The Experts below are selected from a list of 5139 Experts worldwide ranked by ideXlab platform
J.b. Hansen - One of the best experts on this subject based on the ideXlab platform.
-
restricting glycolysis impairs Brown Adipocyte glucose and oxygen consumption
American Journal of Physiology-endocrinology and Metabolism, 2018Co-Authors: Sally Winther, Bjørn Quistorff, Marie S Isidor, Astrid L Basse, Nina Skjoldborg, Amanda Cheung, J.b. HansenAbstract:During thermogenic activation, Brown Adipocytes take up large amounts of glucose. In addition, cold stimulation leads to an upregulation of glycolytic enzymes. Here we have investigated the importa...
-
Dynamic regulation of genes involved in mitochondrial DNA replication and transcription during mouse Brown fat cell differentiation and recruitment.
PLoS ONE, 2009Co-Authors: Maria Murholm, Giorgio Barbatelli, Karen Dixen, Klaus Qvortrup, Lillian H L Hansen, Ez-zoubir Amri, Lise Madsen, Bjørn Quistorff, J.b. HansenAbstract:BACKGROUND: Brown Adipocytes are specialised in dissipating energy through adaptive thermogenesis, whereas white Adipocytes are specialised in energy storage. These essentially opposite functions are possible for two reasons relating to mitochondria, namely expression of uncoupling protein 1 (UCP1) and a remarkably higher mitochondrial abundance in Brown Adipocytes. METHODOLOGY/PRINCIPAL FINDINGS: Here we report a comprehensive characterisation of gene expression linked to mitochondrial DNA replication, transcription and function during white and Brown fat cell differentiation in vitro as well as in white and Brown fat, Brown adipose tissue fractions and in selected adipose tissues during cold exposure. We find a massive induction of the majority of such genes during Brown Adipocyte differentiation and recruitment, e.g. of the mitochondrial transcription factors A (Tfam) and B2 (Tfb2m), whereas only a subset of the same genes were induced during white adipose conversion. In addition, PR domain containing 16 (PRDM16) was found to be expressed at substantially higher levels in Brown compared to white pre-Adipocytes and Adipocytes. We demonstrate that forced expression of Tfam but not Tfb2m in Brown Adipocyte precursor cells promotes mitochondrial DNA replication, and that silencing of PRDM16 expression during Brown fat cell differentiation blunts mitochondrial biogenesis and expression of Brown fat cell markers. CONCLUSIONS/SIGNIFICANCE: Using both in vitro and in vivo model systems of white and Brown fat cell differentiation, we report a detailed characterisation of gene expression linked to mitochondrial biogenesis and function. We find significant differences in differentiating white and Brown Adipocytes, which might explain the notable increase in mitochondrial content observed during Brown adipose conversion. In addition, our data support a key role of PRDM16 in triggering Brown Adipocyte differentiation, including mitochondrial biogenesis and expression of UCP1.
-
regulatory circuits controlling white versus Brown Adipocyte differentiation
Biochemical Journal, 2006Co-Authors: J.b. Hansen, Karsten KristiansenAbstract:Adipose tissue is a major endocrine organ that exerts a profound influence on whole-body homoeostasis. Two types of adipose tissue exist in mammals: WAT (white adipose tissue) and BAT (Brown adipose tissue). WAT stores energy and is the largest energy reserve in mammals, whereas BAT, expressing UCP1 (uncoupling protein 1), can dissipate energy through adaptive thermogenesis. In rodents, ample evidence supports BAT as an organ counteracting obesity, whereas less is known about the presence and significance of BAT in humans. Despite the different functions of white and Brown Adipocytes, knowledge of factors differentially influencing the formation of white and Brown fat cells is sparse. Here we summarize recent progress in the molecular understanding of white versus Brown Adipocyte differentiation, including novel insights into transcriptional and signal transduction pathways. Since expression of UCP1 is the hallmark of BAT and a key factor determining energy expenditure, we also review conditions associated with enhanced energy expenditure and UCP1 expression in WAT that may provide information on processes involved in Brown Adipocyte differentiation.
-
effects of wnt signaling on Brown Adipocyte differentiation and metabolism mediated by pgc 1α
Molecular and Cellular Biology, 2005Co-Authors: Sona Kang, Karsten Kristiansen, J.b. Hansen, Laszlo Bajnok, Kenneth A Longo, Rasmus Koefoed Petersen, Ormond A MacdougaldAbstract:Activation of canonical Wnt signaling inhibits Brown adipogenesis of cultured cells by impeding induction of PPARgamma and C/EBPalpha. Although enforced expression of these adipogenic transcription factors restores lipid accumulation and expression of FABP4 in Wnt-expressing cells, additional expression of PGC-1alpha is required for activation of uncoupling protein 1 (UCP1). Wnt10b blocks Brown adipose tissue development and expression of UCP1 when expressed from the fatty acid binding protein 4 promoter, even when mice are administered a beta3-agonist. In differentiated Brown Adipocytes, activation of Wnt signaling suppresses expression of UCP1 through repression of PGC-1alpha. Consistent with these in vitro observations, UCP1-Wnt10b transgenic mice, which express Wnt10b in interscapular tissue, lack functional Brown adipose tissue. While interscapular tissue of UCP1-Wnt10b mice lacks expression of PGC-1alpha and UCP1, the presence of unilocular lipid droplets and expression of white Adipocyte genes suggest conversion of Brown adipose tissue to white. Reciprocal expression of Wnt10b with UCP1 and PGC-1alpha in interscapular tissue from cold-challenged or genetically obese mice provides further evidence for regulation of Brown Adipocyte metabolism by Wnt signaling. Taken together, these data suggest that activation of canonical Wnt signaling early in differentiation blocks Brown adipogenesis, whereas activating Wnt signaling in mature Brown Adipocytes stimulates their conversion to white Adipocytes.
-
Novel function of the retinoblastoma protein in fat: regulation of white versus Brown Adipocyte differentiation.
Cell Cycle, 2004Co-Authors: J.b. Hansen, Hein Te Riele, Karsten KristiansenAbstract:The differentiation of white and Brown fat cells is controlled by a similar set of transcription factors, including PPAR? and C/EBP?. However, despite many similarities between the two types of fat cells, they carry out essentially opposite functions in vivo, with white Adipocytes being the major energy store and Brown Adipocytes being potent energy-dissipaters through thermogenesis. Yet, little is known about factors differentially regulating the formation of white and Brown fat cells. Members of the retinoblastoma protein family (pRB, p107, p130) have been implicated in the regulation of Adipocyte differentiation, and expression and phosphorylation of the three retinoblastoma family proteins oscillate in a characteristic manner during differentiation of the white preAdipocyte cell line 3T3-L1. We have recently demonstrated a surprising function of the retinoblastoma protein in the regulation of white versus Brown Adipocyte differentiation in vitro and possibly in vivo. Here we summarize the current know...
Jan Nedergaard - One of the best experts on this subject based on the ideXlab platform.
-
promotion of lipid storage rather than of thermogenic competence by fetal versus newborn calf serum in primary cultures of Brown Adipocytes
Adipocyte, 2018Co-Authors: Jasper M A De Jong, Barbara Cannon, Jan NedergaardAbstract:Much current understanding of Brown Adipocyte development comes from in-vitro cell models. Serum type may affect the behavior of cultured cells and thus conclusions drawn. Here, we investigate effects of serum type (“fetal bovine” versus “newborn calf”) on responses to differentiation inducers (the PPARγ agonist rosiglitazone or the neurotransmitter norepinephrine) in cultured primary Brown Adipocytes. Lipid storage was enhanced by fetal versus newborn serum. However, molecular adipose conversion ( Pparg2 and Fabp4 expression) was not affected by serum type. Rosiglitazone-induced (7-days) expression of thermogenic genes (i.e. Ucp1, Pgc1a, Dio2 and Elovl3 ) was not systematically affected by serum type. However, importantly, acute (2 h) norepinephrine-induced thermogenic gene expression was overall markedly higher (and adipose genes somewhat lower) in cells cultured in newborn serum. Thus, newborn serum promotes thermogenic competence, and the use of fetal serum in Brown Adipocyte cultures (as is often routine) counteracts adequate differentiation. Agents that counteract this inhibition may therefore confoundingly be ascribed genuine thermogenic competence-inducing properties.
-
differential involvement of caveolin 1 in Brown Adipocyte signaling impaired beta3 adrenergic but unaffected lpa pdgf and egf receptor signaling
Biochimica et Biophysica Acta, 2010Co-Authors: Charlotte L Mattsson, Emma R Andersson, Jan NedergaardAbstract:Differential involvement of caveolin-1 in Brown Adipocyte signaling: impaired b3-adrenergic but unaffected LPA, PDGF and EGF receptor
-
PPARalpha does not suppress muscle-associated gene expression in Brown Adipocytes but does influence expression of factors that fingerprint the Brown Adipocyte.
Biochemical and biophysical research communications, 2010Co-Authors: Tomas B. Walden, Natasa Petrovic, Jan NedergaardAbstract:Brown Adipocytes and myocytes develop from a common adipomyocyte precursor. PPARalpha is a nuclear receptor important for lipid and glucose metabolism. It has been suggested that in Brown adipose tissue, PPARalpha represses the expression of muscle-associated genes, in this way potentially acting to determine cell fate in Brown Adipocytes. To further understand the possible role of PPARalpha in these processes, we measured expression of muscle-associated genes in Brown adipose tissue and Brown Adipocytes from PPARalpha-ablated mice, including structural genes (Mylpf, Tpm2, Myl3 and MyHC), regulatory genes (myogenin, Myf5 and MyoD) and a myomir (miR-206). However, in our hands, the expression of these genes was not influenced by the presence or absence of PPARalpha, nor by the PPARalpha activator Wy-14,643. Similarly, the expression of genes common for mature Brown Adipocyte and myocytes (Tbx15, Meox2) were not affected. However, the Brown Adipocyte-specific regulatory genes Zic1, Lhx8 and Prdm16 were affected by PPARalpha. Thus, it would not seem that PPARalpha represses muscle-associated genes, but PPARalpha may still play a role in the regulation of the bifurcation of the adipomyocyte precursor into a Brown Adipocyte or myocyte phenotype.
-
pparγ in the control of Brown Adipocyte differentiation
Biochimica et Biophysica Acta, 2005Co-Authors: Jan Nedergaard, Natasa Petrovic, Eva M Lindgren, Anders Jacobsson, Barbara CannonAbstract:Abstract The effects of fatty acids and retinoic acid (carotene) on Brown adipose tissue differentiation are mediated by activation of the transcription factors PPARγ and PPARα in combination with RXR. There is good support for the idea that activated PPARγ promotes adipogenesis also in Brown adipose tissue. However, the issue is more complex concerning the full differentiation to the Brown Adipocyte phenotype, particularly the expression of the Brown-fat-specific marker UCP1. The effect of norepinephrine on PPARγ gene expression, at least in-vitro, is negative, PPARγ-ablated Brown adipose tissue can express UCP1, and PGC-1α coactivates other transcription factors (including PPARα); thus, the significance of PPARγ for the physiological control of UCP1 gene expression is not settled. However, importantly, the effects of PPAR agonists demonstrate the existence of a pathway for Brown adipose tissue recruitment that is not dependent on chronic adrenergic stimulation and may be active in recruitment conditions such as prenatal and prehibernation recruitment. The ability of chronic PPARγ agonist treatment to promote the occurrence of Brown-fat features in white adipose tissue-like depots implies a role in anti-obesity treatment, but this will only be effective if the extra thermogenic capacity is activated by adrenergic stimulation.
-
retinoblastoma protein functions as a molecular switch determining white versus Brown Adipocyte differentiation
Proceedings of the National Academy of Sciences of the United States of America, 2004Co-Authors: J.b. Hansen, R. K. Petersen, PHILIP HALLENBORG, H. A. Boye, C. Jorgensen, Rita De Matteis, N. Petrovič, S Enerback, Jan Nedergaard, Stefano CintiAbstract:Adipocyte precursor cells give raise to two major cell populations with different physiological roles: white and Brown Adipocytes. Here we demonstrate that the retinoblastoma protein (pRB) regulates white vs. Brown Adipocyte differentiation. Functional inactivation of pRB in wild-type mouse embryo fibroblasts (MEFs) and white preAdipocytes by expression of simian virus 40 large T antigen results in the expression of the Brown fat-specific uncoupling protein 1 (UCP-1) in the adipose state. Retinoblastoma gene-deficient (Rb–/–) MEFs and stem cells, but not the corresponding wild-type cells, differentiate into Adipocytes with a gene expression pattern and mitochondria content resembling Brown adipose tissue. pRB-deficient MEFs exhibit an increased expression of the Forkhead transcription factor Foxc2 and its target gene cAMP-dependent protein kinase regulatory subunit RIα, resulting in increased cAMP sensitivity. Suppression of cAMP-dependent protein kinase activity in Rb–/–MEFs blocked the Brown Adipocyte-like gene expression pattern without affecting differentiation per se. Immunohistochemical studies revealed that pRB is present in the nuclei of white but not Brown Adipocyte precursor cells at a developmental stage where both cell types begin to accumulate lipid and Brown Adipocytes express UCP-1. Furthermore, pRB rapidly undergoes phosphorylation upon cold-induced neodifferentiation and up-regulation of UCP-1 expression in Brown adipose tissue. Finally, down-regulation of pRB expression accompanies transdifferentiation of white into Brown Adipocytes in response to β3-adrenergic receptor agonist treatment. We propose that pRB acts as a molecular switch determining white vs. Brown adipogenesis, suggesting a previously uncharacterized function of this key cell cycle regulator in Adipocyte lineage commitment and differentiation.
Karsten Kristiansen - One of the best experts on this subject based on the ideXlab platform.
-
insulin igf i regulation of necdin and Brown Adipocyte differentiation via creb and foxo1 associated pathways
Endocrinology, 2011Co-Authors: Aaron M Cypess, Karsten Kristiansen, Tim J. Schulz, Tian Lian Huang, Hongbin Zhang, Daniel Espinoza, Terry G Unterman, Yuhua TsengAbstract:Brown adipose tissue plays an important role in obesity, insulin resistance, and diabetes. We have previously shown that the transition from Brown preAdipocytes to mature Adipocytes is mediated in part by insulin receptor substrate (IRS)-1 and the cell cycle regulator protein necdin. In this study, we used pharmacological inhibitors and adenoviral dominant negative constructs to demonstrate that this transition involves IRS-1 activation of Ras and ERK1/2, resulting in phosphorylation of cAMP response element-binding protein (CREB) and suppression of necdin expression. This signaling did not include an elevation of intracellular calcium. A constitutively active form of CREB expressed in IRS-1 knockout cells decreased necdin promoter activity, necdin mRNA, and necdin protein levels, leading to a partial restoration of differentiation. By contrast, forkhead box protein (Fox)O1, which is regulated by the phosphoinositide 3 kinase-Akt pathway, increased necdin promoter activity. Based on reporter gene assays using truncations of the necdin promoter and chromatin immunoprecipitation studies, we demonstrated that CREB and FoxO1 are recruited to the necdin promoter, likely interacting with specific consensus sequences in the proximal region. Based on these results, we propose that insulin/IGF-I act through IRS-1 phosphorylation to stimulate differentiation of Brown preAdipocytes via two complementary pathways: 1) the Ras-ERK1/2 pathway to activate CREB and 2) the phosphoinositide 3 kinase-Akt pathway to deactivate FoxO1. These two pathways combine to decrease necdin levels and permit the clonal expansion and coordinated gene expression necessary to complete Brown Adipocyte differentiation.
-
regulatory circuits controlling white versus Brown Adipocyte differentiation
Biochemical Journal, 2006Co-Authors: J.b. Hansen, Karsten KristiansenAbstract:Adipose tissue is a major endocrine organ that exerts a profound influence on whole-body homoeostasis. Two types of adipose tissue exist in mammals: WAT (white adipose tissue) and BAT (Brown adipose tissue). WAT stores energy and is the largest energy reserve in mammals, whereas BAT, expressing UCP1 (uncoupling protein 1), can dissipate energy through adaptive thermogenesis. In rodents, ample evidence supports BAT as an organ counteracting obesity, whereas less is known about the presence and significance of BAT in humans. Despite the different functions of white and Brown Adipocytes, knowledge of factors differentially influencing the formation of white and Brown fat cells is sparse. Here we summarize recent progress in the molecular understanding of white versus Brown Adipocyte differentiation, including novel insights into transcriptional and signal transduction pathways. Since expression of UCP1 is the hallmark of BAT and a key factor determining energy expenditure, we also review conditions associated with enhanced energy expenditure and UCP1 expression in WAT that may provide information on processes involved in Brown Adipocyte differentiation.
-
effects of wnt signaling on Brown Adipocyte differentiation and metabolism mediated by pgc 1α
Molecular and Cellular Biology, 2005Co-Authors: Sona Kang, Karsten Kristiansen, J.b. Hansen, Laszlo Bajnok, Kenneth A Longo, Rasmus Koefoed Petersen, Ormond A MacdougaldAbstract:Activation of canonical Wnt signaling inhibits Brown adipogenesis of cultured cells by impeding induction of PPARgamma and C/EBPalpha. Although enforced expression of these adipogenic transcription factors restores lipid accumulation and expression of FABP4 in Wnt-expressing cells, additional expression of PGC-1alpha is required for activation of uncoupling protein 1 (UCP1). Wnt10b blocks Brown adipose tissue development and expression of UCP1 when expressed from the fatty acid binding protein 4 promoter, even when mice are administered a beta3-agonist. In differentiated Brown Adipocytes, activation of Wnt signaling suppresses expression of UCP1 through repression of PGC-1alpha. Consistent with these in vitro observations, UCP1-Wnt10b transgenic mice, which express Wnt10b in interscapular tissue, lack functional Brown adipose tissue. While interscapular tissue of UCP1-Wnt10b mice lacks expression of PGC-1alpha and UCP1, the presence of unilocular lipid droplets and expression of white Adipocyte genes suggest conversion of Brown adipose tissue to white. Reciprocal expression of Wnt10b with UCP1 and PGC-1alpha in interscapular tissue from cold-challenged or genetically obese mice provides further evidence for regulation of Brown Adipocyte metabolism by Wnt signaling. Taken together, these data suggest that activation of canonical Wnt signaling early in differentiation blocks Brown adipogenesis, whereas activating Wnt signaling in mature Brown Adipocytes stimulates their conversion to white Adipocytes.
-
Novel function of the retinoblastoma protein in fat: regulation of white versus Brown Adipocyte differentiation.
Cell Cycle, 2004Co-Authors: J.b. Hansen, Hein Te Riele, Karsten KristiansenAbstract:The differentiation of white and Brown fat cells is controlled by a similar set of transcription factors, including PPAR? and C/EBP?. However, despite many similarities between the two types of fat cells, they carry out essentially opposite functions in vivo, with white Adipocytes being the major energy store and Brown Adipocytes being potent energy-dissipaters through thermogenesis. Yet, little is known about factors differentially regulating the formation of white and Brown fat cells. Members of the retinoblastoma protein family (pRB, p107, p130) have been implicated in the regulation of Adipocyte differentiation, and expression and phosphorylation of the three retinoblastoma family proteins oscillate in a characteristic manner during differentiation of the white preAdipocyte cell line 3T3-L1. We have recently demonstrated a surprising function of the retinoblastoma protein in the regulation of white versus Brown Adipocyte differentiation in vitro and possibly in vivo. Here we summarize the current know...
Kyunghan Lee - One of the best experts on this subject based on the ideXlab platform.
-
18F-FDG PET/CT Monitoring of b3 Agonist–Stimulated Brown Adipocyte Recruitment in White Adipose Tissue
2016Co-Authors: Jin Won Park, Kyungho Jung, Jin Hee Lee, Seunghwan Moon, Young Seok Cho, Cung Hoa, Thien Quach, Kyunghan LeeAbstract:There is rising interest in recruitment of Brown Adipocytes into white adipose tissue (WAT) as a means to augment energy expenditure for weight reduction. We thus investigated the potential of 18F-FDG uptake as an imaging biomarker that can monitor the process of WAT Browning.Methods: C57BL/6 mice were treated daily with the β3 ago-nist CL316,243 (5-[(2R)-2-[[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl] amino]propyl]-1,3-benzodioxole-2,2-dicarboxylic acid disodium salt), whereas controls received saline. 18F-FDG small-animal PET/CT was serially performed at 1 h after CL316,243 injection. After sacrifice, interscapular Brown adipose tissue (BAT) and WAT depots were extracted, weighed, and measured for 18F-FDG uptake. Tissues underwent immunostaining, and UCP1 content was quantified by Western blotting. Results: PET/CT showed low 18F-FDG uptake in both BAT and inguinal WAT at baseline. BAT uptake was substantially increased by a single stimulation with CL316,243. Uptake in inguinal WAT was only modestly elevated by the first stimulation uptake but gradually increased to BAT level by prolonged stimulation. Ex vivo measurements recapitulated the PET findings, and measured 18F-FDG uptake in other WAT depots was similar to inguinal WAT. WAT Browning by prolonged stimulation was confirmed by a substan-tial increase in uncoupling protein 1 (UCP1), cytochrome-c oxidase 4 (COX4), and PR domain containing 16 (PRDM16) staining as markers of Brown Adipocytes. UCP1 content, which served as a measure for ex-tent of Browning, was low in baseline inguinal WAT but linearly in-creased over 10 d of CL316,243 injection. Finally, image-based and ex vivo–measured 18F-FDG uptake in inguinal WAT correlated well with UCP1 content.Conclusion: 18F-FDG PET/CT has the capacity to mon-itor Brown Adipocyte recruitment into WAT depots in vivo and may thus be useful for screening the efficacy of strategies to promote WAT Browning. Key Words: white adipose tissue; Brown adipose tissue; 18F-FDG; PET; UCP1; beige cel
-
18f fdg pet ct monitoring of β3 agonist stimulated Brown Adipocyte recruitment in white adipose tissue
The Journal of Nuclear Medicine, 2015Co-Authors: Jin Won Park, Kyungho Jung, Jin Hee Lee, Cung Hoa Thien Quach, Seunghwan Moon, Young Seok Cho, Kyunghan LeeAbstract:There is rising interest in recruitment of Brown Adipocytes into white adipose tissue (WAT) as a means to augment energy expenditure for weight reduction. We thus investigated the potential of 18F-FDG uptake as an imaging biomarker that can monitor the process of WAT Browning. Methods: C57BL/6 mice were treated daily with the β3 agonist CL316,243 (5-[(2R)-2-[[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]propyl]-1,3-benzodioxole-2,2-dicarboxylic acid disodium salt), whereas controls received saline. 18F-FDG small-animal PET/CT was serially performed at 1 h after CL316,243 injection. After sacrifice, interscapular Brown adipose tissue (BAT) and WAT depots were extracted, weighed, and measured for 18F-FDG uptake. Tissues underwent immunostaining, and UCP1 content was quantified by Western blotting. Results: PET/CT showed low 18F-FDG uptake in both BAT and inguinal WAT at baseline. BAT uptake was substantially increased by a single stimulation with CL316,243. Uptake in inguinal WAT was only modestly elevated by the first stimulation uptake but gradually increased to BAT level by prolonged stimulation. Ex vivo measurements recapitulated the PET findings, and measured 18F-FDG uptake in other WAT depots was similar to inguinal WAT. WAT Browning by prolonged stimulation was confirmed by a substantial increase in uncoupling protein 1 (UCP1), cytochrome-c oxidase 4 (COX4), and PR domain containing 16 (PRDM16) staining as markers of Brown Adipocytes. UCP1 content, which served as a measure for extent of Browning, was low in baseline inguinal WAT but linearly increased over 10 d of CL316,243 injection. Finally, image-based and ex vivo–measured 18F-FDG uptake in inguinal WAT correlated well with UCP1 content. Conclusion:18F-FDG PET/CT has the capacity to monitor Brown Adipocyte recruitment into WAT depots in vivo and may thus be useful for screening the efficacy of strategies to promote WAT Browning.
-
18f fdg pet ct monitoring of β3 agonist stimulated Brown Adipocyte recruitment in white adipose tissue
The Journal of Nuclear Medicine, 2015Co-Authors: Jin Won Park, Kyungho Jung, Jin Hee Lee, Cung Hoa Thien Quach, Seunghwan Moon, Young Seok Cho, Kyunghan LeeAbstract:UNLABELLED There is rising interest in recruitment of Brown Adipocytes into white adipose tissue (WAT) as a means to augment energy expenditure for weight reduction. We thus investigated the potential of (18)F-FDG uptake as an imaging biomarker that can monitor the process of WAT Browning. METHODS C57BL/6 mice were treated daily with the β3 agonist CL316,243 (5-[(2R)-2-[[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]propyl]-1,3-benzodioxole-2,2-dicarboxylic acid disodium salt), whereas controls received saline. (18)F-FDG small-animal PET/CT was serially performed at 1 h after CL316,243 injection. After sacrifice, interscapular Brown adipose tissue (BAT) and WAT depots were extracted, weighed, and measured for (18)F-FDG uptake. Tissues underwent immunostaining, and UCP1 content was quantified by Western blotting. RESULTS PET/CT showed low (18)F-FDG uptake in both BAT and inguinal WAT at baseline. BAT uptake was substantially increased by a single stimulation with CL316,243. Uptake in inguinal WAT was only modestly elevated by the first stimulation uptake but gradually increased to BAT level by prolonged stimulation. Ex vivo measurements recapitulated the PET findings, and measured (18)F-FDG uptake in other WAT depots was similar to inguinal WAT. WAT Browning by prolonged stimulation was confirmed by a substantial increase in uncoupling protein 1 (UCP1), cytochrome-c oxidase 4 (COX4), and PR domain containing 16 (PRDM16) staining as markers of Brown Adipocytes. UCP1 content, which served as a measure for extent of Browning, was low in baseline inguinal WAT but linearly increased over 10 d of CL316,243 injection. Finally, image-based and ex vivo-measured (18)F-FDG uptake in inguinal WAT correlated well with UCP1 content. CONCLUSION (18)F-FDG PET/CT has the capacity to monitor Brown Adipocyte recruitment into WAT depots in vivo and may thus be useful for screening the efficacy of strategies to promote WAT Browning.
Stefano Cinti - One of the best experts on this subject based on the ideXlab platform.
-
retinoblastoma protein functions as a molecular switch determining white versus Brown Adipocyte differentiation
Proceedings of the National Academy of Sciences of the United States of America, 2004Co-Authors: J.b. Hansen, R. K. Petersen, PHILIP HALLENBORG, H. A. Boye, C. Jorgensen, Rita De Matteis, N. Petrovič, S Enerback, Jan Nedergaard, Stefano CintiAbstract:Adipocyte precursor cells give raise to two major cell populations with different physiological roles: white and Brown Adipocytes. Here we demonstrate that the retinoblastoma protein (pRB) regulates white vs. Brown Adipocyte differentiation. Functional inactivation of pRB in wild-type mouse embryo fibroblasts (MEFs) and white preAdipocytes by expression of simian virus 40 large T antigen results in the expression of the Brown fat-specific uncoupling protein 1 (UCP-1) in the adipose state. Retinoblastoma gene-deficient (Rb–/–) MEFs and stem cells, but not the corresponding wild-type cells, differentiate into Adipocytes with a gene expression pattern and mitochondria content resembling Brown adipose tissue. pRB-deficient MEFs exhibit an increased expression of the Forkhead transcription factor Foxc2 and its target gene cAMP-dependent protein kinase regulatory subunit RIα, resulting in increased cAMP sensitivity. Suppression of cAMP-dependent protein kinase activity in Rb–/–MEFs blocked the Brown Adipocyte-like gene expression pattern without affecting differentiation per se. Immunohistochemical studies revealed that pRB is present in the nuclei of white but not Brown Adipocyte precursor cells at a developmental stage where both cell types begin to accumulate lipid and Brown Adipocytes express UCP-1. Furthermore, pRB rapidly undergoes phosphorylation upon cold-induced neodifferentiation and up-regulation of UCP-1 expression in Brown adipose tissue. Finally, down-regulation of pRB expression accompanies transdifferentiation of white into Brown Adipocytes in response to β3-adrenergic receptor agonist treatment. We propose that pRB acts as a molecular switch determining white vs. Brown adipogenesis, suggesting a previously uncharacterized function of this key cell cycle regulator in Adipocyte lineage commitment and differentiation.
-
Retinoblastoma protein functions as a molecular switch determining white versus Brown Adipocyte differentiation
Proceedings of the National Academy of Sciences, 2004Co-Authors: J.b. Hansen, R. K. Petersen, PHILIP HALLENBORG, H. A. Boye, C. Jorgensen, Rita De Matteis, N. Petrovič, S Enerback, Jan Nedergaard, Stefano CintiAbstract:Adipocyte precursor cells give raise to two major cell populations with different physiological roles: white and Brown Adipocytes. Here we demonstrate that the retinoblastoma protein (pRB) regulates white vs. Brown Adipocyte differentiation. Functional inactivation of pRB in wild-type mouse embryo fibroblasts (MEFs) and white preAdipocytes by expression of simian virus 40 large T antigen results in the expression of the Brown fat-specific uncoupling protein 1 (UCP-1) in the adipose state. Retinoblastoma gene-deficient (Rb-/-) MEFs and stem cells, but not the corresponding wild-type cells, differentiate into Adipocytes with a gene expression pattern and mitochondria content resembling Brown adipose tissue. pRB-deficient MEFs exhibit an increased expression of the Forkhead transcription factor Foxc2 and its target gene cAMP-dependent protein kinase regulatory subunit RIalpha, resulting in increased cAMP sensitivity. Suppression of cAMP-dependent protein kinase activity in Rb(-/-)MEFs blocked the Brown Adipocyte-like gene expression pattern without affecting differentiation per se. Immunohistochemical studies revealed that pRB is present in the nuclei of white but not Brown Adipocyte precursor cells at a developmental stage where both cell types begin to accumulate lipid and Brown Adipocytes express UCP-1. Furthermore, pRB rapidly undergoes phosphorylation upon cold-induced neodifferentiation and up-regulation of UCP-1 expression in Brown adipose tissue. Finally, down-regulation of pRB expression accompanies transdifferentiation of white into Brown Adipocytes in response to beta3-adrenergic receptor agonist treatment. We propose that pRB acts as a molecular switch determining white vs. Brown adipogenesis, suggesting a previously uncharacterized function of this key cell cycle regulator in Adipocyte lineage commitment and differentiation.
-
Tumor necrosis factor α mediates apoptosis of Brown Adipocytes and defective Brown Adipocyte function in obesity
Proceedings of the National Academy of Sciences of the United States of America, 2000Co-Authors: Enzo Nisoli, Stefano Cinti, L. Briscini, Antonio Giordano, Cristina Tonello, S M Wiesbrock, K T Uysal, Michele O. Carruba, Gökhan S. HotamisligilAbstract:Severe quantitative and qualitative Brown Adipocyte defects are common in obesity. To investigate whether aberrant expression of tumor necrosis factor α (TNF-α) in obesity is involved in functional Brown fat atrophy, we have studied genetically obese (ob/ob) mice with targeted null mutations in the genes encoding the two TNF receptors. The absence of both TNF receptors or p55 receptor alone resulted in a significant reduction in Brown Adipocyte apoptosis and an increase in β3-adrenoreceptor and uncoupling protein-1 expression in obese mice. Increased numbers of multilocular functionally active Brown Adipocytes, and improved thermoregulation was also observed in obese animals lacking TNF-α function. These results indicate that TNF-α plays an important role in multiple aspects of Brown adipose tissue biology and mediates the abnormalities that occur at this site in obesity.
