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  • 1.
    Abreu-Vieira, Gustavo
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Hagberg, Carolina E.
    Spalding, Kirsty L.
    Cannon, Barbara
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Nedergaard, Jan
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Adrenergically-stimulated blood flow in brown adipose tissue is not dependent on thermogenesis: Regulation of brown adipose tissue blood flow2015Inngår i: American Journal of Physiology. Endocrinology and Metabolism, ISSN 0193-1849, E-ISSN 1522-1555, Vol. 308, nr 9, s. E822-E829Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Brown adipose tissue (BAT) thermogenesis relies on blood flow to be supplied with nutrients and oxygen, and for the distribution of the generated heat to the rest of the body. It is therefore fundamental to understand the mechanisms by which blood flow is regulated and its relation to thermogenesis. Here we present high-resolution laser-Doppler imaging (HR-LDR) as a novel method for noninvasive, in vivo measurement of BAT blood flow in mice. Using HR-LDR, we found that norepinephrine stimulation increases BAT blood flow in a dose-dependent manner, and that this response is profoundly modulated by environmental temperature acclimation. Surprisingly, we found that mice lacking uncoupling protein 1 (UCP1) have fully preserved BAT blood flow response to norepinephrine, despite failing to perform thermogenesis. BAT blood flow was not directly correlated to systemic glycaemia, but glucose injections could transiently increase tissue perfusion. Inguinal white adipose tissue, also known as a brite/beige adipose tissue, was also sensitive to cold acclimation and similarly increased blood flow in response to norepinephrine. In conclusion, using a novel non-invasive method to detect BAT perfusion, we demonstrate that adrenergically-stimulated BAT blood flow is qualitatively and quantitatively fully independent of thermogenesis, and is therefore not a reliable parameter for the estimation of BAT activation and heat generation.

  • 2.
    Boulet, Nathalie
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Luijten, Ineke H. N.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Cannon, Barbara
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Nedergaard, Jan
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Thermogenic recruitment of brown and brite/beige adipose tissues is not obligatorily associated with macrophage accretion or attrition2021Inngår i: American Journal of Physiology. Endocrinology and Metabolism, ISSN 0193-1849, E-ISSN 1522-1555, Vol. 320, nr 2, s. E359-E378Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Cold- and diet-induced recruitment of brown adipose tissue (BAT) and the browning of white adipose tissue (WAT) are dynamic processes, and the recruited state attained is a state of dynamic equilibrium, demanding continuous stimulation to be maintained. An involvement of macrophages, classical proinflammatory (M1) or alternatively activated anti-inflammatory (M2), is presently discussed as being an integral part of these processes. If these macrophages play a mediatory role in the recruitment process, such an involvement would have to be maintained in the recruited state. We have, therefore, investigated whether the recruited state of these tissues is associated with macrophage accretion or attrition. We found no correlation (positive or negative) between total UCP1 mRNA levels (as a measure of recruitment) and proinflammatory macrophages in any adipose depot. We found that in young chow-fed mice, cold-induced recruitment correlated with accretion of anti-inflammatory macrophages; however, such a correlation was not seen when cold-induced recruitment was studied in diet-induced obese mice. Furthermore, the anti-inflammatory macrophage accretion was mediated via β12-adrenergic receptors; yet, in their absence, and thus in the absence of macrophage accretion, recruitment proceeded normally. We thus conclude that the classical recruited state in BAT and inguinal (brite/beige) WAT is not paralleled by macrophage accretion or attrition. Our results make mediatory roles for macrophages in the recruitment process less likely.

    NEW & NOTEWORTHY A regulatory or mediatory role—positive or negative—for macrophages in the recruitment of brown adipose tissue is presently discussed. As the recruited state in the tissue is a dynamic process, maintenance of the recruited state would need persistent alterations in macrophage complement. Contrary to this expectation, we demonstrate here an absence of alterations in macrophage complement in thermogenically recruited brown—or brite/beige—adipose tissues. Macrophage regulation of thermogenic capacity is thus less likely.

  • 3.
    de Jong, Jasper M. A.
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Larsson, Ola
    Cannon, Barbara
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Nedergaard, Jan
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    A stringent validation of mouse adipose tissue identity markers2015Inngår i: American Journal of Physiology. Endocrinology and Metabolism, ISSN 0193-1849, E-ISSN 1522-1555, Vol. 308, nr 12, s. E1085-E1105Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The nature of brown adipose tissue in humans is presently debated: whether it is classical brown or of brite/beige nature. The dissimilar developmental origins and proposed distinct functions of the brown and brite/beige tissues make it essential to ascertain the identity of human depots with the perspective of recruiting and activating them for the treatment of obesity and type 2 diabetes. For identification of the tissues, a number of marker genes have been proposed, but the validity of the markers has not been well documented. We used established brown (interscapular), brite (inguinal), and white (epididymal) mouse adipose tissues and corresponding primary cell cultures as validators and examined the informative value of a series of suggested markers earlier used in the discussion considering the nature of human brown adipose tissue. Most of these markers unexpectedly turned out to be noninformative concerning tissue classification (Car4, Cited1, Ebf3, Eva1, Fbxo31, Fgf21, Lhx8, Hoxc8, and Hoxc9). Only Zic1 (brown), Cd137, Epsti1, Tbx1, Tmem26 (brite), and Tcf21 (white) proved to be informative in these three tissues. However, the expression of the brite markers was not maintained in cell culture. In a more extensive set of adipose depots, these validated markers provide new information about depot identity. Principal component analysis supported our single-gene conclusions. Furthermore, Zic1, Hoxc8, Hoxc9, and Tcf21 displayed anteroposterior expression patterns, indicating a relationship between anatomic localization and adipose tissue identity (and possibly function). Together, the observed expression patterns of these validated marker genes necessitates reconsideration of adipose depot identity in mice and humans.

  • 4.
    de Jong, Jasper M. A.
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Wouters, René T. F.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Boulet, Nathalie
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Cannon, Barbara
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Nedergaard, Jan
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Petrovic, Natasa
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    The β3-adrenergic receptor is dispensable for browning of adipose tissues2017Inngår i: American Journal of Physiology. Endocrinology and Metabolism, ISSN 0193-1849, E-ISSN 1522-1555, Vol. 312, nr 6, s. E508-E518Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

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

  • 5.
    Fischer, Alexander W.
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut. University Medical Center Hamburg-Eppendorf, Germany.
    Csikasz, Robert I.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    von Essen, Gabriella
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Cannon, Barbara
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Nedergaard, Jan
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    No insulating effect of obesity2016Inngår i: American Journal of Physiology. Endocrinology and Metabolism, ISSN 0193-1849, E-ISSN 1522-1555, Vol. 311, nr 1, s. e202-e213Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 6.
    Fischer, Alexander W.
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut. University Medical Center Hamburg-Eppendorf, Germany.
    Csikasz, Robert I.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    von Essen, Gabriella
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Cannon, Barbara
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Nedergaard, Jan
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Reply to letter to the editor: at thermoneutrality, neither the lean nor the obese freeze2016Inngår i: American Journal of Physiology. Endocrinology and Metabolism, ISSN 0193-1849, E-ISSN 1522-1555, Vol. 311, nr 3, s. E639-E639Artikkel i tidsskrift (Annet vitenskapelig)
  • 7.
    Fischer, Alexander W.
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut. University Medical Center Hamburg-Eppendorf, Germany.
    Schlein, Christian
    Cannon, Barbara
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Heeren, Joerg
    Nedergaard, Jan
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Intact innervation is essential for diet-induced recruitment of brown adipose tissue2019Inngår i: American Journal of Physiology. Endocrinology and Metabolism, ISSN 0193-1849, E-ISSN 1522-1555, Vol. 316, nr 3, s. E487-E503Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

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

  • 8.
    Fischer, Alexander W.
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut. University Medical Center Hamburg-Eppendorf, Germany.
    Shabalina, Irina G.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Mattsson, Charlotte L.
    Abreu-Vieira, Gustavo
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Cannon, Barbara
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Nedergaard, Jan
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Petrovic, Natasa
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    UCP1 inhibition in Cidea-overexpressing mice is physiologically counteracted by brown adipose tissue hyperrecruitment2017Inngår i: American Journal of Physiology. Endocrinology and Metabolism, ISSN 0193-1849, E-ISSN 1522-1555, Vol. 312, nr 1, s. e72-E87Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

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

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

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

  • 10. Gburcik, Valentina
    et al.
    Cawthorn, William P.
    Nedergaard, Jan
    Timmons, James A.
    Cannon, Barbara
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för fysiologi.
    An essential role for Tbx15 in the differentiation of brown and "brite" but not white adipocytes2012Inngår i: American Journal of Physiology. Endocrinology and Metabolism, ISSN 0193-1849, E-ISSN 1522-1555, Vol. 303, nr 8, s. e1053-E1060Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

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

  • 11.
    Jacobsson, Anders
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut.
    Jakobsson, Andreas
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut.
    Jörgensen, Johanna
    Differential regulation of fatty acid elongation enzymes in brown adipocytes imply an unique role for Elovl3 during increased fatty acid oxidation2005Inngår i: American Journal of Physiology. Endocrinology and Metabolism, ISSN 0193-1849, E-ISSN 1522-1555, Vol. 289, s. 517-526Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The expression of the Elovl3 gene, which belongs to the Elovl gene family coding for microsomal enzymes involved in very long-chain fatty acid (VLCFA) elongation, is dramatically increased in mouse brown adipose tissue upon cold stimulation. In the present study, we show that the cold-induced Elovl3 expression is under the control of peroxisome proliferator-activated receptor- (PPAR) and that this regulation is part of a fundamental divergence in the regulation of expression for the different members of the Elovl gene family. In cultured brown adipocytes, a mixture of norepinephrine, dexamethasone, and the PPAR ligand Wy-14643, which rendered the adipocytes a high oxidative state, was required for substantial induction of Elovl3 expression, whereas the same treatment suppressed Elovl1 mRNA levels. The nuclear liver X receptor (LXR) has been implicated in the control of fatty acid synthesis and subsequent lipogenic processes in several tissues. This regulation is also exerted in part by sterol regulatory element-binding protein (SREBP-1), which is a target gene of LXR. We found that stimulation of Elovl3 expression was independent of LXR and SREBP-1 activation. In addition, exposure to the LXR agonist TO-901317 increased nuclear abundance of LXR and mature SREBP-1 as well as expression of the elongases Lce and Elovl1 in a lipogenic fashion but repressed Elovl3 expression. A functional consequence of this was seen on the level of esterified saturated fatty acids, such as C22:0, which was coupled to Elovl3 expression. These data demonstrate differential transcriptional regulation and concomitantly different functional roles for fatty acid elongases in lipid metabolism of brown adipocytes, which reflects the metabolic status of the cells.

  • 12.
    Jörgensen, Johanna A
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut.
    Zadravec, Damir
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut.
    Jacobsson, Anders
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut.
    Norepinephrine and rosiglitazone synergistically induce Elovl3 expression in brown adipocytes2007Inngår i: American Journal of Physiology. Endocrinology and Metabolism, ISSN 0193-1849, E-ISSN 1522-1555, Vol. 293, nr 5, s. E1159-68Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The Elovl3 gene, which putatively encodes for a protein involved in the elongation of saturated and monounsaturated fatty acids in the C20–C24 range, is expressed in murine liver, skin, and brown adipose tissue (BAT). In BAT, Elovl3 is dramatically upregulated during tissue activation in response to cold exposure, and functional data imply that ELOVL3 is a critical enzyme for lipid accumulation in brown adipocytes during the early phase of tissue recruitment. The activation of BAT is controlled by sympathetic nerve activity and norepinephrine release. By using primary cultures of brown adipocytes, we show here that the induced Elovl3 gene expression is synergistically regulated by norepinephrine and the peroxisome proliferator-activated receptor (PPAR) γ ligand rosiglitazone. In addition, the potency of rosiglitazone to induce Elovl3 expression was several orders of magnitude higher than for the PPARα and PPARδ ligands WY-14643 and L-165041, respectively. The maximal increase in mRNA level by norepinephrine and rosiglitazone is achieved by induced transcription as well as increased mRNA stability, and the whole process requires novel protein synthesis. We conclude that norepinehrine and PPARγ, despite having different roles in brown adipocyte activation and differentiation, cooperate in expanding the intracellular lipid pool by synergistically stimulating Elovl3 expression.

    Fulltekst (pdf)
    FULLTEXT01
  • 13. Lateef, Dalya M.
    et al.
    Abreu-Vieira, Gustavo
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Xiao, Cuiying
    Reitman, Marc L.
    Regulation of body temperature and brown adipose tissue thermogenesis by bombesin receptor subtype-32014Inngår i: American Journal of Physiology. Endocrinology and Metabolism, ISSN 0193-1849, E-ISSN 1522-1555, Vol. 306, nr 6, s. E681-E687Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Bombesin receptor subtype-3 (BRS-3) regulates energy homeostasis, with Brs3 knockout (Brs3(-/y)) mice being hypometabolic, hypothermic, and hyperphagic and developing obesity. We now report that the reduced body temperature is more readily detected if body temperature is analyzed as a function of physical activity level and light/dark phase. Physical activity level correlated best with body temperature 4 min later. The Brs3(-/y) metabolic phenotype is not due to intrinsically impaired brown adipose tissue function or in the communication of sympathetic signals from the brain to brown adipose tissue, since Brs3(-/y) mice have intact thermogenic responses to stress, acute cold exposure, and beta 3-adrenergic activation, and Brs3(-/y) mice prefer a cooler environment. Treatment with the BRS-3 agonist MK-5046 increased brown adipose tissue temperature and body temperature in wild-type but not Brs3(-/y) mice. Intrahypothalamic infusion of MK5046 increased body temperature. These data indicate that the BRS-3 regulation of body temperature is via a central mechanism, upstream of sympathetic efferents. The reduced body temperature in Brs3(-/y) mice is due to altered regulation of energy homeostasis affecting higher center regulation of body temperature, rather than an intrinsic defect in brown adipose tissue.

  • 14.
    Luijten, Ineke H. N.
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Feldmann, Helena M.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    von Essen, Gabriella
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Cannon, Barbara
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Nedergaard, Jan
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    In the absence of UCP1-mediated diet-induced thermogenesis, obesity is augmented even in the obesity-resistant 129S mouse strain2019Inngår i: American Journal of Physiology. Endocrinology and Metabolism, ISSN 0193-1849, E-ISSN 1522-1555, Vol. 316, nr 5, s. E729-E740Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The attractive tenet that recruitment and activation of brown adipose tissue (BAT) and uncoupling protein 1 (UCP1) could counteract the development of obesity and its comorbidities in humans has been experimentally corroborated mainly by experiments demonstrating that UCP1-ablated mice on a C57B1/6 background (exempt from thermal stress) become more obese when fed a high-fat diet. However, concerns may be raised that this outcome of UCP1 ablation is restricted to this very special inbred and particularly obesity-prone mouse strain. Therefore, we have examined to which degree UCP1 ablation has similar metabolic effects in a mouse strain known to be obesity resistant: the 129S strain. For this, male 129S2/sv or 129SV/Pas mice and corresponding UCP1-knockout mice were fed chow or a high-fat or a cafeteria diet for 4 w.k. The absence of UCP1 augmented obesity (weight gain, body fat mass, %body fat, fat depot size) in high-fat diet- and cafeteria-fed mice, with a similar or lower food intake, indicating that, when present, UCP1 indeed decreases metabolic efficiency. The increased obesity was due to a decrease in energy expenditure. The consumption of a high-fat or cafeteria diet increased total BAT UCP1 protein levels in wild-type mice, and correspondingly. high-fat diet and cafeteria diet-fed mice demonstrated increased norepinephrine-induced oxygen consumption. There was a positive correlation between body fat and total BAT UCP1 protein content. No evidence for diet-induced adrenergic thermogenesis was found in UCP1-ablated mice. Thus, the obesity-reducing effect of UCP1 is not restricted to a particular, and perhaps not representative, mouse strain.

  • 15.
    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 thermogenesis2011Inngår i: American Journal of Physiology. Endocrinology and Metabolism, ISSN 0193-1849, E-ISSN 1522-1555, Vol. 301, nr 6, s. E1108-E1118Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 16.
    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.
    Shabalina, Irina G
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för fysiologi.
    Nedergaard, Jan
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för fysiologi.
    Cannon, Barbara
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för fysiologi.
    Caveolin-1-ablated mice survive in cold by nonshivering thermogenesis despite desensitized adrenergic responsiveness2010Inngår i: American Journal of Physiology. Endocrinology and Metabolism, ISSN 0193-1849, E-ISSN 1522-1555, Vol. 299, nr 3, s. E374-83Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 17. Norgren, Jakob
    et al.
    Sindi, Shireen
    Sandebring-Matton, Anna
    Kåreholt, Ingemar
    Stockholms universitet, Samhällsvetenskapliga fakulteten, Centrum för forskning om äldre och åldrande (ARC), (tills m KI). Jönköping University, Sweden.
    Akenine, Ulrika
    Nordin, Karin
    Rosenborg, Staffan
    Ngandu, Tiia
    Kivipelto, Miia
    Capillary blood tests may overestimate ketosis: triangulation between three different measures of beta-hydroxybutyrate2020Inngår i: American Journal of Physiology. Endocrinology and Metabolism, ISSN 0193-1849, E-ISSN 1522-1555, Vol. 318, nr 2, s. e184-E188Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The ketone body beta-hydroxybutyrate (BHB), assessed by a point-of-care meter in venous whole blood (BHBv), was used as the main outcome in a study on nutritional ketosis in healthy older adults. Two other BHB measures were also used in the study for validation and exploratory purposes, and here we report findings on correlation and agreement between those three methods. Ketosis in the range of 0-1.5 mmol/L was induced in 15 healthy volunteers by intake of medium-chain fatty acids after a 12-h fast. BHBv was assessed at 12 time points for 4 h. The same point-of-care meter was also used to test capillary blood (BHBc) at three time points, and a laboratory test determined total ketones (TK) in plasma (BHBp + acetoacetate) at four time points. A total of 180 cases included simultaneous data on BHBv, BHBc, BHBp, and TK. TK correlated with BHBp (Pearson's r = 0.99), BHBv (r = 0.91), and BHBc (r = 0.91), all P < 0.0001. BHBv and BHBp had good agreement in absolute values. However, the slope between BHBc and BHBv, measured with the same device, was in the range of 0.64-0.78 in different regression models, indicating substantially higher BHB concentrations in capillary versus venous blood. We conclude that all three methods are valid to detect relative changes in ketosis, but our results highlight the importance of method considerations and the possible need to adjust cutoffs, e.g., in the management of ketoacidosis and in the evaluation and comparison of dietary interventions.

  • 18.
    Robertson, Cayleih
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut. McMaster University, Canada.
    Weaver, F. E.
    Nurse, C. A.
    "Turning up the heat": role of neurotrophic batokines in the postnatal maturation and remodeling of brown adipose tissue in deer mice2023Inngår i: American Journal of Physiology. Endocrinology and Metabolism, ISSN 0193-1849, E-ISSN 1522-1555, Vol. 325, nr 1, s. E32-E45Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Activation of brown adipose tissue (BAT) thermogenesis impacts energy balance and must be tightly regulated. Several neurotrophic factors, expressed in BAT of adult laboratory rodents, have been implicated in remodeling the sympathetic neural network to enhance thermogenesis [e.g., nerve growth factor (NGF), neuregulin-4 (NRG4), and S100b]. Here, we compare, to our knowledge, for the first time, the relative roles of three neurotrophic “batokines” in establishing/remodeling innervation during postnatal development and adult cold stress. We used laboratory-reared Peromyscus maniculatus, which rely heavily on BAT-based thermogenesis for survival in the wild, beginning between postnatal days (P) 8 and 10. BAT sympathetic innervation was enhanced from P6 to P10, and exogenous NGF, NRG4, and S100b stimulated neurite outgrowth from P6 sympathetic neurons. Endogenous BAT protein stores and/or gene expression of NRG4, S100b, and calsyntenin-3β (which may regulate S100b secretion) remained high and constant during development. However, endogenous NGF was low and ngf mRNA was undetectable. Conditioned media (CM) from cultured P10 BAT slices stimulated neurite outgrowth from sympathetic neurons in vitro, which was inhibited by antibodies against all three growth factors. P10 CM had significant amounts of secreted NRG4 and S100b protein, but not NGF. By contrast, BAT slices from cold-acclimated adults released significant amounts of all three factors relative to thermoneutral controls. These data suggest that although neurotrophic batokines regulate sympathetic innervation in vivo, their relative contributions differ depending on the life stage. They also provide novel insights into the regulation of BAT remodeling and BAT’s secretory role, both of which are critical to our understanding of mammalian energy homeostasis.

  • 19. van Beek, Sten M. M.
    et al.
    Kalinovich, Anastasia
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Schaart, Gert
    Bengtsson, Tore
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Hoeks, Joris
    Prolonged b(2)-adrenergic agonist treatment improves glucose homeostasis in diet-induced obese UCP1(-/-) mice2021Inngår i: American Journal of Physiology. Endocrinology and Metabolism, ISSN 0193-1849, E-ISSN 1522-1555, Vol. 320, nr 3, s. E619-E628Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Prolonged supplementation with the b2-agonist clenbuterol improves glucose homeostasis in diabetic rodents, likely via b2-adreno-ceptor (b2-AR)-mediated effects in the skeletal muscle and liver. However, since rodents have, in contrast to—especially diabetic—humans, substantial quantities of brown adipose tissue (BAT) and clenbuterol has affinity to b1- and b3-ARs, the contribution of BAT tothese improvements is unclear. Therefore, we investigated clenbuterol-mediated improvements in glucose homeostasis in uncouplingprotein 1-deficient (UCP1/) mice, lacking thermogenic BAT, versus wild-type (WT) mice. Anesthetized WT and UCP1/C57Bl/6 micewere injected with saline or clenbuterol and whole body oxygen consumption was measured. Furthermore, male WT and UCP1/C57Bl/6 mice were subjected to 17-wk of chow feeding, high-fat feeding, or high-fat feeding with clenbuterol treatment betweenweeks 13 and 17. Body composition was measured weekly with MRI. Oral glucose tolerance and insulin tolerance tests were per-formed in week 15 and 17, respectively. Clenbuterol increased oxygen consumption approximately twofold in WT mice. This increasewas blunted in UCP1/mice, indicating clenbuterol-mediated activation of BAT thermogenesis. High-fat feeding induced diabeto-genic phenotypes in both genotypes. However, low-dose clenbuterol treatment for 2 wk significantly reduced fasting blood glucoseby 12.9% in WT and 14.8% in UCP1/mice. Clenbuterol treatment improved glucose and insulin tolerance in both genotypes com-pared with HFD controls and normalized to chow-fed control mice independent of body mass and composition alterations.Clenbuterol improved whole body glucose homeostasis independent of UCP1. Given the low human abundancy of BAT, b2-AR ago-nist treatment provides a potential novel route for glucose disposal in diabetic humans.

  • 20.
    von Essen, Gabriella
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Lindsund, Erik
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Cannon, Barbara
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Nedergaard, Jan
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Adaptive facultative diet-induced thermogenesis in wild-type but not in UCP1-ablated mice2017Inngår i: American Journal of Physiology. Endocrinology and Metabolism, ISSN 0193-1849, E-ISSN 1522-1555, Vol. 313, nr 5, s. E515-E527Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The significance of diet-induced thermogenesis (DIT) for metabolic control is still debated. Although obesogenic diets recruit UCP1 and adrenergically inducible thermogenesis, and although the absence of UCP1 may promote the development of obesity, no actual UCP1-related thermogenesis identifiable as diet-induced thermogenesis has to date been unambiguously demonstrated. Examining mice living at thermoneutrality, we have identified a process of facultative (directly elicited by acute eating), adaptive (magnitude develops over weeks on an obesogenic diet), and fully UCP1-dependent thermogenesis. We found no evidence for UCP1-independent diet-induced thermogenesis. The thermogenesis was proportional to the total amount of UCP1 protein in brown adipose tissue and was not dependent on any contribution of UCP1 in brite/beige adipose tissue, since no UCP1 protein was found there under these conditions. Total UCP1 protein amount developed proportionally to total body fat content. The physiological messenger linking obesity level and acute eating to increased thermogenesis is not known. Thus UCP1-dependent diet-induced thermogenesis limits obesity development during exposure to obesogenic diets but does not prevent obesity as such.

  • 21.
    Waldén, Tomas B.
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut.
    Hansen, Ida R.
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut.
    Timmons, James A.
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut. The Royal Veterinary College, United Kingdom.
    Cannon, Barbara
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut. The Royal Veterinary College, United Kingdom.
    Nedergaard, Jan
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut.
    Recruited vs. nonrecruited molecular signatures of brown, “brite,” and white adipose tissues2012Inngår i: American Journal of Physiology. Endocrinology and Metabolism, ISSN 0193-1849, E-ISSN 1522-1555, Vol. 302, nr 1, s. E19-E31Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Mainly from cell culture studies, a series of genes have been identified that have been suggested to be characteristic of different types of adipocytes. Here we have examined gene expression patterns in nine defined adipose depots: interscapular BAT, cervical BAT, axillary BAT, mediastinic BAT, cardiac WAT, inguinal WAT, retroperitoneal WAT, mesenteric WAT and epididymal WAT. We found that each depot displayed a distinct gene expression fingerprint, but that three major types of depots were identifiable: the brown, the brite and the white. Although differences in gene expression pattern were generally quantitative, some gene markers showed, even in-vivo, remarkable depot specificities: Zic1 for the classical brown adipose tissue depots, Hoxc9 for the brite depots, Hoxc8 for the brite and white in contrast to the brown, and Tcf21 for the white depots. The significance of these gene expression patterns both for understanding the developmental background of the depots and as possible master regulators is discussed.

  • 22.
    Zouhar, Petr
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut. Institute of Physiology CAS, the Czech Republic.
    Rakipovski, Gunaj
    Bokhari, Muhammad Hamza
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Busby, Oliver
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Paulsson, Johan F.
    Conde-Frieboes, Kilian W.
    Fels, Johannes J.
    Raun, Kirsten
    Andersen, Birgitte
    Cannon, Barbara
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Nedergaard, Jan
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    UCP1-independent glucose-lowering effect of leptin in type 1 diabetes: only in conditions of hypoleptinemia2020Inngår i: American Journal of Physiology. Endocrinology and Metabolism, ISSN 0193-1849, E-ISSN 1522-1555, Vol. 318, nr 1, s. E72-E86Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The possibility to use leptin therapeutically for lowering glucose levels in patients with type 1 diabetes has attracted interest. However, earlier animal models of type 1 diabetes are severely catabolic with very low endogenous leptin levels, unlike most patients with diabetes. Here, we aim to test glucose-lowering effects of leptin in novel, more human-like murine models. We examined the glucose-lowering potential of leptin in diabetic models of two types: streptozotocin-treated mice and mice treated with the insulin receptor antagonist S961. To prevent hypoleptinemia, we used combinations of thermoneutral temperature and high-fat feeding. Leptin fully normalized hyperglycemia in standard chow-fed streptozotocin-treated diabetic mice. However, more humanized physiological conditions (high-fat diets or thermoneutral temperatures) that increased adiposity- and thus also leptin level-sin the diabetic mice abrogated the effects of leptin, i.e., the mice developed leptin resistance also in this respect. The glucose-lowering effect of leptin was not dependent on the presence of the uncoupling protein-1 and was not associated with alterations in plasma insulin, insulin-like growth factor 1, food intake or corticosterone but fully correlated with decreased plasma glucagon levels and gluconeogenesis. An important implication of these observations is that the therapeutic potential of leptin as an additional treatment in patients with type 1 diabetes is probably limited. This is because such patients are treated with insulin and do not display low leptin levels. Thus, the potential for a glucose-lowering effect of leptin would already have been attained with standard insulin therapy, and further effects on blood glucose level through additional leptin cannot be anticipated.

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