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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) (Övrigt vetenskapligt)
    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. Chia, Ling Yeong
    et al.
    Evans, Bronwyn A.
    Mukaida, Saori
    Bengtsson, Tore
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Hutchinson, Dana S.
    Sato, Masaaki
    Adrenoceptor regulation of the mechanistic target of rapamycin in muscle and adipose tissue2019Ingår i: British Journal of Pharmacology, ISSN 0007-1188, E-ISSN 1476-5381, Vol. 176, nr 14, s. 2433-2448Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    A vital role of adrenoceptors in metabolism and energy balance has been well documented in the heart, skeletal muscle, and adipose tissue. It has been only recently demonstrated, however, that activation of the mechanistic target of rapamycin (mTOR) makes a significant contribution to various metabolic and physiological responses to adrenoceptor agonists. mTOR exists as two distinct complexes named mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2) and has been shown to play a critical role in protein synthesis, cell proliferation, hypertrophy, mitochondrial function, and glucose uptake. This review will describe the physiological significance of mTORC1 and 2 as a novel paradigm of adrenoceptor signalling in the heart, skeletal muscle, and adipose tissue. Understanding the detailed signalling cascades of adrenoceptors and how they regulate physiological responses is important for identifying new therapeutic targets and identifying novel therapeutic interventions. Linked Articles This article is part of a themed section on Adrenoceptors-New Roles for Old Players. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.14/issuetoc

  • 3.
    Dehvari, Nodi
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    da Silva Junior, Edilson Dantas
    Bengtsson, Tore
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Hutchinson, Dana Sabine
    Mirabegron: potential off target effects and uses beyond the bladder2018Ingår i: British Journal of Pharmacology, ISSN 0007-1188, E-ISSN 1476-5381, Vol. 175, nr 21, s. 4072-4082Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    The beta(3)-adrenoceptor was initially an attractive target for several pharmaceutical companies due to its high expression in rodent adipose tissue, where its activation resulted in decreased adiposity and improved metabolic outputs (such as glucose handling) in animal models of obesity and Type 2 diabetes. However, several drugs acting at the beta(3)-adrenoceptor failed in clinical trials. This was thought to be due to their lack of efficacy at the human receptor. Recently, mirabegron, a beta(3)-adrenoceptor agonist with human efficacy, was approved in North America, Europe, Japan and Australia for the treatment of overactive bladder syndrome. There are indications that mirabegron may act at other receptors/targets, but whether they have any clinical relevance is relatively unknown. Besides overactive bladder syndrome, mirabegron may have other uses such as in the treatment of heart failure or metabolic disease. This review gives an overview of the off-target effects of mirabegron and its potential use in the treatment of other diseases.

  • 4.
    Dehvari, Nodi
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut.
    Hutchinson, Dana S.
    Nevzorova, Julia
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut. Monash University, Australia.
    Dallner, Olof S.
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut.
    Sato, Masaaki
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut.
    Kocan, Martina
    Merlin, Jon
    Evans, Bronwyn A.
    Summers, Roger J.
    Bengtsson, Tore
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut.
    β2‐Adrenoceptors increase translocation of GLUT4 via GPCR kinase sites in the receptor C‐terminal tail2012Ingår i: British Journal of Pharmacology, ISSN 0007-1188, E-ISSN 1476-5381, Vol. 165, nr 5, s. 1442-1456Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND AND PURPOSE

    beta-Adrenoceptor stimulation induces glucose uptake in several insulin-sensitive tissues by poorly understood mechanisms.

    EXPERIMENTAL APPROACH

    We used a model system in CHO-K1 cells expressing the human beta(2)-adrenoceptor and glucose transporter 4 (GLUT4) to investigate the signalling mechanisms involved.

    KEY RESULTS

    In CHO-K1 cells, there was no response to b-adrenoceptor agonists. The introduction of b2-adrenoceptors and GLUT4 into these cells caused increased glucose uptake in response to beta-adrenoceptor agonists. GLUT4 translocation occurred in response to insulin and beta(2)-adrenoceptor stimulation, although the key insulin signalling intermediate PKB was not phosphorylated in response to beta(2)-adrenoceptor stimulation. Truncation of the C-terminus of the beta(2)-adrenoceptor at position 349 to remove known phosphorylation sites for GPCR kinases (GRKs) or at position 344 to remove an additional PKA site together with the GRK phosphorylation sites did not significantly affect cAMP accumulation but decreased beta(2)-adrenoceptor-stimulated glucose uptake. Furthermore, inhibition of GRK by transfection of the bARKct construct inhibited beta(2)-adrenoceptor-mediated glucose uptake and GLUT4 translocation, and overexpression of a kinase-dead GRK2 mutant (GRK2 K220R) also inhibited GLUT4 translocation. Introducing beta(2)-adrenoceptors lacking phosphorylation sites for GRK or PKA demonstrated that the GRK sites, but not the PKA sites, were necessary for GLUT4 translocation.

    CONCLUSIONS AND IMPLICATIONS

    Glucose uptake in response to activation of beta(2)-adrenoceptors involves translocation of GLUT4 in this model system. The mechanism is dependent on the C-terminus of the beta(2)-adrenoceptor, requires GRK phosphorylation sites, and involves a signalling pathway distinct from that stimulated by insulin.

  • 5.
    Dehvari, Nodi
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för fysiologi.
    Mahmud, Tapan
    Persson, Johanna
    Bengtsson, Tore
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för fysiologi.
    Graff, Caroline
    Winblad, Bengt
    Ronnback, Annica
    Behbahani, Homira
    Amyloid precursor protein accumulates in aggresomes in response to proteasome inhibitor2012Ingår i: Neurochemistry International, ISSN 0197-0186, E-ISSN 1872-9754, Vol. 60, nr 5, s. 533-542Artikel i tidskrift (Refereegranskat)
    Abstract [en]

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

  • 6. Evans, Bronwyn A.
    et al.
    Merlin, Jon
    Bengtsson, Tore
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Hutchinson, Dana S.
    Adrenoceptors in white, brown, and brite adipocytes2019Ingår i: British Journal of Pharmacology, ISSN 0007-1188, E-ISSN 1476-5381, Vol. 176, nr 14, s. 2416-2432Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    Adrenoceptors play an important role in adipose tissue biology and physiology that includes regulating the synthesis and storage of triglycerides (lipogenesis), the breakdown of stored triglycerides (lipolysis), thermogenesis (heat production), glucose metabolism, and the secretion of adipocyte-derived hormones that can control whole-body energy homeostasis. These processes are regulated by the sympathetic nervous system through actions at different adrenoceptor subtypes expressed in adipose tissue depots. In this review, we have highlighted the role of adrenoceptor subtypes in white, brown, and brite adipocytes in both rodents and humans and have included detailed analysis of adrenoceptor expression in human adipose tissue and clonally derived adipocytes. We discuss important considerations when investigating adrenoceptor function in adipose tissue or adipocytes.

  • 7. Hutchinson, Dana S.
    et al.
    Csikasz, Robert I.
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut.
    Yamamoto, Daniel L.
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut.
    Shabalina, Irina G.
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut.
    Wikström, Per
    Wilcke, Mona
    Bengtsson, Tore
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut.
    Diphenylene iodonium stimulates glucose uptake in skeletal muscle cells through mitochondrial complex I inhibition and activation of AMP-activated protein kinase2007Ingår i: Cellular Signalling, ISSN 0898-6568, E-ISSN 1873-3913, Vol. 19, nr 7, s. 1610-1620Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    NADPH oxidase inhibitors such as diphenylene iodonium (DPI) and apocynin lower whole body and blood glucose levels and improve diabetes when administered to rodents. Skeletal muscle has an important role in managing glucose homeostasis and we have used L6 cells, C2C12 cells and primary muscle cells as model systems to investigate whether these drugs regulate glucose uptake in skeletal muscle cells. The data presented in this study show that apocynin does not affect glucose uptake in skeletal muscle cells in culture. Tat gp91ds, a chimeric peptide that inhibits NADPH oxidase activity, also failed to affect glucose uptake and we found no significant evidence of NADPH oxidase (subunits tested were Nox4, p22phox, gp91phox and p47phox mRNA) in skeletal muscle cells in culture. However, DPI increases basal and insulin-stimulated glucose uptake in L6 cells, C2C12 cells and primary muscle cells. Detailed studies on L6 cells demonstrate that the increase of glucose uptake is via a mechanism independent of phosphoinositide-3 kinase (PI3K)/Akt but dependent on AMP-activated protein kinase (AMPK). We postulate that DPI through inhibition of mitochondrial complex 1 and decreases in oxygen consumption, leading to decreases of ATP and activation of AMPK, stimulates glucose uptake in skeletal muscle cells.

  • 8. Kupferschmidt, Natalia
    et al.
    Csikasz, Robert I.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Ballell, Lluis
    Bengtsson, Tore
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Garcia-Bennett, Alfonso E.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för material- och miljökemi (MMK).
    Large pore mesoporous silica induced weight loss in obese mice2014Ingår i: Nanomedicine, ISSN 1743-5889, E-ISSN 1748-6963, Vol. 9, nr 9, s. 1353-1362Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: There is a need for medical treatments to curb the rising rate of obesity. Weight reduction is correlated with a decrease in associated risk factors and cholesterol levels in humans. Amorphous silica particles have been found to exert a hypocholesterolemic effect in humans, making them popular dietary additives. Aim: To investigate the effect of mesoporous silica, which possess sharp pore size distributions, on: weight loss, cholesterol, triglycerides and glucose blood levels in obese mice. Materials & methods: Mesoporous silicas with differing pore size were mixed in the high-fat diet of obese mice. Results: Animals receiving large pore mesoporous silica with a high-fat diet show a significant reduction in body weight and fat composition, with no observable negative effects. Conclusion: Pore size is an important parameter for reduction of body weight and body fat composition by mesoporous silica, demonstrating promising signs for the treatment of obesity.

  • 9.
    Masaaki, Sato
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Dehvari, Nodi
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Öberg, Anette I.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Dallner, Olof S.
    Sandström, Anna L.
    Olsen, Jessica M.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Csikasz, Robert I.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Summers, Roger J.
    Hutchinson, Dana S.
    Bengtsson, Tore
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    An insulin-independent pathway including β-adrenoceptors and mTORC2 that translocates GLUT4 and increases glucose uptake in skeletal muscleManuskript (preprint) (Övrigt vetenskapligt)
  • 10.
    Mattsson, Charlotte L.
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för fysiologi.
    Csikasz, Robert I.
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för fysiologi.
    Chernogubova, Ekaterina
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för fysiologi.
    Yamamoto, Daniel L.
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för fysiologi.
    Högberg, Helena T.
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för fysiologi.
    Amri, Ez-Zoubir
    Hutchinson, Dana S.
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för fysiologi.
    Bengtsson, Tore
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för fysiologi.
    β₁-Adrenergic receptors increase UCP1 in human MADS brown adipocytes and rescue cold-acclimated β₃-adrenergic receptor-knockout mice via nonshivering thermogenesis2011Ingår i: American Journal of Physiology. Endocrinology and Metabolism, ISSN 0193-1849, E-ISSN 1522-1555, Vol. 301, nr 6, s. E1108-E1118Artikel i tidskrift (Refereegranskat)
    Abstract [en]

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

  • 11. Merlin, Jon
    et al.
    Evans, Bronwyn A
    Csikasz, Robert I
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för fysiologi.
    Bengtsson, Tore
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för fysiologi.
    Summers, Roger J
    Hutchinson, Dana S
    The M3-muscarinic acetylcholine receptor stimulates glucose uptake in L6 skeletal muscle cells by a CaMKK-AMPK-dependent mechanism2010Ingår i: Cellular Signalling, ISSN 0898-6568, E-ISSN 1873-3913, Vol. 22, nr 7, s. 1104-13Artikel i tidskrift (Refereegranskat)
    Abstract [en]

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

  • 12. Merlin, Jon
    et al.
    Evans, Bronwyn A.
    Dehvari, Nodi
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Sato, Masaaki
    Bengtsson, Tore
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Hutchinson, Dana S.
    Could burning fat start with a brite spark? Pharmacological and nutritional ways to promote thermogenesis2016Ingår i: Molecular Nutrition & Food Research, ISSN 1613-4125, E-ISSN 1613-4133, Vol. 60, nr 1, s. 18-42Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    There are two types of adipose tissue with distinct functions-white adipose tissue stores chemical energy as triglycerides, whereas brown adipose tissue consumes energy and releases heat (thermogenesis) in response to sympathetic nerve activity. In humans, treatments that promote greater brown adipose tissue deposition and/or activity would be highly beneficial in regimes aimed at reducing obesity. Adult humans have restricted populations of prototypical brown adipocytes in the neck and chest areas, but recent advances have established that adipocytes with similar properties, termed brite adipocytes, can be recruited in subcutaneous depots thought to be primarily white adipose tissue. These brite adipocytes express the protein machinery required for thermogenesis, but to assess brite adipocytes as viable therapeutic targets we need to understand how to promote conversion of white adipocytes to brite adipocytes and ways to increase optimal energy consumption and thermogenesis in these brite adipocytes. This can be accomplished by pharmacological and nutritional therapies to differing degrees, as reviewed in detail here.

  • 13. Merlin, Jon
    et al.
    Sato, Masaaki
    Chia, Ling Yeong
    Fahey, Richard
    Pakzad, Mohsen
    Nowell, Cameron J.
    Summers, Roger J.
    Bengtsson, Tore
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Evans, Bronwyn A.
    Hutchinson, Dana S.
    Rosiglitazone and a beta(3)-Adrenoceptor Agonist Are Both Required for Functional Browning of White Adipocytes in Culture2018Ingår i: Frontiers in Endocrinology, ISSN 1664-2392, E-ISSN 1664-2392, Vol. 9, artikel-id 249Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The recruitment of brite (or beige) adipocytes has been advocated as a means to combat obesity, due to their ability to phenotypically resemble brown adipocytes (BA). Lineage studies indicate that brite adipocytes are formed by differentiation of precursor cells or by direct conversion of existing white adipocytes, depending on the adipose depot examined. We have systematically compared the gene expression profile and a functional output (oxygen consumption) in mouse adipocytes cultured from two contrasting depots, namely interscapular brown adipose tissue, and inguinal white adipose tissue (iWAT), following treatment with a known browning agent, the peroxisome proliferator-activated receptor (PPAR gamma) activator rosiglitazone. Prototypical BA readily express uncoupling protein (UCP)1, and upstream regulators including the beta(3)-adrenoceptor and transcription factors involved in energy homeostasis. Adipocytes from inguinal WAT display maximal UCP1 expression and mitochondrial uncoupling only when treated with a combination of the PPAR. activator rosiglitazone and a beta(3)-adrenoceptor agonist. In conclusion, brite adipocytes are fully activated only when a browning agent (rosiglitazone) and a thermogenic agent (beta(3)-adrenoceptor agonist) are added in combination. The presence of rosiglitazone throughout the 7-day culture period partially masks the effects of beta(3)-adrenoceptor signaling in inguinal white adipocyte cultures, whereas including rosiglitazone only for the first 3 days promotes robust beta(3)-adrenoceptor expression and provides an improved window for detection of beta(3)-adrenoceptor responses.

  • 14. Merlin, Jon
    et al.
    Sato, Masaaki
    Nowell, Cameron
    Pakzad, Mohsen
    Fahey, Richard
    Gao, Jie
    Dehvari, Nodi
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Summers, Roger J.
    Bengtsson, Tore
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Evans, Bronwyn A.
    Hutchinson, Dana S.
    The PPAR gamma agonist rosiglitazone promotes the induction of brite adipocytes, increasing beta-adrenoceptor-mediated mitochondrial function and glucose uptake2018Ingår i: Cellular Signalling, ISSN 0898-6568, E-ISSN 1873-3913, Vol. 42, s. 54-66Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Recruitment and activation of brite (or beige) adipocytes has been advocated as a potential avenue for manipulating whole-body energy expenditure. Despite numerous studies illustrating the differences in gene and protein markers between brown, brite and white adipocytes, there is very little information on the adrenergic regulation and function of these brite adipocytes. We have compared the functional (cyclic AMP accumulation, oxygen consumption rates, mitochondrial function, glucose uptake, extracellular acidification rates, calcium influx) profiles of mouse adipocytes cultured from three contrasting depots, namely interscapular brown adipose tissue, and inguinal or epididymal white adipose tissues, following chronic treatment with the peroxisome proliferator-activated receptor gamma (PPAR gamma) agonist rosiglitazone. Prototypical brown adipocytes readily express beta(3)-adrenoceptors, and beta(3)-adrenoceptor stimulation increases cyclic AMP accumulation, oxygen consumption rates, mitochondrial function, glucose uptake, and extracellular acidification rates. Treatment of brown adipocytes with rosiglitazone increases uncoupling protein 1 (UCP1) levels, and increases beta(3)-adrenoceptor mitochondrial function but does not affect glucose uptake responses. In contrast, inguinal white adipocytes only express UCP1 and beta(3)-adrenoceptors following rosiglitazone treatment, which results in an increase in all beta(3)-adrenoceptor-mediated functions. The effect of rosiglitazone in epididymal white adipocytes, was much lower compared to inguinal white adipocytes. Rosiglitazone also increased alpha(1)-adrenoceptor mediated increases in calcium influx and glucose uptake (but not mitochondrial function) in inguinal and epididymal white adipocytes. In conclusion, the PPAR gamma agonist rosiglitazone promotes the induction and function of brite adipocytes cultured from inguinal and epididymal white adipose depots.

  • 15. Mukaida, Saori
    et al.
    Evans, Bronwyn A.
    Bengtsson, Tore
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Hutchinson, Dana S.
    Sato, Masaaki
    Adrenoceptors promote glucose uptake into adipocytes and muscle by an insulin-independent signaling pathway involving mechanistic target of rapamycin complex 22017Ingår i: Pharmacological Research, ISSN 1043-6618, E-ISSN 1096-1186, Vol. 116, s. 87-92Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Uptake of glucose into skeletal muscle and adipose tissue plays a vital role in metabolism and energy balance. Insulin released from beta-islet cells of the pancreas promotes glucose uptake in these target tissues by stimulating translocation of CLUT4 transporters to the cell surface. This process is complex, involving signaling proteins including the mechanistic (or mammalian) target of rapamycin (mTOR) and Akt that intersect with multiple pathways controlling cell survival, growth and proliferation. mTOR exists in two forms, mTOR complex 1 (mTORC1), and mTOR complex 2 (mTORC2). mTORC1 has been intensively studied, acting as a key regulator of protein and lipid synthesis that integrates cellular nutrient availability and energy balance. Studies on mTORC2 have focused largely on its capacity to activate Akt by phosphorylation at Ser473, however recent findings demonstrate a novel role for mTORC2 in cellular glucose uptake. For example, agonists acting at beta(2)-adrenoceptors (ARs) in skeletal muscle or beta(3)-ARs in brown adipose tissue increase glucose uptake in vitro and in vivo via mechanisms dependent on mTORC2 but not Akt. In this review, we will focus on the signaling pathways downstream of beta-ARs that promote glucose uptake in skeletal muscle and brown adipocytes, and will highlight how the insulin and adrenergic pathways converge and interact in these cells. The identification of insulin-independent mechanisms that promote glucose uptake should facilitate novel treatment strategies for metabolic disease.

  • 16. Mukaida, Saori
    et al.
    Sato, Masaaki
    Öberg, Anette I.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Dehvari, Nodi
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Olsen, Jessica M.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Kocan, Martina
    Halls, Michelle Louise
    Merlin, Jon
    Sandström, Anna L.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Csikasz, Robert
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Evans, Bronwyn Anne
    Summers, Roger James
    Hutchinson, Ana Sabine
    Bengtsson, Tore
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    BRL37344 stimulates GLUT4 translocation and glucose uptake in skeletal muscle via beta(2)-adrenoceptors without causing classical receptor desensitization2019Ingår i: American Journal of Physiology. Regulatory Integrative and Comparative Physiology, ISSN 0363-6119, E-ISSN 1522-1490, Vol. 316, nr 5, s. R666-R677Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The type 2 diabetes epidemic makes it important to find insulinin-dependent ways to improve glucose homeostasis. This study examines the mechanisms activated by a dual beta(2)-/beta(3)-adrenoceptor agonist, BRL37344, to increase glucose uptake in skeletal muscle and its effects on glucose homeostasis in vivo. We measured the effect of BRL37344 on glucose uptake, glucose transporter 4 (GLUT4) translocation, cAMP levels, beta(2)-adrenoceptor desensitization, beta-arrestin recruitment, Akt, AMPK, and mammalian target of rapamycin (mTOR) phosphorylation using L6 skeletal muscle cells as a model. We further tested the ability of BRL37344 to modulate skeletal muscle glucose metabolism in animal models (glucose tolerance tests and in vivo and ex vivo skeletal muscle glucose uptake). In L6 cells, BRL37344 increased GLUT4 translocation and glucose uptake only by activation of beta(2)-adrenoceptors, with a similar potency and efficacy to that of the nonselective beta-adrenoceptor agonist isoprenaline, despite being a partial agonist with respect to cAMP generation. GLUT4 translocation occurred independently of Akt and AMPK phosphorylation but was dependent on mTORC2. Furthermore, in contrast to isoprenaline, BRL37344 did not promote agonist-mediated desensitization and failed to recruit beta-arrestin1/2 to the beta(2)-adrenoceptor. In conclusion, BRL37344 improved glucose tolerance and increased glucose uptake into skeletal muscle in vivo and ex vivo through a beta(2)-adrenoceptor-mediated mechanism independently of Akt. BRL37344 was a partial agonist with respect to cAMP, but a full agonist for glucose uptake, and importantly did not cause classical receptor desensitization or internalization of the receptor.

  • 17.
    Nedergaard, Jan
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut.
    Bengtsson, Tore
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut.
    Cannon, Barbara
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut.
    New Powers of Brown Fat: Fighting the Metabolic Syndrome2011Ingår i: Cell Metabolism, ISSN 1550-4131, E-ISSN 1932-7420, Vol. 13, nr 3, s. 238-240Artikel i tidskrift (Refereegranskat)
    Abstract [en]

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

  • 18.
    Nedergaard, Jan
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för fysiologi.
    Bengtsson, Tore
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för fysiologi.
    Cannon, Barbara
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för fysiologi.
    Three years with adult human brown adipose tissue2010Ingår i: Annals of the New York Academy of Sciences, ISSN 0077-8923, E-ISSN 1749-6632, Vol. 1212, s. E20-E36Artikel i tidskrift (Refereegranskat)
    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.

  • 19.
    Olsen, Jessica M.
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut. Karolinska University Hospital Solna, Sweden.
    Csikasz, Robert I.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut. Karolinska University Hospital Solna, Sweden.
    Dehvari, Nodi
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Lu, Li
    Sandström, Anna
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Öberg, Anette I.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Nedergaard, Jan
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Stone-Elander, Sharon
    Bengtsson, Tore
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    β3-Adrenergically induced glucose uptake in brown adipose tissue is independent of UCP1 presence or activity: Mediation through the mTOR pathway2017Ingår i: Molecular Metabolism, ISSN 2212-8778, Vol. 6, nr 6, s. 611-619Artikel i tidskrift (Refereegranskat)
    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.

  • 20.
    Olsen, Jessica M.
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Sato, Masaaki
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut. Monash Institute of Pharmaceutical Sciences, Australia.
    Dallner, Olof S.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut. The Rockefeller University, USA.
    Sandström, Anna L.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Pisani, Didier F.
    Jean-Claude, Chambard
    Amri, Ez-Zoubir
    Hutchinson, Dana S.
    Bengtsson, Tore
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Glucose uptake in brown fat cells is dependent on mTOR complex 2-promoted GLUT1 translocation2014Ingår i: Journal of Cell Biology, ISSN 0021-9525, E-ISSN 1540-8140, Vol. 207, nr 3, artikel-id 365Artikel i tidskrift (Refereegranskat)
    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.

  • 21.
    Olsen, Jessica M.
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Åslund, Alice
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Bokhari, Muhammad Hamza
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Hutchinson, Dana S.
    Bengtsson, Tore
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Acute beta-adrenoceptor mediated glucose clearance in brown adipose tissue; a distinct pathway independent of functional insulin signaling2019Ingår i: Molecular Metabolism, ISSN 2212-8778, Vol. 30, s. 240-249Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Objective: beta-adrenoceptor mediated activation of brown adipose tissue (BAT) has been associated with improvements in metabolic health in models of type 2 diabetes and obesity due to its unique ability to increase whole body energy expenditure, and rate of glucose and free fatty acid disposal. While the thermogenic arm of this phenomenon has been studied in great detail, the underlying mechanisms involved in beta-adrenoceptor mediated glucose uptake in BAT are relatively understudied. As beta-adrenoceptor agonist administration results in increased hepatic gluconeogenesis that can consequently result in secondary pancreatic insulin release, there is uncertainty regarding the importance of insulin and the subsequent activation of its downstream effectors in mediating beta-adrenoceptor stimulated glucose uptake in BAT. Therefore, in this study, we made an effort to discriminate between the two pathways and address whether the insulin signaling pathway is dispensable for the effects of beta-adrenoceptor activation on glucose uptake in BAT. Methods: Using a specific inhibitor of phosphoinositide beta-kinase alpha (PI3K alpha), which effectively inhibits the insulin signaling pathway, we examined the effects of various beta-adrenoceptor agonists, including the physiological endogenous agonist norepinephrine on glucose uptake and respiration in mouse brown adipocytes in vitro and on glucose clearance in mice in vivo. Results: PI3K alpha inhibition in mouse primary brown adipocytes in vitro, did not inhibit beta-adrenoceptor stimulated glucose uptake, GLUT1 synthesis, GLUT1 translocation or respiration. Furthermore, beta-adrenoceptor mediated glucose clearance in vivo did not require insulin or Akt activation but was attenuated upon administration of a beta(3)-adrenoceptor antagonist. Conclusions: We conclude that the beta-adrenergic pathway is still functionally intact upon the inhibition of PI3K alpha, showing that the activation of downstream insulin effectors is not required for the acute effects of beta-adrenoceptor agonists on glucose homeostasis or thermogenesis. 

  • 22.
    Pauter, Anna M.
    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 Medical Center Hamburg-Eppendorf, Germany.
    Bengtsson, Tore
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Asadi, Abolfazl
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Talamonti, Emanuela
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Jacobsson, Anders
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Synergistic Effects of DHA and Sucrose on Body Weight Gain in PUFA-Deficient Elovl2-/- Mice2019Ingår i: Nutrients, ISSN 2072-6643, E-ISSN 2072-6643, Vol. 11, nr 4, artikel-id 852Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The omega-3 polyunsaturated fatty acid docosahexaenoic acid (DHA) is implicated in the regulation of both lipid and carbohydrate metabolism. Thus, we questioned whether dietary DHA and low or high content of sucrose impact on metabolism in mice deficient for elongation of very long-chain fatty acids 2 (ELOVL2), an enzyme involved in the endogenous DHA synthesis. We found that Elovl2 -/- mice fed a high-sucrose DHA-enriched diet followed by the high sucrose, high fat challenge significantly increased body weight. This diet affected the triglyceride rich lipoprotein fraction of plasma lipoproteins and changed the expression of several genes involved in lipid metabolism in a white adipose tissue. Our findings suggest that lipogenesis in mammals is synergistically influenced by DHA dietary and sucrose content.

  • 23.
    Rinde, Mia
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Kupferschmidt, Natalia
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Iqbal, Muhammad Naeem
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för material- och miljökemi (MMK).
    Robert-Nicoud, Ghislaine
    Johnston, Eric V.
    Lindgren, Maria
    Bengtsson, Tore
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Mesoporous silica with precisely controlled pores reduces food efficiency and suppresses weight gain in mice2020Ingår i: Nanomedicine, ISSN 1743-5889, E-ISSN 1748-6963, Vol. 15, nr 2, s. 131-144Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Aim: Obesity is a risk factor for cardiovascular disease and diabetes. We aimed to elucidate the effects of distinct mesoporous silica particles (MSPs) supplemented in food on metabolic parameters in obesity. Materials & methods: MSPs with precisely controlled pore size were synthesized, characterized and compared with a control in a C57Bl/6 mouse diet-induced obesity model, studying weight, adiposity, metabolic regulation and food efficiency. Results: The most effective MSPs reduced adipose tissue formation to 6.5 +/- 0.5 g compared with 9.4 +/- 1.2 g, leptin levels nearly halved from 32.8 +/- 7.4 to 16.9 +/- 1.9 ng/ml and a 33% reduction of food efficiency. Control MSP showed no effects. Conclusion: Results demonstrate potential of distinct MSPs to improve metabolic risk factors. Further studies investigating mechanism of action and confirming human safety are needed.

  • 24.
    Sato, Masaaki
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut. Monash University, Australia.
    Dehvari, Nodi
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Öberg, Anette I.
    Dallner, Olof S.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut. The Rockefeller University, USA.
    Sandström, Anna L.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Olsen, Jessica M.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Csikasz, Robert I.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Summers, Roger J.
    Hutchinson, Dana S.
    Bengtsson, Tore
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Improving type 2 diabetes through a distinct adrenergic signaling pathway involving mTORC2 that mediates glucose uptake in skeletal muscle2014Ingår i: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 63, nr 12, s. 4115-4129Artikel i tidskrift (Refereegranskat)
    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.

  • 25.
    Sato, Masaaki
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut. Monash University, Australia.
    Evans, Bronwyn A.
    Sandström, Anna L.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Chia, Ling Yeong
    Mukaida, Saori
    Bui, San
    Anh, Nguyen
    Lim, Linzi
    Tan, Christina Y. R.
    Baltos, Jo-Anne
    White, Paul J.
    May, Lauren T.
    Hutchinson, Dana S.
    Summers, Roger J.
    Bengtsson, Tore
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    alpha(1A)-Adrenoceptors activate mTOR signalling and glucose uptake in cardiomyocytes2018Ingår i: Biochemical Pharmacology, ISSN 0006-2952, E-ISSN 1356-1839, Vol. 148, s. 27-40Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The capacity of G protein-coupled receptors to modulate mechanistic target of rapamycin (mTOR) activity is a newly emerging paradigm with the potential to link cell surface receptors with cell survival. Cardiomyocyte viability is linked to signalling pathways involving Akt and mTOR, as well as increased glucose uptake and utilization. Our aim was to determine whether the am-adrenoceptor (AR) couples to these protective pathways, and increased glucose uptake. We characterised alpha(1A)-AR signalling in CHO-K1 cells co-expressing the human alpha(1A)-AR and GLUT4 (CHO alpha(1A)GLUT4myc) and in neonatal rat ventricular cardiomyocytes (NRVM), and measured glucose uptake, intracellular Ga2* mobilization, and phosphorylation of mTOR, Akt, 5' adenosine monophosphate-activated kinase (AMPK) and S6 ribosomal protein (S6rp). In both systems, noradrenaline and the alpha(1A)-AR selective agonist A61603 stimulated glucose uptake by parallel pathways involving mTOR and AMPK, whereas another alpha(1A)-AR agonist oxymetazoline increased glucose uptake predominantly by mTOR. All agonists promoted phosphorylation of mTOR at Ser2448 and Ser2481, indicating activation of both mTORC1 and mTORC2, but did not increase Akt phosphorylation. In CHO alpha(1A)GLUT4myc cells, siRNA directed against rictor but not raptor suppressed alpha(1A)-AR mediated glucose uptake. We have thus identified mTORC2 as a key component in glucose uptake stimulated by alpha(1A)-AR agonists. Our findings identify a novel link between the alpha(1A)-AR, mTORC2 and glucose uptake, that have been implicated separately in cardiomyocyte survival. Our studies provide an improved framework for examining the utility of alpha(1A)-AR selective agonists as tools in the treatment of cardiac dysfunction.

  • 26.
    Wang, Yanling
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Sato, Masaaki
    Bengtsson, Tore
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Nedergaard, Jan
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    cAMP-stimulated cell proliferation in brown preadipocytes is mediated by protein kinase A, but is independent of ERK1/2, PI3K and mTORManuskript (preprint) (Övrigt vetenskapligt)
    Abstract [en]

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

  • 27.
    Wang, Yanling
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Sato, Masaaki
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Guo, Yuan
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Bengtsson, Tore
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Nedergaard, Jan
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Protein kinase A-mediated cell proliferation in brown preadipocytes is independent of Erk1/2, PI3K and mTOR2014Ingår i: Experimental Cell Research, ISSN 0014-4827, E-ISSN 1090-2422, Vol. 328, nr 1, s. 143-155Artikel i tidskrift (Refereegranskat)
    Abstract [en]

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

  • 28.
    Yamamoto, Daniel L.
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut.
    Csikasz, Robert I.
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut.
    Li, Yu
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut.
    Sharma, Gunjana
    Hjort, Klas
    Karlsson, Roger
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut.
    Bengtsson, Tore
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut.
    Myotube Formation on Micro-patterned Glass: Intracellular organization and protein distribution in C2C12 skeletal muscle cells2008Ingår i: Journal of Histochemistry and Cytochemistry, ISSN 0022-1554, E-ISSN 1551-5044, Vol. 56, nr 10, s. 881-892Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Proliferation and fusion of myoblasts are needed for the generation and repair of multinucleated skeletal muscle fibers in vivo. Studies of myocyte differentiation, cell fusion, and muscle repair are limited by an appropriate in vitro muscle cell culture system. We developed a novel cell culture technique [two-dimensional muscle syncytia (2DMS) technique] that results in formation of myotubes, organized in parallel much like the arrangement in muscle tissue. This technique is based on UV lithography-produced micro-patterned glass on which conventionally cultured C2C12 myoblasts proliferate, align, and fuse to neatly arranged contractile myotubes in parallel arrays. Combining this technique with fluorescent microscopy, we observed alignment of actin filament bundles and a peri-nuclear distribution of glucose transporter 4 after myotube formation. Newly formed myotubes contained adjacently located MyoD-positive and MyoD-negative nuclei, suggesting fusion of MyoD-positive and MyoD-negative cells. In comparison, the closely related myogenic factor Myf5 did not exhibit this pattern of distribution. Furthermore, cytoplasmic patches of MyoD colocalized with bundles of filamentous actin near myotube nuclei. At later stages of differentiation, all nuclei in the myotubes were MyoD negative. The 2DMS system is thus a useful tool for studies on muscle alignment, differentiation, fusion, and subcellular protein localization.

  • 29.
    Öberg, Anette I.
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för fysiologi.
    Dehvari, Nodi
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för fysiologi.
    Bengtsson, Tore
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för fysiologi.
    beta-Adrenergic Inhibition of Contractility in L6 Skeletal Muscle Cells2011Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 6, nr 7, s. e22304-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The beta-adrenoceptors (beta-ARs) control many cellular processes. Here, we show that beta-ARs inhibit calcium depletion-induced cell contractility and subsequent cell detachment of L6 skeletal muscle cells. The mechanism underlying the cell detachment inhibition was studied by using a quantitative cell detachment assay. We demonstrate that cell detachment induced by depletion of extracellular calcium is due to myosin-and ROCK-dependent contractility. The beta-AR inhibition of L6 skeletal muscle cell detachment was shown to be mediated by the beta(2)-AR and increased cAMP but was surprisingly not dependent on the classical downstream effectors PKA or Epac, nor was it dependent on PKG, PI3K or PKC. However, inhibition of potassium channels blocks the beta(2)-AR mediated effects. Furthermore, activation of potassium channels fully mimicked the results of beta(2)-AR activation. In conclusion, we present a novel finding that beta(2)-AR signaling inhibits contractility and thus cell detachment in L6 skeletal muscle cells by a cAMP and potassium channel dependent mechanism.

  • 30.
    Öberg, Anette I.
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Sato, Masaaki
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Merlin, Jon
    Csikasz, Robert I.
    Sandström, Anna L.
    Hutchinson, Dana S.
    Summers, Roger J.
    Bengtsson, Tore
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Glucose uptake in skeletal muscle can be fully induced via the β2-adrenoceptor and GRK2 without cAMP-productionManuskript (preprint) (Övrigt vetenskapligt)
  • 31.
    Öberg, Anette I.
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för fysiologi.
    Yassin, Kamal
    Csikasz, Robert I.
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för fysiologi.
    Dehvari, Nodi
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för fysiologi.
    Shabalina, Irina G.
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för fysiologi.
    Hutchinson, Dana S.
    Wilcke, Mona
    Östenson, Claes-Göran
    Bengtsson, Tore
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för fysiologi.
    Shikonin Increases Glucose Uptake in Skeletal Muscle Cells and Improves Plasma Glucose Levels in Diabetic Goto-Kakizaki Rats2011Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 6, nr 7, s. e22510-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: There is considerable interest in identifying compounds that can improve glucose homeostasis. Skeletal muscle, due to its large mass, is the principal organ for glucose disposal in the body and we have investigated here if shikonin, a naphthoquinone derived from the Chinese plant Lithospermum erythrorhizon, increases glucose uptake in skeletal muscle cells. Methodology/Principal Findings: Shikonin increases glucose uptake in L6 skeletal muscle myotubes, but does not phosphorylate Akt, indicating that in skeletal muscle cells its effect is medaited via a pathway distinct from that used for insulin-stimulated uptake. Furthermore we find no evidence for the involvement of AMP-activated protein kinase in shikonin induced glucose uptake. Shikonin increases the intracellular levels of calcium in these cells and this increase is necessary for shikonin-mediated glucose uptake. Furthermore, we found that shikonin stimulated the translocation of GLUT4 from intracellular vesicles to the cell surface in L6 myoblasts. The beneficial effect of shikonin on glucose uptake was investigated in vivo by measuring plasma glucose levels and insulin sensitivity in spontaneously diabetic Goto-Kakizaki rats. Treatment with shikonin (10 mg/kg intraperitoneally) once daily for 4 days significantly decreased plasma glucose levels. In an insulin sensitivity test (s.c. injection of 0.5 U/kg insulin), plasma glucose levels were significantly lower in the shikonin-treated rats. In conclusion, shikonin increases glucose uptake in muscle cells via an insulin-independent pathway dependent on calcium. Conclusions/Significance: Shikonin increases glucose uptake in skeletal muscle cells via an insulin-independent pathway dependent on calcium. The beneficial effects of shikonin on glucose metabolism, both in vitro and in vivo, show that the compound possesses properties that make it of considerable interest for developing novel treatment of type 2 diabetes.

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