP2-hCidea mice) and show that Cidea is mechanistically associated with a robust increase in adipose tissue expandability. Under humanized conditions (thermoneutrality, mature age and prolonged exposure to high-fat diet), aP2-hCidea mice develop a much more pronounced obesity than their wild-type littermates. Remarkably, the malfunctioning of visceral fat normally caused by massive obesity is fully overcome-perilipin 1 and Akt expression are preserved, tissue degradation is prevented, macrophage accumulation is decreased and adiponectin expression remains high. Importantly, the aP2-hCidea mice display enhanced insulin sensitivity. Our data establish a functional role for Cidea and suggest that, in humans, the association between Cidea levels in white fat and metabolic health is not only correlative but also causative.

  • 3.
    Cannon, Barbara
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    de Jong, Jasper M. A.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Fischer, Alexander W.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Nedergaard, Jan
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Petrovic, Natasa
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Human brown adipose tissue: Classical brown rather than brite/beige?2020Inngår i: Experimental Physiology, ISSN 0958-0670, E-ISSN 1469-445X, Vol. 105, nr 8, s. 1191-1200Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    New Findings What is the topic of this review? It has been suggested that human brown adipose tissue (BAT) is more similar to the brite/beige adipose tissue of mice than to classical BAT of mice. The basis of this is discussed in relationship to the physiological conditions of standard experimental mice.

  • 4. Cheung, L.
    et al.
    Gertow, J.
    Werngren, O.
    Folkersen, L.
    Petrovic, Natasa
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Nedergaard, Jan
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Franco-Cereceda, A.
    Eriksson, P.
    Fisher, R. M.
    Human mediastinal adipose tissue displays certain characteristics of brown fat2013Inngår i: Nutrition & Diabetes, E-ISSN 2044-4052, Vol. 3, nr UNSP e66Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND: The amount of intra-thoracic fat, of which mediastinal adipose tissue comprises the major depot, is related to various cardiometabolic risk factors. Autopsy and imaging studies indicate that the mediastinal depot in adult humans could contain brown adipose tissue (BAT). To gain a better understanding of this intra-thoracic fat depot, we examined possible BAT characteristics of human mediastinal in comparison with subcutaneous adipose tissue. MATERIALS AND METHODS: Adipose tissue biopsies from thoracic subcutaneous and mediastinal depots were obtained during open-heart surgery from 33 subjects (26 male, 63.7 +/- 13.8 years, body mass index 29.3 +/- 5.1 kg m(-2)). Microarray analysis was performed on 10 patients and genes of interest confirmed by quantitative PCR (qPCR) in samples from another group of 23 patients. Adipocyte size was determined and uncoupling protein 1 (UCP1) protein expression investigated with immunohistochemistry. RESULTS: The microarray data showed that a number of BAT-specific genes had significantly higher expression in the mediastinal depot than in the subcutaneous depot. Higher expression of UCP1 (24-fold, P < 0.001) and PPARGC1A (1.7-fold, P = 0.0047), and lower expression of SHOX2 (0.12-fold, P < 0.001) and HOXC8 (0.14-fold, P < 0.001) in the mediastinal depot was confirmed by qPCR. Gene set enrichment analysis identified two gene sets related to mitochondria, which were significantly more highly expressed in the mediastinal than in the subcutaneous depot (P < 0.01). No significant changes in UCP1 gene expression were observed in the subcutaneous or mediastinal depots following lowering of body temperature during surgery. UCP1 messenger RNA levels in the mediastinal depot were lower than those in murine BAT and white adipose tissue. In some mediastinal adipose tissue biopsies, a small number of multilocular adipocytes that stained positively for UCP1 were observed. Adipocytes were significantly smaller in the mediastinal than the subcutaneous depot (cross-sectional area 2400 +/- 810 versus 3260 +/- 980 mu m(2), P < 0.001). CONCLUSIONS: Human mediastinal adipose tissue displays some characteristics of BAT when compared with the subcutaneous depot at microscopic and molecular levels.

  • 5. Dahlman, I
    et al.
    Mejhert, N
    Linder, K
    Agustsson, T
    Mutch, D M
    Kulyte, A
    Isaksson, B
    Permert, J
    Petrovic, Natasa
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för fysiologi.
    Nedergaard, Jan
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för fysiologi.
    Sjölin, E
    Brodin, D
    Clement, K
    Dahlman-Wright, K
    Rydén, M
    Arner, P
    Adipose tissue pathways involved in weight loss of cancer cachexia2010Inngår i: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 102, nr 10, s. 1541-8Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

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

  • 6.
    Davies, Victoria S.
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Lindsund, Erik
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Petrovic, Natasa
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Cannon, Barbara
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Nedergaard, Jan
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Repeated short excursions from thermoneutrality suffice to restructure brown adipose tissue2023Inngår i: Biochimie, ISSN 0300-9084, E-ISSN 1638-6183, Vol. 210, s. 40-49Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Given the presence of brown adipose tissue in adult humans, an important issue is whether human brown adipose tissue is recruitable. Cold exposure is the canonical recruitment treatment; however, in experimental animals (mice), recruitment of brown adipose tissue is normally induced by placing the mice in constant cold, a procedure not feasible in humans. For possible translational applications, we have therefore investigated whether shorter daily excursions from thermoneutrality would suffice to qualitatively and quantitatively induce recruitment in mice. Mice, housed at thermoneutrality (30 °C) to mimic human conditions, were transferred every day for 4 weeks to cool conditions (18 °C), for 0, 15, 30, 120 and 420 min (or placed constantly in 18 °C). On the examination day, the mice were not exposed to cold. Very short daily exposures (≤30 minutes) were sufficient to induce structural changes in the form of higher protein density in brown adipose tissue, changes that may affect the identification of the tissue in e.g. computer tomography and other scan studies. To estimate thermogenic capacity, UCP1 protein levels were followed. No UCP1 protein was detectable in inguinal white adipose tissue. In the interscapular brown adipose tissue, a remarkable two-phase reaction was seen. Very short daily exposures (≤30 minutes) were sufficient to induce a significant increase in total UCP1 levels. For attainment of full cold acclimation, the mice had, however, to remain exposed to the cold. The studies indicate that marked alterations in brown adipose tissue composition can be induced in mammals through relatively modest stimulation events.

  • 7.
    de Jong, Jasper
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Fischer, Alexander
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut. University Medical Center Hamburg-Eppendorf, Germany.
    von Essen, Gabriella
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Cannon, Barbara
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Nedergaard, Jan
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Petrovic, Natasa
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Brown adipose tissue in physiologically humanized mice phenocopies human brown fatManuskript (preprint) (Annet vitenskapelig)
  • 8.
    de Jong, Jasper M. A.
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut. Yale School of Medicine, USA.
    Sun, Wenfei
    Pires, Nuno D.
    Frontini, Andrea
    Balaz, Miroslav
    Jespersen, Naja Z.
    Feizi, Amir
    Petrovic, Katarina
    Fischer, Alexander W.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut. University Medical Center Hamburg-Eppendorf, Germany; Chan School of Public Health, USA; Harvard Medical School, USA.
    Bokhari, Muhammad Hamza
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Niemi, Tarja
    Nuutila, Pirjo
    Cinti, Saverio
    Nielsen, Soren
    Scheele, Camilla
    Virtanen, Kirsi
    Cannon, Barbara
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Nedergaard, Jan
    Wolfrum, Christian
    Petrovic, Natasa
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Human brown adipose tissue is phenocopied by classical brown adipose tissue in physiologically humanized mice2019Inngår i: Nature Metabolism, E-ISSN 2522-5812, Vol. 1, nr 8, s. 830-843Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Human and rodent brown adipose tissues (BAT) appear morphologically and molecularly different. Here we compare human BAT with both classical brown and brite/beige adipose tissues of 'physiologically humanized' mice: middle-aged mice living under conditions approaching human thermal and nutritional conditions, that is, prolonged exposure to thermoneutral temperature (approximately 30 degrees C) and to an energy-rich (high-fat, high-sugar) diet. We find that the morphological, cellular and molecular characteristics (both marker and adipose-selective gene expression) of classical brown fat, but not of brite/beige fat, of these physiologically humanized mice are notably similar to human BAT. We also demonstrate, both in silico and experimentally, that in physiologically humanized mice only classical BAT possesses a high thermogenic potential. These observations suggest that classical rodent BAT is the tissue of choice for translational studies aimed at recruiting human BAT to counteract the development of obesity and its comorbidities.

  • 9.
    de Jong, Jasper M. A.
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Wouters, René T. F.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Boulet, Nathalie
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Cannon, Barbara
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Nedergaard, Jan
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Petrovic, Natasa
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    The β3-adrenergic receptor is dispensable for browning of adipose tissues2017Inngår i: American Journal of Physiology. Endocrinology and Metabolism, ISSN 0193-1849, E-ISSN 1522-1555, Vol. 312, nr 6, s. E508-E518Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Brown and brite/beige adipocytes are attractive therapeutic targets to treat metabolic diseases. To maximally utilize their functional potential, further understanding is required about their identities and their functional differences. Recent studies with β3-adrenergic receptor knockout mice reported that brite/beige adipocytes, but not classical brown adipocytes, require the β3-adrenergic receptor for cold-induced transcriptional activation of thermogenic genes. We aimed to further characterize this requirement of the β3-adrenergic receptor as a functional distinction between classical brown and brite/beige adipocytes. However, when comparing wild-type and β3-adrenergic receptor knockout mice, we observed no differences in cold-induced thermogenic gene expression (Ucp1, Pgc1a, Dio2 and Cidea) in brown or white (brite/beige) adipose tissues. Irrespective of the duration of the cold exposure or the sex of the mice, we observed no effect of the absence of the β3-adrenergic receptor. Experiments with the β3-adrenergic receptor agonist CL-316,243 verified the functional absence of β3-adrenergic signaling in these knockout mice. The β3-adrenergic receptor knockout model in the present study was maintained on a FVB/N background, whereas earlier reports used C57BL/6 and 129Sv mice. Thus, our data imply background-dependent differences in adrenergic signaling mechanisms in response to cold exposure. Nonetheless, the present data indicate that the β3-adrenergic receptor is dispensable for cold-induced transcriptional activation in both classical brown and, as opposed to earlier studies, brite/beige cells. This should be taken into account in the increasing number of studies on the induction of browning and their extrapolation to human physiology.

  • 10. Dixen, Karen
    et al.
    Basse, Astrid L.
    Murholm, Maria
    Isidor, Marie S.
    Hansen, Lillian H. L.
    Petersen, M. Christine H.
    Madsen, Lise
    Petrovic, Natasa
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Nedergaard, Jan
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Quistorff, Bjorn
    Hansen, Jacob B.
    ERR gamma Enhances UCP1 Expression and Fatty Acid Oxidation in Brown Adipocytes2013Inngår i: Obesity, ISSN 1930-7381, E-ISSN 1930-739X, Vol. 21, nr 3, s. 516-524Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Objective: Estrogen-related receptors (ERRs) are important regulators of energy metabolism. Here we investigated the hypothesis that ERR gamma impacts on differentiation and function of brown adipocytes. Design and Methods: We characterize the expression of ERR gamma in adipose tissues and cell models and investigate the effects of modulating ERR? activity on UCP1 gene expression and metabolic features of brown and white adipocytes. Results: ERR gamma was preferentially expressed in brown compared to white fat depots, and ERR gamma was induced during cold-induced browning of subcutaneous white adipose tissue and brown adipogenesis. Overexpression of ERR gamma positively regulated uncoupling protein 1 (UCP1) expression levels during brown adipogenesis. This ERR gamma-induced augmentation of UCP1 expression was independent of the presence of peroxisome proliferator-activated receptor coactivator-1 (PGC-1 alpha) but was associated with increased rates of fatty acid oxidation in adrenergically stimulated cells. ERR? did not influence mitochondrial biogenesis, and its reduced expression in white adipocytes could not explain their low expression level of UCP1. Conclusions: Through its augmenting effect on expression of UCP1, ERR gamma may physiologically be involved in increasing the potential for energy expenditure in brown adipocytes, a function that is becoming of therapeutic interest.

  • 11.
    Fischer, Alexander W.
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut. University Medical Center Hamburg-Eppendorf, Germany.
    de Jong, Jasper M. A.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Sass, Frederike
    Schlein, Christian
    Heeren, Joerg
    Petrovic, Natasa
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Thermoneutrality-Induced Macrophage Accumulation in Brown Adipose Tissue Does Not Impair the Tissue's Competence for Cold-Induced Thermogenic Recruitment2020Inngår i: Frontiers in Endocrinology, E-ISSN 1664-2392, Vol. 11, artikkel-id 568682Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Brown adipose tissue from mice living under conditions approaching human thermal and nutritional conditions (prolonged exposure to thermoneutral temperature and to an energy-rich (high-fat, high-sugar) diet) - referred to as physiologically humanized mice, displays morphological and molecular characteristics significantly different from those observed in young, chow-fed mice maintained at room temperature - referred to as standard mice. Here, we further examined brown fat from physiologically humanized and standard mice, as well as from mice exposed to thermoneutrality for a long time but not to an energy-rich diet - referred to here as long-term thermoneutral mice. Global transcriptome analysis of brown fat revealed that genes that were the most upregulated in brown fat of thermoneutral mice (both physiologically humanized and long-term thermoneutral) were those related to inflammatory processes, including genes expressed selectively in macrophages. Cellular and molecular analyses confirmed that brown fat from thermoneutral mice was heavily infiltrated by macrophages, predominantly organized into crown-like structures. However, despite this, the brown fat of thermoneutral mice retained full competence to attain the greatest possible recruitment state and became macrophage-depleted during the process of cold acclimation. Thus, profound macrophage accumulation does not influence the thermogenic recruitment competence of brown fat.

  • 12.
    Fischer, Alexander W.
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut. University Medical Center Hamburg-Eppendorf, Germany.
    Hoefig, Carolin S.
    Abreu-Vieira, Gustavo
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    de Jong, Jasper M. A.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Petrovic, Natasa
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Mittag, Jens
    Cannon, Barbara
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Nedergaard, Jan
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Leptin Raises Defended Body Temperature without Activating Thermogenesis2016Inngår i: Cell Reports, E-ISSN 2211-1247, Vol. 14, nr 7, s. 1621-1631Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Leptin has been believed to exert its weight-reducing action not only by inducing hypophagia but also by increasing energy expenditure/thermogenesis. Leptin-deficient ob/ob mice have correspondingly been thought to be thermogenically limited and to show hypothermia, mainly due to atrophied brown adipose tissue (BAT). In contrast to these established views, we found that BAT is fully functional and that leptin treatment did not increase thermogenesis in wildtype or in ob/ob mice. Rather, ob/ob mice showed a decreased but defended body temperature (i. e., were anapyrexic, not hypothermic) that was normalized to wild-type levels after leptin treatment. This was not accompanied by increased energy expenditure or BAT recruitment but, instead, was mediated by decreased tail heat loss. The weight-reducing hypophagic effects of leptin are, therefore, not augmented through a thermogenic effect of leptin; leptin is, however, pyrexic, i. e., it alters centrally regulated thresholds of thermoregulatory mechanisms, in parallel to effects of other cytokines.

  • 13.
    Fischer, Alexander W.
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut. University Medical Center Hamburg-Eppendorf, Germany.
    Shabalina, Irina G.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Mattsson, Charlotte L.
    Abreu-Vieira, Gustavo
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Cannon, Barbara
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Nedergaard, Jan
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Petrovic, Natasa
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    UCP1 inhibition in Cidea-overexpressing mice is physiologically counteracted by brown adipose tissue hyperrecruitment2017Inngår i: American Journal of Physiology. Endocrinology and Metabolism, ISSN 0193-1849, E-ISSN 1522-1555, Vol. 312, nr 1, s. e72-E87Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Cidea is a gene highly expressed in thermogenesis- competent (UCP1-containing) adipose cells, both brown and brite/beige. Here, we initially demonstrate a remarkable adipose-depot specific regulation of Cidea expression. In classical brown fat, Cidea mRNA is expressed continuously and invariably, irrespective of tissue recruitment. However, Cidea protein levels are regulated posttranscriptionally, being conspicuously induced in the thermogenically recruited state. In contrast, in brite fat, Cidea protein levels are regulated at the transcriptional level, and Cidea mRNA and protein levels are proportional to tissue briteness. Although routinely followed as a thermogenic molecular marker, Cidea function is not clarified. Here, we employed a gain-of-function approach to examine a possible role of Cidea in the regulation of thermogenesis. We utilized transgenic aP2-hCidea mice that overexpress human Cidea in all adipose tissues. We demonstrate that UCP1 activity is markedly suppressed in brown-fat mitochondria isolated from aP2-hCidea mice. However, mitochondrial UCP1 protein levels were identical in wildtype and transgenic mice. This implies a regulatory effect of Cidea on UCP1 activity, but as we demonstrate that Cidea itself is not localized to mitochondria, we propose an indirect inhibitory effect. The Cidea-induced inhibition of UCP1 activity (observed in isolated mitochondria) is physiologically relevant since the mice, through an appropriate homeostatic compensatory mechanism, increased the total amount of UCP1 in the tissue to exactly match the diminished thermogenic capacity of the UCP1 protein and retain unaltered nonshivering thermogenic capacity. Thus, we verified Cidea as being a marker of thermogenesis-competent adipose tissues, but we conclude that Cidea, unexpectedly, functions molecularly as an indirect inhibitor of thermogenesis.

  • 14. Fischer, Katrin
    et al.
    Ruiz, Henry H.
    Jhun, Kevin
    Finan, Brian
    Oberlin, Douglas J.
    van der Heide, Verena
    Kalinovich, Anastasia V.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Petrovic, Natasa
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Wolf, Yochai
    Clemmensen, Christoffer
    Shin, Andrew C.
    Divanovic, Senad
    Brombacher, Frank
    Glasmacher, Elke
    Keipert, Susanne
    Jastroch, Martin
    Nagler, Joachim
    Schramm, Karl-Werner
    Medrikova, Dasa
    Collden, Gustav
    Woods, Stephen C.
    Herzig, Stephan
    Homann, Dirk
    Jung, Steffen
    Nedergaard, Jan
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Cannon, Barbara
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Tschoep, Matthias H.
    Mueller, Timo D.
    Buettner, Christoph
    Alternatively activated macrophages do not synthesize catecholamines or contribute to adipose tissue adaptive thermogenesis2017Inngår i: Nature Medicine, ISSN 1078-8956, E-ISSN 1546-170X, Vol. 23, nr 5, s. 623-630Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Adaptive thermogenesis is the process of heat generation in response to cold stimulation. It is under the control of the sympathetic nervous system, whose chief effector is the catecholamine norepinephrine (NE). NE enhances thermogenesis through beta 3-adrenergic receptors to activate brown adipose tissue and by 'browning' white adipose tissue. Recent studies have reported that alternative activation of macrophages in response to interleukin (IL)-4 stimulation induces the expression of tyrosine hydroxylase (TH), a key enzyme in the catecholamine synthesis pathway, and that this activation provides an alternative source of locally produced catecholamines during the thermogenic process. Here we report that the deletion of Th in hematopoietic cells of adult mice neither alters energy expenditure upon cold exposure nor reduces browning in inguinal adipose tissue. Bone marrow-derived macrophages did not release NE in response to stimulation with IL-4, and conditioned media from IL-4-stimulated macrophages failed to induce expression of thermogenic genes, such as uncoupling protein 1 (Ucp1), in adipocytes cultured with the conditioned media. Furthermore, chronic treatment with IL-4 failed to increase energy expenditure in wild-type, Ucp1(-/-) and interleukin-4 receptor-alpha double-negative (Il4ra(-/-)) mice. In agreement with these findings, adipose-tissue-resident macrophages did not express TH. Thus, we conclude that alternatively activated macrophages do not synthesize relevant amounts of catecholamines, and hence, are not likely to have a direct role in adipocyte metabolism or adaptive thermogenesis.

  • 15. Fredriksson, Katarina
    et al.
    Tjader, Inga
    Keller, Pernille
    Petrovic, Natasa
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut.
    Ahlman, Bo
    Scheele, Camilla
    Wernerman, Jan
    Timmons, James A.
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut.
    Rooyackers, Olav
    Dysregulation of Mitochondrial Dynamics and the Muscle Transcriptome in ICU Patients Suffering from Sepsis Induced Multiple Organ Failure2008Inngår i: PLOS ONE, ISSN 1932-6203, Vol. 3, nr 11, s. e3686-Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Septic patients treated in the intensive care unit (ICU) often develop multiple organ failure including persistent skeletal muscle dysfunction which results in the patient's protracted recovery process. We have demonstrated that muscle mitochondrial enzyme activities are impaired in septic ICU patients impairing cellular energy balance, which will interfere with muscle function and metabolism. Here we use detailed phenotyping and genomics to elucidate mechanisms leading to these impairments and the molecular consequences. Methodology/Principal Findings: Utilising biopsy material from seventeen patients and ten age-matched controls we demonstrate that neither mitochondrial in vivo protein synthesis nor expression of mitochondrial genes are compromised. Indeed, there was partial activation of the mitochondrial biogenesis pathway involving NRF2a/GABP and its target genes TFAM, TFB1M and TFB2M yet clearly this failed to maintain mitochondrial function. We therefore utilised transcript profiling and pathway analysis of ICU patient skeletal muscle to generate insight into the molecular defects driving loss of muscle function and metabolic homeostasis. Gene ontology analysis of Affymetrix analysis demonstrated substantial loss of muscle specific genes, a global oxidative stress response related to most probably cytokine signalling, altered insulin related signalling and a substantial overlap between patients and muscle wasting/inflammatory animal models. MicroRNA 21 processing appeared defective suggesting that post-transcriptional protein synthesis regulation is altered by disruption of tissue microRNA expression. Finally, we were able to demonstrate that the phenotype of skeletal muscle in ICU patients is not merely one of inactivity, it appears to be an actively remodelling tissue, influenced by several mediators, all of which may be open to manipulation with the aim to improve clinical outcome. Conclusions/Significance: This first combined protein and transcriptome based analysis of human skeletal muscle obtained from septic patients demonstrated that losses of mitochondria and muscle mass are accompanied by sustained protein synthesis (anabolic process) while dysregulation of transcription programmes appears to fail to compensate for increased damage and proteolysis. Our analysis identified both validated and novel clinically tractable targets to manipulate these failing processes and pursuit of these could lead to new potential treatments.

  • 16. Galvão Valdivia, Luís Felipe
    et al.
    Castro, Érique
    dos Santos Eichler, Rosangela Aparecida
    Moreno, Mayara Franzoi
    de Sousa, Érica
    Rodrigues Jardim, Giovanna Freitas
    Souza Peixoto, Álbert
    Moraes, Maria Nathália
    de Lauro Castrucci, Ana Maria
    Nedergaard, Jan
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Petrovic, Natasa
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Festuccia, William T.
    Reckziegel, Patricia
    Cold acclimation and pioglitazone combined increase thermogenic capacity of brown and white adipose tissues but this does not translate into higher energy expenditure in mice2023Inngår i: American Journal of Physiology. Endocrinology and Metabolism, ISSN 0193-1849, E-ISSN 1522-1555, Vol. 324, nr 4, s. E358-E373Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Cold acclimation and pharmacological peroxisome proliferator-activated receptor γ (PPARγ) activation have each earlier been shown to recruit brown adipose tissue (BAT) and beige adipocytes thermogenic machinery, enhancing uncoupling protein 1 (UCP1)-mediated thermogenic capacity. We here investigated whether cold acclimation and PPARγ agonism combined have additive effects in inducing brown and beige adipocytes UCP1 content and whether this translates into a higher thermogenic capacity and energy expenditure. C57BL/6J mice treated or not with pioglitazone (30 mg/kg/day) were maintained at 21°C or exposed to cold (7°C) for 15 days and evaluated for thermogenic capacity, energy expenditure and interscapular BAT (iBAT) and inguinal white adipose tissue (iWAT) mass, morphology, UCP1 content and gene expression, glucose uptake and oxygen consumption. Cold acclimation and PPARγ agonism combined synergistically increased iBAT and iWAT total UCP1 content and mRNA levels of the thermogenesis-related proteins PGC1a, CIDEA, FABP4, GYK, PPARa, LPL, GLUTs (GLUT1 in iBAT and GLUT4 in iWAT), and ATG when compared to cold and pioglitazone individually. This translated into a stronger increase in body temperature in response to the β3-adrenergic agonist CL316,243 and iBAT and iWAT respiration induced by succinate and pyruvate in comparison to that seen in either cold-acclimated or pioglitazone-treated mice. However, basal energy expenditure, BAT glucose uptake and glucose tolerance were not increased above that seen in cold-acclimated untreated mice. In conclusion, cold acclimation and PPARγ agonism combined induced a robust increase in brown and beige adipocytes UCP1 content and thermogenic capacity, much higher than each treatment individually. However, our findings enforce the concept that increases in total UCP1 do not innately lead to higher energy expenditure.

  • 17.
    Holmström, Therese E.
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut.
    Mattsson, Charlotte L.
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut.
    Wang, Yanling
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut.
    Iakovleva, Irina
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut.
    Petrovic, Natasa
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut.
    Nedergaard, Jan
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut.
    Non-transactivational, dual pathways for LPA-induced Erk1/2 activation in primary cultures of brown pre-adipocytes2010Inngår i: Experimental Cell Research, ISSN 0014-4827, E-ISSN 1090-2422, Vol. 316, nr 16, s. 2664-75Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    In many cell types, G-protein-coupled receptor (GPCR)-induced Erk1/2 MAP kinase activation is mediated via receptor tyrosine kinase (RTK) transactivation, in particular via the epidermal growth factor (EGF) receptor. Lysophosphatidic acid (LPA), acting via GPCRs, is a mitogen and MAP kinase activator in many systems, and LPA can regulate adipocyte proliferation. The mechanism by which LPA activates the Erk1/2 MAP kinase is generally accepted to be via EGF receptor transactivation. In primary cultures of brown pre-adipocytes, EGF can induce Erk1/2 activation, which is obligatory and determinant for EGF-induced proliferation of these cells. Therefore, we have here examined whether LPA, via EGF transactivation, can activate Erk1/2 in brown pre-adipocytes. We found that LPA could induce Erk1/2 activation. However, the LPA-induced Erk1/2 activation was independent of transactivation of EGF receptors (or PDGF receptors) in these cells (whereas in transformed HIB-1B brown adipocytes, the LPA-induced Erk1/2 activation indeed proceeded via EGF receptor transactivation). In the brown pre-adipocytes, LPA instead induced Erk1/2 activation via two distinct non-transactivational pathways, one G(i)-protein dependent, involving PKC and Src activation, the other, a PTX-insensitive pathway, involving PI3K (but not Akt) activation. Earlier studies showing LPA-induced Erk1/2 activation being fully dependent on RTK transactivation have all been performed in cell lines and transfected cells. The present study implies that in non-transformed systems, RTK transactivation may not be involved in the mediation of GPCR-induced Erk1/2 MAP kinase activation

  • 18. Jespersen, Naja Z.
    et al.
    Feizi, Amir
    Andersen, Eline S.
    Heywood, Sarah
    Hattel, Helle B.
    Daugaard, Søren
    Peijs, Lone
    Bagi, Per
    Feldt-Rasmussen, Bo
    Schultz, Heidi S.
    Hansen, Ninna S.
    Krogh-Madsen, Rikke
    Pedersen, Bente K.
    Petrovic, Natasa
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Nielsen, Søren
    Scheele, Camilla
    Heterogeneity in the perirenal region of humans suggests presence of dormant brown adipose tissue that contains brown fat precursor cells2019Inngår i: Molecular Metabolism, ISSN 2212-8778, Vol. 24, s. 30-43Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Objective:

    Increasing the amounts of functionally competent brown adipose tissue (BAT) in adult humans has the potential to restore dysfunctional metabolism and counteract obesity. In this study, we aimed to characterize the human perirenal fat depot, and we hypothesized that there would be regional, within-depot differences in the adipose signature depending on local sympathetic activity.

    Methods:

    We characterized fat specimens from four different perirenal regions of adult kidney donors, through a combination of qPCR mapping, immunohistochemical staining, RNA-sequencing, and pre-adipocyte isolation. Candidate gene signatures, separated by adipocyte morphology, were recapitulated in a murine model of unilocular brown fat induced by thermoneutrality and high fat diet.

    Results:

    We identified widespread amounts of dormant brown adipose tissue throughout the perirenal depot, which was contrasted by multilocular BAT, primarily found near the adrenal gland. Dormant BAT was characterized by a unilocular morphology and a distinct gene expression profile, which partly overlapped with that of subcutaneous white adipose tissue (WAT). Brown fat precursor cells, which differentiated into functional brown adipocytes were present in the entire perirenal fat depot, regardless of state. We identified SPARC as a candidate adipokine contributing to a dormant BAT state, and CLSTN3 as a novel marker for multilocular BAT.

    Conclusions:

    We propose that perirenal adipose tissue in adult humans consists mainly of dormant BAT and provide a data set for future research on factors which can reactivate dormant BAT into active BAT, a potential strategy for combatting obesity and metabolic disease.

  • 19.
    Kalinovich, Anastasia V.
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut. Lomonosov Moscow State University, Russian Federation.
    Mattsson, C. L.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Youssef, M. R.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Petrovic, Natasa
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Ost, M.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Skulachev, V. P.
    Shabalina, Irina G.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut. Lomonosov Moscow State University, Russian Federation.
    Mitochondria-targeted dodecyltriphenylphosphonium (C12TPP) combats high-fat-diet-induced obesity in mice2016Inngår i: International Journal of Obesity, ISSN 0307-0565, E-ISSN 1476-5497, Vol. 40, nr 12, s. 1864-1874Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND: A membrane-penetrating cation, dodecyltriphenylphosphonium (C12TPP), facilitates the recycling of fatty acids in the artificial lipid membrane and mitochondria. C12TPP can dissipate mitochondrial membrane potential and may affect total energy expenditure and body weight in animals and humans. METHODS: We investigated the metabolic effects of C12TPP in isolated brown-fat mitochondria, brown adipocyte cultures and mice in vivo. Experimental approaches included the measurement of oxygen consumption, carbon dioxide production, western blotting, magnetic resonance imaging and bomb calorimetry. RESULTS: In mice, C12TPP (50 mu mol per (day.kg body weight)) in the drinking water significantly reduced body weight (12%, P<0.001) and body fat mass (24%, P<0.001) during the first 7 days of treatment. C12TPP did not affect water palatability and intake or the energy and lipid content in feces. The addition of C12TPP to isolated brown-fat mitochondria resulted in increased oxygen consumption. Three hours of pretreatment with C12TPP also increased oligomycin-insensitive oxygen consumption in brown adipocyte cultures (P<0.01). The effects of C12TPP on mitochondria, cells and mice were independent of uncoupling protein 1 (UCP1). However, C12TPP treatment increased the mitochondrial protein levels in the brown adipose tissue of both wild-type and UCP1-knockout mice. Pair-feeding revealed that one-third of the body weight loss in C12TPP-treated mice was due to reduced food intake. C12TPP treatment elevated the resting metabolic rate (RMR) by up to 18% (P<0.05) compared with pair-fed animals. C12TPP reduced the respiratory exchange ratio, indicating enhanced fatty acid oxidation in mice. CONCLUSIONS: C12TPP combats diet-induced obesity by reducing food intake, increasing the RMR and enhancing fatty acid oxidation.

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

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

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

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

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

  • 21.
    Otton, Rosemari
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut. Cruzeiro do Sul University, Brazil.
    Petrovic, Natasa
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Cannon, Barbara
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Nedergaard, Jan
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    On the Validity of Adipogenic Cell Lines as Model Systems for Browning Processes: In Authentic Brown, Brite/Beige, and White Preadipocytes, There is No Cell-Autonomous Thermogenic Recruitment by Green Tea Compounds2021Inngår i: Frontiers in Nutrition, E-ISSN 2296-861X, Vol. 8, artikkel-id 715859Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

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

  • 22.
    Petrovic, Natasa
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för fysiologi.
    Walden, Tomas B
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för fysiologi.
    Shabalina, Irina G
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för fysiologi.
    Timmons, James A
    Cannon, Barbara
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för fysiologi.
    Nedergaard, Jan
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för fysiologi.
    Chronic Perixosome Proliferator-activated Receptor gamma (PPARgamma) activation of epididymally derived white adipocyte cultures reveals a population of thermogenically competent, UCP1-containing adipocytes molecularly distinct from classical brown adipocytes.2010Inngår i: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 285, nr 10, s. 7153-7164Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

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

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

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

  • 24. Rohm, Maria
    et al.
    Schäfer, Michaela
    Laurent, Victor
    Üstünel, Bilgen Ekim
    Niopek, Katharina
    Algire, Carolyn
    Hautzinger, Oksana
    Sijmonsma, Tjeerd P.
    Zota, Annika
    Medrikova, Dasa
    Pellegata, Natalia S.
    Ryden, Mikael
    Kulyte, Agné
    Dahlman, Ingrid
    Arner, Peter
    Petrovic, Natasa
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Cannon, Barbara
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Amri, Ez-Zoubir
    Kemp, Bruce E.
    Steinberg, Gregory R.
    Janovska, Petra
    Kopecky, Jan
    Wolfrum, Christian
    Blüher, Matthias
    Diaz, Mauricio Berriel
    Herzig, Stephan
    An AMP-activated protein kinase-stabilizing peptide ameliorates adipose tissue wasting in cancer cachexia in mice2016Inngår i: Nature Medicine, ISSN 1078-8956, E-ISSN 1546-170X, Vol. 22, nr 10, s. 1120-1130Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Cachexia represents a fatal energy-wasting syndrome in a large number of patients with cancer that mostly results in a pathological loss of skeletal muscle and adipose tissue. Here we show that tumor cell exposure and tumor growth in mice triggered a futile energy-wasting cycle in cultured white adipocytes and white adipose tissue (WAT), respectively. Although uncoupling protein 1 (Ucp1)-dependent thermogenesis was dispensable for tumor-induced body wasting, WAT from cachectic mice and tumor-cell-supernatant-treated adipocytes were consistently characterized by the simultaneous induction of both lipolytic and lipogenic pathways. Paradoxically, this was accompanied by an inactivated AMP-activated protein kinase (Ampk), which is normally activated in peripheral tissues during states of low cellular energy. Ampk inactivation correlated with its degradation and with upregulation of the Ampk-interacting protein Cidea. Therefore, we developed an Ampk-stabilizing peptide, ACIP, which was able to ameliorate WAT wasting in vitro and in vivo by shielding the Cidea-targeted interaction surface on Ampk. Thus, our data establish the Ucp1-independent remodeling of adipocyte lipid homeostasis as a key event in tumor-induced WAT wasting, and we propose the ACIP-dependent preservation of Ampk integrity in the WAT as a concept in future therapies for cachexia.

  • 25.
    Shabalina, Irina
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Edgar, Daniel
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Gibanova, Natalia
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Kalinovich, Anastasia
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Petrovic, Natasa
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Vyssokikh, Mikhail Yu.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Cannon, Barbara
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Nedergaard, Jan
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Enhanced ROS Production in Mitochondria from Prematurely Aging mtDNA Mutator Mice2024Inngår i: Biochemistry (Moscow), ISSN 0006-2979, E-ISSN 1608-3040, Vol. 89, nr 2, s. 279-298Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

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

  • 26.
    Shabalina, Irina G.
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Kramarova, Tatiana V.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Mattsson, Charlotte L.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Petrovic, Natasa
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Qazi, Mousumi Rahman
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Csikasz, Robert I.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Chang, Shu-Ching
    Butenhoff, John
    DePierre, Joseph W.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Cannon, Barbara
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Nedergaard, Jan
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    The Environmental Pollutants Perfluorooctane Sulfonate and Perfluorooctanoic Acid Upregulate Uncoupling Protein 1 (UCP1) in Brown-Fat Mitochondria Through a UCP1-Dependent Reduction in Food Intake2015Inngår i: Toxicological Sciences, ISSN 1096-6080, E-ISSN 1096-0929, Vol. 146, nr 2, s. 334-343Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

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

  • 27.
    Shabalina, Irina G.
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Landreh, Luise
    Edgar, Daniel
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut. Karolinska Institutet, Sweden.
    Hou, Mi
    Gibanova, Natalia
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Atanassova, Nina
    Petrovic, Natasa
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Hultenby, Kjell
    Söder, Olle
    Nedergaard, Jan
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Svechnikov, Konstantin
    Leydig cell steroidogenesis unexpectedly escapes mitochondrial dysfunction in prematurely aging mice2015Inngår i: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 29, nr 8, s. 3274-3286Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

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

  • 28.
    Shabalina, Irina G
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för fysiologi.
    Ost, Mario
    Petrovic, Natasa
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för fysiologi.
    Vrbacky, Marek
    Nedergaard, Jan
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för fysiologi.
    Cannon, Barbara
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för fysiologi.
    Uncoupling protein-1 is not leaky.2010Inngår i: Biochimica et Biophysica Acta, ISSN 0006-3002, E-ISSN 1878-2434, Vol. 1797, nr 6-7, s. 773-84Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

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

  • 29.
    Shabalina, Irina G.
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Petrovic, Natasa
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    de Jong, Jasper M. A.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Kalinovich, Anastasia
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Cannon, Barbara
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Nedergaard, Jan
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    UCP1 in Brite/Beige Adipose Tissue Mitochondria Is Functionally Thermogenic2013Inngår i: Cell Reports, E-ISSN 2211-1247, Vol. 5, nr 5, s. 1196-1203Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

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

  • 30. Siersbaek, Majken S.
    et al.
    Loft, Anne
    Aagaard, Mads M.
    Nielsen, Ronni
    Schmidt, Soren F.
    Petrovic, Natasa
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut.
    Nedergaard, Jan
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut.
    Mandrup, Susanne
    Genome-Wide Profiling of Peroxisome Proliferator-Activated Receptor gamma in Primary Epididymal, Inguinal, and Brown Adipocytes Reveals Depot-Selective Binding Correlated with Gene Expression2012Inngår i: Molecular and Cellular Biology, ISSN 0270-7306, E-ISSN 1098-5549, Vol. 32, nr 17, s. 3452-3463Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

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

  • 31. Timmons, James A
    et al.
    Wennmalm, Kristian
    Larsson, Ola
    Walden, Tomas B
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut.
    Lassmann, Timo
    Petrovic, Natasa
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut.
    Hamilton, D Lee
    Gimeno, Ruth E
    Wahlestedt, Claes
    Baar, Keith
    Nedergaard, Jan
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut.
    Cannon, Barbara
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut.
    Myogenic gene expression signature establishes that brown and white adipocytes originate from distinct cell lineages.2007Inngår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 104, nr 11, s. 4401-4406Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

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

  • 32.
    Walden, Tomas B.
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för fysiologi. Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut.
    Petrovic, Natasa
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut.
    Nedergaard, Jan
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut.
    PPARa is not involved in the regulation of muscle-associated genesin brown adipose tissue.Manuskript (preprint) (Annet vitenskapelig)
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  • 33.
    Waldén, Tomas B
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut.
    Petrovic, Natasa
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut.
    Nedergaard, Jan
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut.
    PPARalpha does not suppress muscle-associated gene expression in brown adipocytes but does influence expression of factors that fingerprint the brown adipocyte.2010Inngår i: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 397, nr 2, s. 146-51Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

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

  • 34.
    Wikström, Jakob D.
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut. Boston University, USA.
    Mahdaviani, Kiana
    Liesa, Marc
    Sereda, Samuel B.
    Si, Yaguang
    Las, Guy
    Twig, Gilad
    Petrovic, Natasa
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Zingaretti, Cristina
    Graham, Adam
    Cinti, Saverio
    Corkey, Barbara E.
    Cannon, Barbara
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Nedergaard, Jan
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Shirihai, Orian S.
    Hormone-induced mitochondrial fission is utilized by brown adipocytes as an amplification pathway for energy expenditure2014Inngår i: EMBO Journal, ISSN 0261-4189, E-ISSN 1460-2075, Vol. 33, nr 5, s. 418-436Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

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

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

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

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