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  • 1. Alvarez-Crespo, Mayte
    et al.
    Csikasz, Robert I.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Martinez-Sanchez, Noelia
    Dieguez, Carlos
    Cannon, Barbara
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Nedergaard, Jan
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Lopez, Miguel
    Essential role of UCP1 modulating the central effects of thyroid hormones on energy balance2016In: Molecular metabolism, ISSN 2212-8778, Vol. 5, no 4, p. 271-282Article in journal (Refereed)
    Abstract [en]

    Objective: Classically, metabolic effects of thyroid hormones (THs) have been considered to be peripherally mediated, i.e. different tissues in the body respond directly to thyroid hormones with an increased metabolism. An alternative view is that the metabolic effects are centrally regulated. We have examined here the degree to which prolonged, centrally infused triiodothyronine (T3) could in itself induce total body metabolic effects and the degree to which brown adipose tissue (BAT) thermogenesis was essential for such effects, by examining uncoupling protein 1 (UCP1) KO mice. Methods: Wildtype and UPC1 KO mice were centrally-treated with T3 by using minipumps. Metabolic measurements were analyzed by indirect calorimetry and expression analysis by RT-PCR or western blot. BAT morphology and histology were studied by immunohistochemistry. Results: We found that central T3-treatment led to reduced levels of hypothalamic AMP-activated protein kinase (AMPK) and elevated body temperature (0.7 degrees C). UCP1 was essential for the T3-induced increased rate of energy expenditure, which was only observable at thermoneutrality and notably only during the active phase, for the increased body weight loss, for the increased hypothalamic levels of neuropeptide Y (NPY) and agouti-related peptide (AgRP) and for the increased food intake induced by central T3-treatment. Prolonged central T3-treatment also led to recruitment of BAT and britening/beiging (browning) of inguinal white adipose tissue (iWAT). Conclusions: We conclude that UCP1 is essential for mediation of the central effects of thyroid hormones on energy balance, and we suggest that similar UCP1-dependent effects may underlie central energy balance effects of other agents.

  • 2.
    Fischer, Alexander W.
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. University Medical Center Hamburg-Eppendorf, Germany.
    Csikasz, Robert I.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    von Essen, Gabriella
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Cannon, Barbara
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Nedergaard, Jan
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    No insulating effect of obesity2016In: American Journal of Physiology. Endocrinology and Metabolism, ISSN 0193-1849, E-ISSN 1522-1555, Vol. 311, no 1, p. e202-e213Article in journal (Refereed)
    Abstract [en]

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

  • 3.
    Fischer, Alexander W.
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. University Medical Center Hamburg-Eppendorf, Germany.
    Csikasz, Robert I.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    von Essen, Gabriella
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Cannon, Barbara
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Nedergaard, Jan
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Reply to letter to the editor: at thermoneutrality, neither the lean nor the obese freeze2016In: American Journal of Physiology. Endocrinology and Metabolism, ISSN 0193-1849, E-ISSN 1522-1555, Vol. 311, no 3, p. E639-E639Article in journal (Refereed)
  • 4. Hutchinson, Dana S.
    et al.
    Csikasz, Robert I.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Yamamoto, Daniel L.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Shabalina, Irina G.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Wikström, Per
    Wilcke, Mona
    Bengtsson, Tore
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Diphenylene iodonium stimulates glucose uptake in skeletal muscle cells through mitochondrial complex I inhibition and activation of AMP-activated protein kinase2007In: Cellular Signalling, ISSN 0898-6568, E-ISSN 1873-3913, Vol. 19, no 7, p. 1610-1620Article in journal (Refereed)
    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.

  • 5. Kupferschmidt, Natalia
    et al.
    Csikasz, Robert I.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Ballell, Lluis
    Bengtsson, Tore
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Garcia-Bennett, Alfonso E.
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK).
    Large pore mesoporous silica induced weight loss in obese mice2014In: Nanomedicine, ISSN 1743-5889, E-ISSN 1748-6963, Vol. 9, no 9, p. 1353-1362Article in journal (Refereed)
    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.

  • 6.
    Masaaki, Sato
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Dehvari, Nodi
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Öberg, Anette I.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Dallner, Olof S.
    Sandström, Anna L.
    Olsen, Jessica M.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Csikasz, Robert I.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Summers, Roger J.
    Hutchinson, Dana S.
    Bengtsson, Tore
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    An insulin-independent pathway including β-adrenoceptors and mTORC2 that translocates GLUT4 and increases glucose uptake in skeletal muscleManuscript (preprint) (Other academic)
  • 7.
    Mattsson, Charlotte L.
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Physiology.
    Csikasz, Robert I.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Physiology.
    Chernogubova, Ekaterina
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Physiology.
    Yamamoto, Daniel L.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Physiology.
    Högberg, Helena T.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Physiology.
    Amri, Ez-Zoubir
    Hutchinson, Dana S.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Physiology.
    Bengtsson, Tore
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Physiology.
    β₁-Adrenergic receptors increase UCP1 in human MADS brown adipocytes and rescue cold-acclimated β₃-adrenergic receptor-knockout mice via nonshivering thermogenesis2011In: American Journal of Physiology. Endocrinology and Metabolism, ISSN 0193-1849, E-ISSN 1522-1555, Vol. 301, no 6, p. E1108-E1118Article in journal (Refereed)
    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.

  • 8.
    Mattsson, Charlotte L.
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Csikasz, Robert I.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Shabalina, Irina G.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Nedergaard, Jan
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Cannon, Barbara
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Caveolin-1-ablated mice survive cold by nonshivering thermogenesis, despite desensitized adrenergic receptorsManuscript (preprint) (Other academic)
  • 9.
    Mattsson, Charlotte L
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Physiology.
    Csikasz, Robert I
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Physiology.
    Shabalina, Irina G
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Physiology.
    Nedergaard, Jan
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Physiology.
    Cannon, Barbara
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Physiology.
    Caveolin-1-ablated mice survive in cold by nonshivering thermogenesis despite desensitized adrenergic responsiveness2010In: American Journal of Physiology. Endocrinology and Metabolism, ISSN 0193-1849, E-ISSN 1522-1555, Vol. 299, no 3, p. E374-83Article in journal (Refereed)
    Abstract [en]

    Caveolin-1 (Cav1)-ablated mice display impaired lipolysis in white adipose tissue. They also seem to have an impairment in brown adipose tissue function, implying that Cav1-ablated mice could encounter problems in surviving longer periods in cold temperatures. To investigate this, Cav1-ablated mice and wild-type mice were transferred to cold temperatures for extended periods of time, and parameters related to metabolism and thermogenesis were investigated. Unexpectedly, the Cav1-ablated mice survived in the cold. There were no differences between Cav1-ablated and wild-type mice with regard to food intake, in behavior related to shivering, or in body temperature. The Cav1-ablated mice had a halved total fat content independently of acclimation temperature. There was no difference in brown adipose tissue uncoupling protein-1 (UCP1) protein amount, and isolated brown fat mitochondria were thermogenically competent but displayed 30% higher thermogenic capacity. However, the beta(3)-adrenergic receptor amount was reduced by about one-third in the Cav1-ablated mice at all acclimation temperatures. Principally in accordance with this, a higher than standard dose of norepinephrine was needed to obtain full norepinephrine-induced thermogenesis in the Cav1-ablated mice; the higher dose was also needed for the Cav1-ablated mice to be able to utilize fat as a substrate for thermogenesis. In conclusion, the ablation of Cav1 impairs brown adipose tissue function by a desensitization of the adrenergic response; however, the desensitization is not evident in the animal as it is overcome physiologically, and Cav1-ablated mice can therefore survive in prolonged cold by nonshivering thermogenesis.

  • 10. Merlin, Jon
    et al.
    Evans, Bronwyn A
    Csikasz, Robert I
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Physiology.
    Bengtsson, Tore
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Physiology.
    Summers, Roger J
    Hutchinson, Dana S
    The M3-muscarinic acetylcholine receptor stimulates glucose uptake in L6 skeletal muscle cells by a CaMKK-AMPK-dependent mechanism2010In: Cellular Signalling, ISSN 0898-6568, E-ISSN 1873-3913, Vol. 22, no 7, p. 1104-13Article in journal (Refereed)
    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.

  • 11.
    Olsen, Jessica M.
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. Karolinska University Hospital Solna, Sweden.
    Csikasz, Robert I.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. Karolinska University Hospital Solna, Sweden.
    Dehvari, Nodi
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Lu, Li
    Sandström, Anna
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Öberg, Anette I.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Nedergaard, Jan
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Stone-Elander, Sharon
    Bengtsson, Tore
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    β3-Adrenergically induced glucose uptake in brown adipose tissue is independent of UCP1 presence or activity: Mediation through the mTOR pathway2017In: Molecular Metabolism, ISSN 2109-5671, E-ISSN 1762-3162, Vol. 6, no 6, p. 611-619Article in journal (Refereed)
    Abstract [en]

    Objective

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

    Methods

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

    Results

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

    Conclusions

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

  • 12.
    Pauter, Anna M.
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Olsson, Petter
    Stockholm University, Faculty of Science, Department of Analytical Chemistry.
    Asadi, Abolfazl
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Herslöf, Bengt
    Stockholm University, Faculty of Science, Department of Analytical Chemistry.
    Csikasz, Robert I.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Zadravec, Damir
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Jacobsson, Anders
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Elovl2 ablation demonstrates that systemic DHA is endogenously produced and is essential for lipid homeostasis in mice2014In: Journal of Lipid Research, ISSN 0022-2275, E-ISSN 1539-7262, Vol. 55, no 4, p. 718-728Article in journal (Refereed)
    Abstract [en]

    The potential role of endogenously synthesized polyunsaturated fatty acids (PUFAs) is a highly overlooked area. Elongation of very long chain (ELOVL) fatty acids in mammals is catalyzed by the ELOVL enzymes to which the PUFA elongase ELOVL2 belongs. To determine its in vivo function, we have investigated how ablation of ELOVL2, which is highly expressed in liver, affects hepatic lipid composition and function in mice. The Elovl2 ablated mice displayed substantial decreased levels of 22:6(n3), docosahexaenoic acid (DHA), and 22:5(n6), docosapentaenoic acid (DPAn6), followed by an accumulation of 22:5(n3) and 22:4(n6) in both liver and serum showing that ELOVL2 primarily controls the elongation process of PUFAs with 22 carbons to produce 24 carbon precursors for DHA and DPA(n6) formation in vivo. The impaired PUFA levels positively influenced hepatic levels of the key lipogenic transcriptional regulator sterol regulatory element binding protein 1c (SREBP1c) as well as its downstream target genes. Surprisingly, the Elovl2 ablated mice were resistant against hepatic steatosis and diet induced weight gain implying that hepatic DHA synthesis via ELOVL2, except controlling de novo lipogenesis, also regulates lipid storage and fat mass expansion in an SREBP1c independent fashion. The changes in fatty acid metabolism were reversed by dietary supplementation with DHA.

  • 13.
    Sato, Masaaki
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. Monash University, Australia.
    Dehvari, Nodi
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Öberg, Anette I.
    Dallner, Olof S.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. The Rockefeller University, USA.
    Sandström, Anna L.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Olsen, Jessica M.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Csikasz, Robert I.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Summers, Roger J.
    Hutchinson, Dana S.
    Bengtsson, Tore
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Improving type 2 diabetes through a distinct adrenergic signaling pathway involving mTORC2 that mediates glucose uptake in skeletal muscle2014In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 63, no 12, p. 4115-4129Article in journal (Refereed)
    Abstract [en]

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

  • 14.
    Shabalina, Irina G.
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Kramarova, Tatiana V.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Mattsson, Charlotte L.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Petrovic, Natasa
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Qazi, Mousumi Rahman
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Csikasz, Robert I.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Chang, Shu-Ching
    Butenhoff, John
    DePierre, Joseph W.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Cannon, Barbara
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Nedergaard, Jan
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    The Environmental Pollutants Perfluorooctane Sulfonate and Perfluorooctanoic Acid Upregulate Uncoupling Protein 1 (UCP1) in Brown-Fat Mitochondria Through a UCP1-Dependent Reduction in Food Intake2015In: Toxicological Sciences, ISSN 1096-6080, E-ISSN 1096-0929, Vol. 146, no 2, p. 334-343Article in journal (Refereed)
    Abstract [en]

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

  • 15.
    Shabalina, Irina G.
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Vyssokikh, Mikhail Yu.
    Gibanova, Natalia
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Csikasz, Robert I.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Edgar, Daniel
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Hallden-Waldemarson, Anne
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Rozhdestvenskaya, Zinaida
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Bakeeva, Lora E.
    Vays, Valeria B.
    Pustovidko, Antonina V.
    Skulachev, Maxim V.
    Cannon, Barbara
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Skulachev, Vladimir P.
    Nedergaard, Jan
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Improved health-span and lifespan in mtDNA mutator mice treated with the mitochondrially targeted antioxidant SkQ12017In: Aging, ISSN 1945-4589, E-ISSN 1945-4589, Vol. 9, no 2, p. 315-339Article in journal (Refereed)
    Abstract [en]

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

  • 16. Whittle, Andrew J.
    et al.
    Carobbio, Stefania
    Martins, Luis
    Slawik, Marc
    Hondares, Elayne
    Jesus Vazquez, Maria
    Morgan, Donald
    Csikasz, Robert I.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Physiology.
    Gallego, Rosalia
    Rodriguez-Cuenca, Sergio
    Dale, Martin
    Virtue, Samuel
    Villarroya, Francesc
    Cannon, Barbara
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Physiology.
    Rahmouni, Kamal
    Lopez, Miguel
    Vidal-Puig, Antonio
    BMP8B Increases Brown Adipose Tissue Thermogenesis through Both Central and Peripheral Actions2012In: Cell, ISSN 0092-8674, E-ISSN 1097-4172, Vol. 149, no 4, p. 871-885Article in journal (Refereed)
    Abstract [en]

    Thermogenesis in brown adipose tissue (BAT) is fundamental to energy balance and is also relevant for humans. Bone morphogenetic proteins (BMPs) regulate adipogenesis, and, here, we describe a role for BMP8B in the direct regulation of thermogenesis. BMP8B is induced by nutritional and thermogenic factors in mature BAT, increasing the response to noradrenaline through enhanced p38MAPK/CREB signaling and increased lipase activity. Bmp8b(-/-) mice exhibit impaired thermogenesis and reduced metabolic rate, causing weight gain despite hypophagia. BMP8B is also expressed in the hypothalamus, and Bmp8b(-/-) mice display altered neuropeptide levels and reduced phosphorylation of AMP-activated protein kinase (AMPK), indicating an anorexigenic state. Central BMP8B treatment increased sympathetic activation of BAT, dependent on the status of AMPK in key hypothalamic nuclei. Our results indicate that BMP8B is a thermogenic protein that regulates energy balance in partnership with hypothalamic AMPK. BMP8B may offer a mechanism to specifically increase energy dissipation by BAT.

  • 17.
    Yamamoto, Daniel L.
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Csikasz, Robert I.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Li, Yu
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Sharma, Gunjana
    Hjort, Klas
    Karlsson, Roger
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Bengtsson, Tore
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Myotube Formation on Micro-patterned Glass: Intracellular organization and protein distribution in C2C12 skeletal muscle cells2008In: Journal of Histochemistry and Cytochemistry, ISSN 0022-1554, E-ISSN 1551-5044, Vol. 56, no 10, p. 881-892Article in journal (Refereed)
    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.

  • 18.
    Zadravec, Damir
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Brolinson, Annelie
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Fisher, Rachel
    Carneheim, Claes
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Csikasz, Robert
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Bertrand-Michel, Justine
    Borén, Jan
    Guillou, Hervé
    Rudling, Mats
    Jacobsson, Anders
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Ablation of the very long chain fatty acid elongase ELOVL3 in mice leads to constrained lipid storage and resistance to diet-induced obesity2010In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 24, no 11, p. 4366-4377Article in journal (Refereed)
    Abstract [en]

    Although saturated and monounsaturated very-long-chain fatty acids (VLCFA) have long been associated with undesirable effects on health, including obesity, heart failure and atherosclerosis, the physiological role of endogenous synthesis is largely unknown. The fatty acid elongase ELOVL3 is involved in the synthesis of C20-C24 saturated and monounsaturated VLCFA mainly in liver, brown and white adipose tissue and in triglyceride rich glands such as the sebaceous and meibomian glands. Here we show that ablation of ELOVL3 leads to reduced adiponectin levels, constrained expansion of adipose tissue and resistance against diet-induced obesity, a situation that is more exaggerated in female mice. Both female and male knockout mice show reduced hepatic lipogenic gene expression and triglyceride content, a situation, which is associated with, reduced expression of PPARg and its target genes. As a consequence, the VLDL-triglyceride level in serum is significantly reduced. Remarkably, despite increased energy expenditure, markedly reduced serum levels of leptin and increased expression of orexigenic peptides in the hypothalamus, the Elovl3-/- mice do not compensate by increased food intake. Thus, these results reveal that C20-C22 saturated and monounsaturated VLCFA produced by ELOVL3 are indispensable for appropriate synthesis of liver triglycerides, fatty acid uptake and storage in adipose tissue.

  • 19.
    Öberg, Anette I.
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Physiology.
    Yassin, Kamal
    Csikasz, Robert I.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Physiology.
    Dehvari, Nodi
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Physiology.
    Shabalina, Irina G.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Physiology.
    Hutchinson, Dana S.
    Wilcke, Mona
    Östenson, Claes-Göran
    Bengtsson, Tore
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Physiology.
    Shikonin Increases Glucose Uptake in Skeletal Muscle Cells and Improves Plasma Glucose Levels in Diabetic Goto-Kakizaki Rats2011In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 6, no 7, p. e22510-Article in journal (Refereed)
    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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