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Publications (10 of 34) Show all publications
Galvão Valdivia, L. F., Castro, É., dos Santos Eichler, R. A., Moreno, M. F., de Sousa, É., Rodrigues Jardim, G. F., . . . Reckziegel, P. (2023). Cold acclimation and pioglitazone combined increase thermogenic capacity of brown and white adipose tissues but this does not translate into higher energy expenditure in mice. American Journal of Physiology. Endocrinology and Metabolism, 324(4), E358-E373
Open this publication in new window or tab >>Cold acclimation and pioglitazone combined increase thermogenic capacity of brown and white adipose tissues but this does not translate into higher energy expenditure in mice
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2023 (English)In: American Journal of Physiology. Endocrinology and Metabolism, ISSN 0193-1849, E-ISSN 1522-1555, Vol. 324, no 4, p. E358-E373Article in journal (Refereed) Published
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.

Keywords
adipogenesis, browning, pioglitazone, thermogenesis, UCP1
National Category
Physiology Cell and Molecular Biology
Identifiers
urn:nbn:se:su:diva-216979 (URN)10.1152/ajpendo.00217.2022 (DOI)000974585600001 ()36856189 (PubMedID)2-s2.0-85152170431 (Scopus ID)
Available from: 2023-05-09 Created: 2023-05-09 Last updated: 2023-05-09Bibliographically approved
Davies, V. S., Lindsund, E., Petrovic, N., Cannon, B. & Nedergaard, J. (2023). Repeated short excursions from thermoneutrality suffice to restructure brown adipose tissue. Biochimie, 210, 40-49
Open this publication in new window or tab >>Repeated short excursions from thermoneutrality suffice to restructure brown adipose tissue
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2023 (English)In: Biochimie, ISSN 0300-9084, E-ISSN 1638-6183, Vol. 210, p. 40-49Article in journal (Refereed) Published
Abstract [en]

Given the presence of brown adipose tissue in adult humans, an important issue is whether human brown adipose tissue is recruitable. Cold exposure is the canonical recruitment treatment; however, in experimental animals (mice), recruitment of brown adipose tissue is normally induced by placing the mice in constant cold, a procedure not feasible in humans. For possible translational applications, we have therefore investigated whether shorter daily excursions from thermoneutrality would suffice to qualitatively and quantitatively induce recruitment in mice. Mice, housed at thermoneutrality (30 °C) to mimic human conditions, were transferred every day for 4 weeks to cool conditions (18 °C), for 0, 15, 30, 120 and 420 min (or placed constantly in 18 °C). On the examination day, the mice were not exposed to cold. Very short daily exposures (≤30 minutes) were sufficient to induce structural changes in the form of higher protein density in brown adipose tissue, changes that may affect the identification of the tissue in e.g. computer tomography and other scan studies. To estimate thermogenic capacity, UCP1 protein levels were followed. No UCP1 protein was detectable in inguinal white adipose tissue. In the interscapular brown adipose tissue, a remarkable two-phase reaction was seen. Very short daily exposures (≤30 minutes) were sufficient to induce a significant increase in total UCP1 levels. For attainment of full cold acclimation, the mice had, however, to remain exposed to the cold. The studies indicate that marked alterations in brown adipose tissue composition can be induced in mammals through relatively modest stimulation events.

National Category
Medical Bioscience
Identifiers
urn:nbn:se:su:diva-214074 (URN)10.1016/j.biochi.2023.01.006 (DOI)36657658 (PubMedID)2-s2.0-85148701823 (Scopus ID)
Available from: 2023-01-23 Created: 2023-01-23 Last updated: 2023-10-12Bibliographically approved
Otton, R., Petrovic, N., Cannon, B. & Nedergaard, J. (2021). On the Validity of Adipogenic Cell Lines as Model Systems for Browning Processes: In Authentic Brown, Brite/Beige, and White Preadipocytes, There is No Cell-Autonomous Thermogenic Recruitment by Green Tea Compounds. Frontiers in Nutrition, 8, Article ID 715859.
Open this publication in new window or tab >>On the Validity of Adipogenic Cell Lines as Model Systems for Browning Processes: In Authentic Brown, Brite/Beige, and White Preadipocytes, There is No Cell-Autonomous Thermogenic Recruitment by Green Tea Compounds
2021 (English)In: Frontiers in Nutrition, E-ISSN 2296-861X, Vol. 8, article id 715859Article in journal (Refereed) Published
Abstract [en]

The potential ability of nutritional compounds to induce or enhance the browning of adipocytes has attracted large interest as a workable means of combatting the obesity epidemic. Green tea compounds are discussed as such inducers of an enhanced thermogenic capacity and activity. However, the cell-autonomous effects of green tea compounds on adipocytes have until now only been demonstrated in adipogenic cell lines (3T3-L1 and 3T3-F442A), i.e., cells of undefined tissue lineage. In this study, we examine the ability of green tea compounds to cell-autonomously induce thermogenic recruitment in authentic brown and brite/beige adipocytes in vitro. In primary brown adipocytes, the green tea compounds suppressed basal UCP1 gene expression, and there was no positive interaction between the compounds and adrenergic stimulation. In white adipocytes, green tea compounds decreased both basal and norepinephrine-induced UCP1 mRNA levels, and this was associated with the suppression of cell differentiation, indicated by reduced lipogenic gene expression and lipid accumulation. A lack of interaction between rosiglitazone and green tea compounds suggests that the green tea compounds do not directly interact with the PPARγ pathway. We conclude that there is a negative effect of the green tea compounds on basal UCP1 gene expression, in both brown and white primary adipocytes, in contrast to the positive effects earlier reported from studies in adipogenic cell lines. We posit that the epigenetic status of the adipogenic cell lines is fundamentally different from that of genuine brown and white adipocytes, reflected, e.g., in several-thousand-fold differences in UCP1 gene expression levels. Thus, results obtained with adipogenic cell lines cannot unreservedly be extrapolated as being relevant for authentic effects in brown and white adipocytes. We suggest that this conclusion can be of general concern for studies attempting to establish physiologically relevant cell-autonomous effects.

Keywords
thermogenesis, adipogenesis, polyphenols, PPAR gamma, green tea (Camellia sinensis L.)
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:su:diva-198385 (URN)10.3389/fnut.2021.715859 (DOI)000693058400001 ()34485365 (PubMedID)
Available from: 2021-11-12 Created: 2021-11-12 Last updated: 2021-11-12Bibliographically approved
Cannon, B., de Jong, J. M. A., Fischer, A. W., Nedergaard, J. & Petrovic, N. (2020). Human brown adipose tissue: Classical brown rather than brite/beige?. Experimental Physiology, 105(8), 1191-1200
Open this publication in new window or tab >>Human brown adipose tissue: Classical brown rather than brite/beige?
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2020 (English)In: Experimental Physiology, ISSN 0958-0670, E-ISSN 1469-445X, Vol. 105, no 8, p. 1191-1200Article in journal (Refereed) Published
Abstract [en]

New Findings What is the topic of this review? It has been suggested that human brown adipose tissue (BAT) is more similar to the brite/beige adipose tissue of mice than to classical BAT of mice. The basis of this is discussed in relationship to the physiological conditions of standard experimental mice.

Keywords
beige fat, brown fat, thermoneutrality
National Category
Biological Sciences Cell and Molecular Biology
Identifiers
urn:nbn:se:su:diva-182885 (URN)10.1113/EP087875 (DOI)000536138300001 ()32378255 (PubMedID)
Available from: 2020-08-09 Created: 2020-08-09 Last updated: 2022-03-23Bibliographically approved
Fischer, A. W., de Jong, J. M. A., Sass, F., Schlein, C., Heeren, J. & Petrovic, N. (2020). Thermoneutrality-Induced Macrophage Accumulation in Brown Adipose Tissue Does Not Impair the Tissue's Competence for Cold-Induced Thermogenic Recruitment. Frontiers in Endocrinology, 11, Article ID 568682.
Open this publication in new window or tab >>Thermoneutrality-Induced Macrophage Accumulation in Brown Adipose Tissue Does Not Impair the Tissue's Competence for Cold-Induced Thermogenic Recruitment
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2020 (English)In: Frontiers in Endocrinology, E-ISSN 1664-2392, Vol. 11, article id 568682Article in journal (Refereed) Published
Abstract [en]

Brown adipose tissue from mice living under conditions approaching human thermal and nutritional conditions (prolonged exposure to thermoneutral temperature and to an energy-rich (high-fat, high-sugar) diet) - referred to as physiologically humanized mice, displays morphological and molecular characteristics significantly different from those observed in young, chow-fed mice maintained at room temperature - referred to as standard mice. Here, we further examined brown fat from physiologically humanized and standard mice, as well as from mice exposed to thermoneutrality for a long time but not to an energy-rich diet - referred to here as long-term thermoneutral mice. Global transcriptome analysis of brown fat revealed that genes that were the most upregulated in brown fat of thermoneutral mice (both physiologically humanized and long-term thermoneutral) were those related to inflammatory processes, including genes expressed selectively in macrophages. Cellular and molecular analyses confirmed that brown fat from thermoneutral mice was heavily infiltrated by macrophages, predominantly organized into crown-like structures. However, despite this, the brown fat of thermoneutral mice retained full competence to attain the greatest possible recruitment state and became macrophage-depleted during the process of cold acclimation. Thus, profound macrophage accumulation does not influence the thermogenic recruitment competence of brown fat.

Keywords
brown fat, thermogenic capacity, UCP1, macrophages, thermoneutrality
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:su:diva-188202 (URN)10.3389/fendo.2020.568682 (DOI)000588782900001 ()33193086 (PubMedID)
Available from: 2020-12-29 Created: 2020-12-29 Last updated: 2024-01-17Bibliographically approved
Jespersen, N. Z., Feizi, A., Andersen, E. S., Heywood, S., Hattel, H. B., Daugaard, S., . . . Scheele, C. (2019). Heterogeneity in the perirenal region of humans suggests presence of dormant brown adipose tissue that contains brown fat precursor cells. Molecular Metabolism, 24, 30-43
Open this publication in new window or tab >>Heterogeneity in the perirenal region of humans suggests presence of dormant brown adipose tissue that contains brown fat precursor cells
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2019 (English)In: Molecular Metabolism, ISSN 2212-8778, Vol. 24, p. 30-43Article in journal (Refereed) Published
Abstract [en]

Objective:

Increasing the amounts of functionally competent brown adipose tissue (BAT) in adult humans has the potential to restore dysfunctional metabolism and counteract obesity. In this study, we aimed to characterize the human perirenal fat depot, and we hypothesized that there would be regional, within-depot differences in the adipose signature depending on local sympathetic activity.

Methods:

We characterized fat specimens from four different perirenal regions of adult kidney donors, through a combination of qPCR mapping, immunohistochemical staining, RNA-sequencing, and pre-adipocyte isolation. Candidate gene signatures, separated by adipocyte morphology, were recapitulated in a murine model of unilocular brown fat induced by thermoneutrality and high fat diet.

Results:

We identified widespread amounts of dormant brown adipose tissue throughout the perirenal depot, which was contrasted by multilocular BAT, primarily found near the adrenal gland. Dormant BAT was characterized by a unilocular morphology and a distinct gene expression profile, which partly overlapped with that of subcutaneous white adipose tissue (WAT). Brown fat precursor cells, which differentiated into functional brown adipocytes were present in the entire perirenal fat depot, regardless of state. We identified SPARC as a candidate adipokine contributing to a dormant BAT state, and CLSTN3 as a novel marker for multilocular BAT.

Conclusions:

We propose that perirenal adipose tissue in adult humans consists mainly of dormant BAT and provide a data set for future research on factors which can reactivate dormant BAT into active BAT, a potential strategy for combatting obesity and metabolic disease.

Keywords
Perirenal adipose tissue, Brown fat precursor cells, Human brown fat, Sympathetic activation, Dormant brown fat
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:su:diva-170132 (URN)10.1016/j.molmet.2019.03.005 (DOI)000468472300003 ()31079959 (PubMedID)
Available from: 2019-06-27 Created: 2019-06-27 Last updated: 2022-03-23Bibliographically approved
de Jong, J. M. A., Sun, W., Pires, N. D., Frontini, A., Balaz, M., Jespersen, N. Z., . . . Petrovic, N. (2019). Human brown adipose tissue is phenocopied by classical brown adipose tissue in physiologically humanized mice. Nature Metabolism, 1(8), 830-843
Open this publication in new window or tab >>Human brown adipose tissue is phenocopied by classical brown adipose tissue in physiologically humanized mice
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2019 (English)In: Nature Metabolism, E-ISSN 2522-5812, Vol. 1, no 8, p. 830-843Article in journal (Refereed) Published
Abstract [en]

Human and rodent brown adipose tissues (BAT) appear morphologically and molecularly different. Here we compare human BAT with both classical brown and brite/beige adipose tissues of 'physiologically humanized' mice: middle-aged mice living under conditions approaching human thermal and nutritional conditions, that is, prolonged exposure to thermoneutral temperature (approximately 30 degrees C) and to an energy-rich (high-fat, high-sugar) diet. We find that the morphological, cellular and molecular characteristics (both marker and adipose-selective gene expression) of classical brown fat, but not of brite/beige fat, of these physiologically humanized mice are notably similar to human BAT. We also demonstrate, both in silico and experimentally, that in physiologically humanized mice only classical BAT possesses a high thermogenic potential. These observations suggest that classical rodent BAT is the tissue of choice for translational studies aimed at recruiting human BAT to counteract the development of obesity and its comorbidities.

National Category
Cell Biology Cell and Molecular Biology Physiology
Identifiers
urn:nbn:se:su:diva-177813 (URN)10.1038/s42255-019-0101-4 (DOI)000500745300010 ()
Available from: 2020-01-09 Created: 2020-01-09 Last updated: 2022-02-28Bibliographically approved
Fischer, K., Ruiz, H. H., Jhun, K., Finan, B., Oberlin, D. J., van der Heide, V., . . . Buettner, C. (2017). Alternatively activated macrophages do not synthesize catecholamines or contribute to adipose tissue adaptive thermogenesis. Nature Medicine, 23(5), 623-630
Open this publication in new window or tab >>Alternatively activated macrophages do not synthesize catecholamines or contribute to adipose tissue adaptive thermogenesis
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2017 (English)In: Nature Medicine, ISSN 1078-8956, E-ISSN 1546-170X, Vol. 23, no 5, p. 623-630Article in journal (Refereed) Published
Abstract [en]

Adaptive thermogenesis is the process of heat generation in response to cold stimulation. It is under the control of the sympathetic nervous system, whose chief effector is the catecholamine norepinephrine (NE). NE enhances thermogenesis through beta 3-adrenergic receptors to activate brown adipose tissue and by 'browning' white adipose tissue. Recent studies have reported that alternative activation of macrophages in response to interleukin (IL)-4 stimulation induces the expression of tyrosine hydroxylase (TH), a key enzyme in the catecholamine synthesis pathway, and that this activation provides an alternative source of locally produced catecholamines during the thermogenic process. Here we report that the deletion of Th in hematopoietic cells of adult mice neither alters energy expenditure upon cold exposure nor reduces browning in inguinal adipose tissue. Bone marrow-derived macrophages did not release NE in response to stimulation with IL-4, and conditioned media from IL-4-stimulated macrophages failed to induce expression of thermogenic genes, such as uncoupling protein 1 (Ucp1), in adipocytes cultured with the conditioned media. Furthermore, chronic treatment with IL-4 failed to increase energy expenditure in wild-type, Ucp1(-/-) and interleukin-4 receptor-alpha double-negative (Il4ra(-/-)) mice. In agreement with these findings, adipose-tissue-resident macrophages did not express TH. Thus, we conclude that alternatively activated macrophages do not synthesize relevant amounts of catecholamines, and hence, are not likely to have a direct role in adipocyte metabolism or adaptive thermogenesis.

National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:su:diva-143404 (URN)10.1038/nm.4316 (DOI)000400650700017 ()28414329 (PubMedID)
Available from: 2017-05-29 Created: 2017-05-29 Last updated: 2022-02-28Bibliographically approved
de Jong, J. M. A., Wouters, R. T. F., Boulet, N., Cannon, B., Nedergaard, J. & Petrovic, N. (2017). The β3-adrenergic receptor is dispensable for browning of adipose tissues. American Journal of Physiology. Endocrinology and Metabolism, 312(6), E508-E518
Open this publication in new window or tab >>The β3-adrenergic receptor is dispensable for browning of adipose tissues
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2017 (English)In: American Journal of Physiology. Endocrinology and Metabolism, ISSN 0193-1849, E-ISSN 1522-1555, Vol. 312, no 6, p. E508-E518Article in journal (Refereed) Published
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.

Keywords
β3-adrenergic receptor, adipose browning, brown adipocytes, brite/beige adipocytes, UCP
National Category
Cell Biology
Research subject
Physiology
Identifiers
urn:nbn:se:su:diva-140882 (URN)10.1152/ajpendo.00437.2016 (DOI)000404391300005 ()28223294 (PubMedID)
Available from: 2017-03-21 Created: 2017-03-21 Last updated: 2022-02-28Bibliographically approved
Fischer, A. W., Shabalina, I. G., Mattsson, C. L., Abreu-Vieira, G., Cannon, B., Nedergaard, J. & Petrovic, N. (2017). UCP1 inhibition in Cidea-overexpressing mice is physiologically counteracted by brown adipose tissue hyperrecruitment. American Journal of Physiology. Endocrinology and Metabolism, 312(1), e72-E87
Open this publication in new window or tab >>UCP1 inhibition in Cidea-overexpressing mice is physiologically counteracted by brown adipose tissue hyperrecruitment
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2017 (English)In: American Journal of Physiology. Endocrinology and Metabolism, ISSN 0193-1849, E-ISSN 1522-1555, Vol. 312, no 1, p. e72-E87Article in journal (Refereed) Published
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.

Keywords
cell death-inducing DNA fragmentation factor alpha-like effector A, uncoupling protein 1, nonshivering thermogenesis, brown adipose tissue, brite adipose tissue, beige adipose tissue
National Category
Cell and Molecular Biology Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:su:diva-141290 (URN)10.1152/ajpendo.00284.2016 (DOI)000393898700008 ()27923808 (PubMedID)
Available from: 2017-04-04 Created: 2017-04-04 Last updated: 2022-02-28Bibliographically approved
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0002-4435-9651

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