| 1. |
- Abreu-Vieira, Gustavo, 1987-, et al.
(författare)
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Adrenergically-stimulated blood flow in brown adipose tissue is not dependent on thermogenesis : Regulation of brown adipose tissue blood flow
- 2015
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Ingår i: American Journal of Physiology. Endocrinology and Metabolism. - : American Physiological Society. - 0193-1849 .- 1522-1555. ; 308:9, s. E822-E829
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 2. |
- Boulet, Nathalie, et al.
(författare)
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Thermogenic recruitment of brown and brite/beige adipose tissues is not obligatorily associated with macrophage accretion or attrition
- 2021
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Ingår i: American Journal of Physiology. Endocrinology and Metabolism. - : American Physiological Society. - 0193-1849 .- 1522-1555. ; 320:2, s. E359-E378
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Tidskriftsartikel (refereegranskat)abstract
- 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 β1/β2-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.
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| 3. |
- de Jong, Jasper M. A., et al.
(författare)
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A stringent validation of mouse adipose tissue identity markers
- 2015
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Ingår i: American Journal of Physiology. Endocrinology and Metabolism. - : American Physiological Society. - 0193-1849 .- 1522-1555. ; 308:12, s. E1085-E1105
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 4. |
- de Jong, Jasper M. A., et al.
(författare)
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The β3-adrenergic receptor is dispensable for browning of adipose tissues
- 2017
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Ingår i: American Journal of Physiology. Endocrinology and Metabolism. - : American Physiological Society. - 0193-1849 .- 1522-1555. ; 312:6, s. E508-E518
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 5. |
- Fischer, Alexander W., et al.
(författare)
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Intact innervation is essential for diet-induced recruitment of brown adipose tissue
- 2019
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Ingår i: American Journal of Physiology. Endocrinology and Metabolism. - : American Physiological Society. - 0193-1849 .- 1522-1555. ; 316:3, s. E487-E503
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 6. |
- Fischer, Alexander W., et al.
(författare)
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No insulating effect of obesity
- 2016
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Ingår i: American Journal of Physiology. Endocrinology and Metabolism. - : American Physiological Society. - 0193-1849 .- 1522-1555. ; 311:1, s. e202-e213
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 7. |
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| 8. |
- Fischer, Alexander W., et al.
(författare)
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UCP1 inhibition in Cidea-overexpressing mice is physiologically counteracted by brown adipose tissue hyperrecruitment
- 2017
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Ingår i: American Journal of Physiology. Endocrinology and Metabolism. - : American Physiological Society. - 0193-1849 .- 1522-1555. ; 312:1, s. e72-E87
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 9. |
- Gburcik, Valentina, et al.
(författare)
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An essential role for Tbx15 in the differentiation of brown and "brite" but not white adipocytes
- 2012
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Ingår i: American Journal of Physiology. Endocrinology and Metabolism. - : American Physiological Society. - 0193-1849 .- 1522-1555. ; 303:8, s. e1053-E1060
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 10. |
- Luijten, Ineke H. N., et al.
(författare)
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In the absence of UCP1-mediated diet-induced thermogenesis, obesity is augmented even in the obesity-resistant 129S mouse strain
- 2019
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Ingår i: American Journal of Physiology. Endocrinology and Metabolism. - : American Physiological Society. - 0193-1849 .- 1522-1555. ; 316:5, s. E729-E740
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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