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Csikasz, Robert
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Publications (10 of 21) Show all publications
Bokhari, M. H., Halleskog, C., Åslund, A., Boulet, N., Casadesús Rendos, E., de Jong, J. M., . . . Bengtsson, T. (2021). Isothermal microcalorimetry measures UCP1-mediated thermogenesis in mature brite adipocytes. Communications Biology, 4(1), Article ID 1108.
Open this publication in new window or tab >>Isothermal microcalorimetry measures UCP1-mediated thermogenesis in mature brite adipocytes
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2021 (English)In: Communications Biology, E-ISSN 2399-3642, Vol. 4, no 1, article id 1108Article in journal (Refereed) Published
Abstract [en]

The activation of thermogenesis in adipose tissue has emerged as an important target for the development of novel anti-obesity therapies. Using multi-well isothermal microcalorimetry, we have demonstrated that mature murine brown and brite adipocytes produce quantifiable heat upon β3-AR stimulation, independently of any anaerobic mechanisms. Additionally, in brite adipocytes lacking UCP1 protein, β3-AR stimulation still induces heat production, albeit to a much lower extent than in their wildtype counterparts, suggesting that UCP1 is an essential component of adrenergic induced thermogenesis in murine brite adipocytes exvivo. Similarly, we could observe an increase in heat production in human-derived adipocytes (hMADS) upon β-AR stimulation. Collectively, these results establish the use of isothermal microcalorimetry as a sensitive and accurate technique for measuring thermogenic responses in intact mature brite adipocytes from murine and human origin.

National Category
Biological Sciences
Identifiers
urn:nbn:se:su:diva-198698 (URN)10.1038/s42003-021-02639-4 (DOI)000697665400003 ()34548622 (PubMedID)
Available from: 2021-11-15 Created: 2021-11-15 Last updated: 2022-02-28Bibliographically approved
Mukaida, S., Sato, M., Öberg, A. I., Dehvari, N., Olsen, J. M., Kocan, M., . . . Bengtsson, T. (2019). BRL37344 stimulates GLUT4 translocation and glucose uptake in skeletal muscle via beta(2)-adrenoceptors without causing classical receptor desensitization. American Journal of Physiology. Regulatory Integrative and Comparative Physiology, 316(5), R666-R677
Open this publication in new window or tab >>BRL37344 stimulates GLUT4 translocation and glucose uptake in skeletal muscle via beta(2)-adrenoceptors without causing classical receptor desensitization
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2019 (English)In: American Journal of Physiology. Regulatory Integrative and Comparative Physiology, ISSN 0363-6119, E-ISSN 1522-1490, Vol. 316, no 5, p. R666-R677Article in journal (Refereed) Published
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.

Keywords
beta(2)-adrenoceptor, beta-arrestin, BRL37344, glucose uptake, GLUT4, isoprenaline, receptor desensitization, skeletal muscle
National Category
Biological Sciences
Identifiers
urn:nbn:se:su:diva-170219 (URN)10.1152/ajpregu.00285.2018 (DOI)000468436400010 ()30892909 (PubMedID)
Available from: 2019-07-15 Created: 2019-07-15 Last updated: 2022-02-26Bibliographically approved
Shabalina, I. G., Vyssokikh, M. Y., Gibanova, N., Csikasz, R. I., Edgar, D., Hallden-Waldemarson, A., . . . Nedergaard, J. (2017). Improved health-span and lifespan in mtDNA mutator mice treated with the mitochondrially targeted antioxidant SkQ1. Aging, 9(2), 315-339
Open this publication in new window or tab >>Improved health-span and lifespan in mtDNA mutator mice treated with the mitochondrially targeted antioxidant SkQ1
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2017 (English)In: Aging, E-ISSN 1945-4589, Vol. 9, no 2, p. 315-339Article in journal (Refereed) Published
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.

Keywords
reactive oxygen species, oxidative stress, mitochondria, cardiolipin, thermogenesis, brown adipose tissue, longevity
National Category
Biological Sciences
Identifiers
urn:nbn:se:su:diva-142559 (URN)10.18632/aging.101174 (DOI)000396892500005 ()28209927 (PubMedID)
Available from: 2017-05-03 Created: 2017-05-03 Last updated: 2024-07-04Bibliographically approved
Olsen, J. M., Csikasz, R. I., Dehvari, N., Lu, L., Sandström, A., Öberg, A. I., . . . Bengtsson, T. (2017). β3-Adrenergically induced glucose uptake in brown adipose tissue is independent of UCP1 presence or activity: Mediation through the mTOR pathway. Molecular Metabolism, 6(6), 611-619
Open this publication in new window or tab >>β3-Adrenergically induced glucose uptake in brown adipose tissue is independent of UCP1 presence or activity: Mediation through the mTOR pathway
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2017 (English)In: Molecular Metabolism, ISSN 2212-8778, Vol. 6, no 6, p. 611-619Article in journal (Refereed) Published
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.

Keywords
Brown adipose tissue, Uncoupling protein 1, Glucose uptake, Adrenergic signaling, Positron emission tomography
National Category
Physiology
Research subject
Physiology
Identifiers
urn:nbn:se:su:diva-143137 (URN)10.1016/j.molmet.2017.02.006 (DOI)000405453000015 ()
Available from: 2017-05-15 Created: 2017-05-15 Last updated: 2022-03-23Bibliographically approved
Alvarez-Crespo, M., Csikasz, R. I., Martinez-Sanchez, N., Dieguez, C., Cannon, B., Nedergaard, J. & Lopez, M. (2016). Essential role of UCP1 modulating the central effects of thyroid hormones on energy balance. Molecular metabolism, 5(4), 271-282
Open this publication in new window or tab >>Essential role of UCP1 modulating the central effects of thyroid hormones on energy balance
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2016 (English)In: Molecular metabolism, ISSN 2212-8778, Vol. 5, no 4, p. 271-282Article in journal (Refereed) Published
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.

Keywords
AMPK, Brown adipose tissue, Hypothalamus, Thyroid hormones, UCP1
National Category
Biological Sciences
Identifiers
urn:nbn:se:su:diva-129906 (URN)10.1016/j.molmet.2016.01.008 (DOI)000372823000004 ()27069867 (PubMedID)
Available from: 2016-05-03 Created: 2016-05-03 Last updated: 2022-03-23Bibliographically approved
Fischer, A. W., Csikasz, R. I., von Essen, G., Cannon, B. & Nedergaard, J. (2016). No insulating effect of obesity. American Journal of Physiology. Endocrinology and Metabolism, 311(1), e202-e213
Open this publication in new window or tab >>No insulating effect of obesity
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2016 (English)In: American Journal of Physiology. Endocrinology and Metabolism, ISSN 0193-1849, E-ISSN 1522-1555, Vol. 311, no 1, p. e202-e213Article in journal (Refereed) Published
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.

Keywords
obesity, insulation, ob/ob
National Category
Biological Sciences Physiology
Research subject
Physiology
Identifiers
urn:nbn:se:su:diva-133223 (URN)10.1152/ajpendo.00093.2016 (DOI)000380372000016 ()27189935 (PubMedID)
Available from: 2016-09-13 Created: 2016-09-05 Last updated: 2022-02-23Bibliographically approved
Fischer, A. W., Csikasz, R. I., von Essen, G., Cannon, B. & Nedergaard, J. (2016). Reply to letter to the editor: at thermoneutrality, neither the lean nor the obese freeze [Letter to the editor]. American Journal of Physiology. Endocrinology and Metabolism, 311(3), E639-E639
Open this publication in new window or tab >>Reply to letter to the editor: at thermoneutrality, neither the lean nor the obese freeze
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2016 (English)In: American Journal of Physiology. Endocrinology and Metabolism, ISSN 0193-1849, E-ISSN 1522-1555, Vol. 311, no 3, p. E639-E639Article in journal, Letter (Other academic) Published
National Category
Biological Sciences
Identifiers
urn:nbn:se:su:diva-135155 (URN)10.1152/ajpendo.00309.2016 (DOI)000384772100011 ()27619918 (PubMedID)
Available from: 2016-10-31 Created: 2016-10-31 Last updated: 2022-02-28Bibliographically approved
Shabalina, I. G., Kramarova, T. V., Mattsson, C. L., Petrovic, N., Qazi, M. R., Csikasz, R. I., . . . Nedergaard, J. (2015). The Environmental Pollutants Perfluorooctane Sulfonate and Perfluorooctanoic Acid Upregulate Uncoupling Protein 1 (UCP1) in Brown-Fat Mitochondria Through a UCP1-Dependent Reduction in Food Intake. Toxicological Sciences, 146(2), 334-343
Open this publication in new window or tab >>The Environmental Pollutants Perfluorooctane Sulfonate and Perfluorooctanoic Acid Upregulate Uncoupling Protein 1 (UCP1) in Brown-Fat Mitochondria Through a UCP1-Dependent Reduction in Food Intake
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2015 (English)In: Toxicological Sciences, ISSN 1096-6080, E-ISSN 1096-0929, Vol. 146, no 2, p. 334-343Article in journal (Refereed) Published
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.

Keywords
thermogenesis, food restriction, adipose tissue, fatty acid oxidation, body temperature
National Category
Pharmacology and Toxicology Biological Sciences
Identifiers
urn:nbn:se:su:diva-120704 (URN)10.1093/toxsci/kfv098 (DOI)000359630300013 ()
Available from: 2015-09-18 Created: 2015-09-15 Last updated: 2022-02-23Bibliographically approved
Pauter, A. M., Olsson, P., Asadi, A., Herslöf, B., Csikasz, R. I., Zadravec, D. & Jacobsson, A. (2014). Elovl2 ablation demonstrates that systemic DHA is endogenously produced and is essential for lipid homeostasis in mice. Journal of Lipid Research, 55(4), 718-728
Open this publication in new window or tab >>Elovl2 ablation demonstrates that systemic DHA is endogenously produced and is essential for lipid homeostasis in mice
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2014 (English)In: Journal of Lipid Research, ISSN 0022-2275, E-ISSN 1539-7262, Vol. 55, no 4, p. 718-728Article in journal (Refereed) Published
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.

Keywords
fatty acid elongase, elongase of very longchain fatty acid 2, docosahexaenoic acid, liver steatosis, weight gain
National Category
Biological Sciences
Research subject
Physiology
Identifiers
urn:nbn:se:su:diva-104591 (URN)10.1194/jlr.M046151 (DOI)000336425600010 ()
Note

AuthorCount:7;

Available from: 2014-01-31 Created: 2014-06-11 Last updated: 2022-03-23Bibliographically approved
Sato, M., Dehvari, N., Öberg, A. I., Dallner, O. S., Sandström, A. L., Olsen, J. M., . . . Bengtsson, T. (2014). Improving type 2 diabetes through a distinct adrenergic signaling pathway involving mTORC2 that mediates glucose uptake in skeletal muscle. Diabetes, 63(12), 4115-4129
Open this publication in new window or tab >>Improving type 2 diabetes through a distinct adrenergic signaling pathway involving mTORC2 that mediates glucose uptake in skeletal muscle
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2014 (English)In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 63, no 12, p. 4115-4129Article in journal (Refereed) Published
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.

National Category
Physiology Endocrinology and Diabetes
Research subject
Physiology
Identifiers
urn:nbn:se:su:diva-143131 (URN)10.2337/db13-1860 (DOI)000345335500023 ()
Available from: 2017-05-15 Created: 2017-05-15 Last updated: 2022-02-28Bibliographically approved
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