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Saverio Cinti - One of the best experts on this subject based on the ideXlab platform.
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white brown and pink Adipocytes the extraordinary plasticity of the adipose organ
European Journal of Endocrinology, 2014Co-Authors: Antonio Giordano, Andrea Frontini, Arianna Smorlesi, Giorgio Barbatelli, Saverio CintiAbstract:In mammals, Adipocytes are lipid-laden cells making up the parenchyma of the multi-depot adipose organ. White Adipocytes store lipids for release as free fatty acids during fasting periods; brown Adipocytes burn glucose and lipids to maintain thermal homeostasis. A third type of Adipocyte, the pink Adipocyte, has recently been characterised in mouse subcutaneous fat depots during pregnancy and lactation. Pink Adipocytes are mammary gland alveolar epithelial cells whose role is to produce and secrete milk. Emerging evidence suggests that they derive from the transdifferentiation of subcutaneous white Adipocytes. The functional response of the adipose organ to a range of metabolic and environmental challenges highlights its extraordinary plasticity. Cold exposure induces an increase in the 'brown' component of the organ to meet the increased thermal demand; in states of positive energy balance, the 'white' component expands to store excess nutrients; finally, the 'pink' component develops in subcutaneous depots during pregnancy to ensure litter feeding. At the cell level, plasticity is provided not only by stem cell proliferation and differentiation but also, distinctively, by direct transdifferentiation of fully differentiated Adipocytes by the stimuli that induce genetic expression reprogramming and through it a change in phenotype and, consequently function. A greater understanding of Adipocyte transdifferentiation mechanisms would have the potential to shed light on their biology as well as inspire novel therapeutic strategies against metabolic syndrome (browning) and breast cancer (pinking).
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the adipose organ of obesity prone c57bl 6j mice is composed of mixed white and brown Adipocytes
Journal of Lipid Research, 2012Co-Authors: Alessandra Vitali, Incoronata Murano, Maria Cristina Zingaretti, Andrea Frontini, Daniel Ricquier, Saverio CintiAbstract:White and brown Adipocytes are believed to occupy different sites in the body. We studied the anatomical features and quantitative histology of the fat depots in obesity and type 2 diabetes-prone C57BL/6J mice acclimated to warm or cold temperatures. Most of the fat tissue was contained in depots with discrete anatomical features, and most depots contained both white and brown Adipocytes. Quantitative analysis showed that cold acclimation induced an increase in brown Adipocytes and an almost equal reduction in white Adipocytes; however, there were no significant differences in total Adipocyte count or any signs of apoptosis or mitosis, in line with the hypothesis of the direct transformation of white into brown Adipocytes. The brown Adipocyte increase was accompanied by enhanced density of noradrenergic parenchymal nerve fibers, with a significant correlation between the density of these fibers and the number of brown Adipocytes. Comparison with data from obesity-resistant Sv129 mice disclosed a significantly different brown Adipocyte content in C57BL/6J mice, suggesting that this feature could underpin the propensity of the latter strain to develop obesity. However, the greater C57BL/6J browning capacity can hopefully be harnessed to curb obesity and type 2 diabetes in patients with constitutively low amounts of brown adipose tissue.
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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: Jacob B Hansen, R. K. Petersen, PHILIP HALLENBORG, H. A. Boye, C. Jorgensen, Rita De Matteis, N. Petrovič, S Enerback, Jan Nedergaard, Saverio 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.
Jacob B Hansen - One of the best experts on this subject based on the ideXlab platform.
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mct1 and mct4 expression and lactate flux activity increase during white and brown adipogenesis and impact Adipocyte metabolism
Scientific Reports, 2017Co-Authors: Charlotte Petersen, Lasse K Markussen, Marie S Isidor, Elise S Andersen, Mette D Nielsen, Astrid L Basse, B Viuff, Ian Henry Lambert, Jacob B Hansen, Stine F PedersenAbstract:Adipose tissue takes up glucose and releases lactate, thereby contributing significantly to systemic glucose and lactate homeostasis. This implies the necessity of upregulation of net acid and lactate flux capacity during Adipocyte differentiation and function. However, the regulation of lactate- and acid/base transporters in Adipocytes is poorly understood. Here, we tested the hypothesis that Adipocyte thermogenesis, browning and differentiation are associated with an upregulation of plasma membrane lactate and acid/base transport capacity that in turn is important for Adipocyte metabolism. The mRNA and protein levels of the lactate-H+ transporter MCT1 and the Na+,HCO3- cotransporter NBCe1 were upregulated in mouse interscapular brown and inguinal white adipose tissue upon cold induction of thermogenesis and browning. MCT1, MCT4, and NBCe1 were furthermore strongly upregulated at the mRNA and protein level upon differentiation of cultured pre-Adipocytes. Adipocyte differentiation was accompanied by increased plasma membrane lactate flux capacity, which was reduced by MCT inhibition and by MCT1 knockdown. Finally, in differentiated brown Adipocytes, glycolysis (assessed as ECAR), and after noradrenergic stimulation also oxidative metabolism (OCR), was decreased by MCT inhibition. We suggest that upregulation of MCT1- and MCT4-mediated lactate flux capacity and NBCe1-mediated HCO3-/pH homeostasis are important for the physiological function of mature Adipocytes.
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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: Jacob B Hansen, R. K. Petersen, PHILIP HALLENBORG, H. A. Boye, C. Jorgensen, Rita De Matteis, N. Petrovič, S Enerback, Jan Nedergaard, Saverio 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.
Mengle Shao - One of the best experts on this subject based on the ideXlab platform.
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CM-Zfp423 Maintains White Adipocyte Identity through Suppression of the Beige Cell Thermogenic Gene Program.pdf
2019Co-Authors: Mengle Shao, Jeff Ishibashi, Christine M. Kusminski, Chelsea Hepler, Lavanya Vishvanath, Karen A. Macpherson, Stephen B. Spurgin, Kai Sun, Qiong Wang, William HollandAbstract:The transcriptional regulators Ebf2 and Prdm16establish and maintain the brown and/or beige fatcell identity. However, the mechanisms operating inwhite Adipocytes to suppress the thermogenic geneprogram and maintain an energy-storing phenotypeare less understood. Here, we report that the transcriptionalregulator Zfp423 is critical for maintainingwhite Adipocyte identity through suppression of thethermogenic gene program. Zfp423 expression isenriched in white versus brown Adipocytes and suppressedupon cold exposure. Doxycycline-inducibleinactivation of Zfp423 in mature Adipocytes, combinedwith b-adrenergic stimulation, triggers aconversion of differentiated adiponectin-expressinginguinal and gonadal Adipocytes into beige-like Adipocytes;this reprogramming event is sufficient toprevent and reverse diet-induced obesity and insulinresistance. Mechanistically, Zfp423 acts in Adipocytesto inhibit the activity of Ebf2 and suppressPrdm16 activation. These data identify Zfp423 as amolecular brake on Adipocyte thermogenesis andsuggest a therapeutic strategy to unlock the thermogenicpotential of white Adipocytes in obesity.
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peroxisome proliferator activated receptor γ and its role in Adipocyte homeostasis and thiazolidinedione mediated insulin sensitization
Molecular and Cellular Biology, 2018Co-Authors: Mengle Shao, Qiong A. Wang, Fang Zhang, Lei Jiang, Caroline Tao, Rana K Gupta, Philipp E SchererAbstract:Adipose tissue is a dynamic organ that makes critical contributions to whole-body metabolic homeostasis. Although recent studies have revealed that different fat depots have distinct molecular signatures, metabolic functions and adipogenic mechanisms, peroxisome proliferator-activated receptor γ (PPARγ) is still widely viewed as the master regulator of adipogenesis and critical for maintaining mature Adipocyte function. Using an inducible, Adipocyte-specific knockout system, we explored the role of PPARγ in mature Adipocytes in vivo Short-term PPARγ deficiency in Adipocytes reduces whole-body insulin sensitivity, but Adipocytes are viable both in vitro and in vivo However, after exposure to a high-fat diet, even short-term PPARγ deficiency leads to rapid Adipocyte death. When mature Adipocytes are depleted of both PPARγ and CCAAT-enhancer-binding protein α (C/EBPα), they are rapidly depleted of lipids and undergo Adipocyte death, both in vitro and in vivo Surprisingly, although thiazolidinediones (TZDs; PPARγ agonists) are thought to act mainly on PPARγ, PPARγ in Adipocytes is not required for the whole-body insulin-sensitizing effect of TZDs. This offers new mechanistic aspects of PPARγ/TZD action and its effect on whole-body metabolic homeostasis.
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Zfp423 Maintains White Adipocyte Identity through Suppression of the Beige Cell Thermogenic Gene Program
Cell Metabolism, 2016Co-Authors: Mengle Shao, Jeff Ishibashi, Christine M. Kusminski, Qiong A. Wang, Chelsea Hepler, Lavanya Vishvanath, Karen A. Macpherson, Stephen B. Spurgin, Kai Sun, William L. HollandAbstract:The transcriptional regulators Ebf2 and Prdm16 establish and maintain the brown and/or beige fat cell identity. However, the mechanisms operating in white Adipocytes to suppress the thermogenic gene program and maintain an energy-storing phenotype are less understood. Here, we report that the transcriptional regulator Zfp423 is critical for maintaining white Adipocyte identity through suppression of the thermogenic gene program. Zfp423 expression is enriched in white versus brown Adipocytes and suppressed upon cold exposure. Doxycycline-inducible inactivation of Zfp423 in mature Adipocytes, combined with β-adrenergic stimulation, triggers a conversion of differentiated adiponectin-expressing inguinal and gonadal Adipocytes into beige-like Adipocytes; this reprogramming event is sufficient to prevent and reverse diet-induced obesity and insulin resistance. Mechanistically, Zfp423 acts in Adipocytes to inhibit the activity of Ebf2 and suppress Prdm16 activation. These data identify Zfp423 as a molecular brake on Adipocyte thermogenesis and suggest a therapeutic strategy to unlock the thermogenic potential of white Adipocytes in obesity.
Manuel Gillozano - One of the best experts on this subject based on the ideXlab platform.
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hand2 is a novel obesity linked adipogenic transcription factor regulated by glucocorticoid signalling
Diabetologia, 2021Co-Authors: Maude Giroud, Foivos Filippos Tsokanos, Giorgio Caratti, Sajjad Khani, Elena Sophie Vogl, Martin Irmler, Christina Glantschnig, Stefan Kotschi, Celine Jouffe, Manuel GillozanoAbstract:Adipocytes are critical cornerstones of energy metabolism. While obesity-induced Adipocyte dysfunction is associated with insulin resistance and systemic metabolic disturbances, adipogenesis, the formation of new Adipocytes and healthy adipose tissue expansion are associated with metabolic benefits. Understanding the molecular mechanisms governing adipogenesis is of great clinical potential to efficiently restore metabolic health in obesity. Here we investigate the role of heart and neural crest derivatives-expressed 2 (HAND2) in adipogenesis. Human white adipose tissue (WAT) was collected from two cross-sectional studies of 318 and 96 individuals. In vitro, for mechanistic experiments we used primary Adipocytes from humans and mice as well as human multipotent adipose-derived stem (hMADS) cells. Gene silencing was performed using siRNA or genetic inactivation in primary Adipocytes from loxP and or tamoxifen-inducible Cre-ERT2 mouse models with Cre-encoding mRNA or tamoxifen, respectively. Adipogenesis and Adipocyte metabolism were measured by Oil Red O staining, quantitative PCR (qPCR), microarray, glucose uptake assay, western blot and lipolysis assay. A combinatorial RNA sequencing (RNAseq) and ChIP qPCR approach was used to identify target genes regulated by HAND2. In vivo, we created a conditional Adipocyte Hand2 deletion mouse model using Cre under control of the Adipoq promoter (Hand2AdipoqCre) and performed a large panel of metabolic tests. We found that HAND2 is an obesity-linked white Adipocyte transcription factor regulated by glucocorticoids that was necessary but insufficient for Adipocyte differentiation in vitro. In a large cohort of humans, WAT HAND2 expression was correlated to BMI. The HAND2 gene was enriched in white Adipocytes compared with brown, induced early in differentiation and responded to dexamethasone (DEX), a typical glucocorticoid receptor (GR, encoded by NR3C1) agonist. Silencing of NR3C1 in hMADS cells or deletion of GR in a transgenic conditional mouse model results in diminished HAND2 expression, establishing that Adipocyte HAND2 is regulated by glucocorticoids via GR in vitro and in vivo. Furthermore, we identified gene clusters indirectly regulated by the GR–HAND2 pathway. Interestingly, silencing of HAND2 impaired Adipocyte differentiation in hMADS and primary mouse Adipocytes. However, a conditional Adipocyte Hand2 deletion mouse model using Cre under control of the Adipoq promoter did not mirror these effects on adipose tissue differentiation, indicating that HAND2 was required at stages prior to Adipoq expression. In summary, our study identifies HAND2 as a novel obesity-linked Adipocyte transcription factor, highlighting new mechanisms of GR-dependent adipogenesis in humans and mice. Array data have been submitted to the GEO database at NCBI (GSE148699).
S Enerback - One of the best experts on this subject based on the ideXlab platform.
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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: Jacob B Hansen, R. K. Petersen, PHILIP HALLENBORG, H. A. Boye, C. Jorgensen, Rita De Matteis, N. Petrovič, S Enerback, Jan Nedergaard, Saverio 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.
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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.