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1
Dimitri, Federica. "MicroRNAs in brown and white adipocytes." Thesis, University of Warwick, 2017. http://wrap.warwick.ac.uk/99123/.
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The adipose tissue has an important role in maintaining the energy homeostasis balance. Understanding its physiology is important for the development of treatments against diseases where this equilibrium is compromised, such as obesity and associated metabolic disorders. MicroRNAs (miRNAs) are important gene regulators and an increasing body of evidence suggests their involvement in adipogenesis and adipose metabolism. MiRNAs can also be secreted into the extracellular environment and be taken up by distal cells, mediating cell-to-cell communication. However, very little is known about adipose tissue-derived circulating miRNAs. Through miRNA PCR array analysis we identified several miRNAs that are differentially secreted among mouse undifferentiated and differentiated brown and white adipocytes, among which, miR-196a and miR-378a-3p showed a conservative pattern of secretion in different adipocyte models. MiR-138-5p was identified as the unique miRNA differentially secreted between human brown and white adipocytes. Bioinformatics target prediction revealed that these miRNAs are potentially involved in important processes regulating the functioning of adipose tissue and its cross-talk with distal cells. By ultracentrifugation of adipose conditioned media and Nanosight technology, we investigated vesicle and vesicle-free miRNA carriers and characterized adipose derived vesicles. Finally, through microRNA array and mRNA sequencing we identified genes, miRNAs and pathways differentially enriched in human brown and white adipocytes contributing to improve the knowledge on the nature of human adipocytes, hampered by the scarce availability of human brown adipose samples. Through integration of the two analyses, we identify poorly known or novel miRNAs, potentially involved in the pathways associated with the genes differentially expressed between human brown and white adipocytes. Among the significantly downregulated miRNAs in brown versus white adipocytes we highlighted miR-513a-3p, miR-4511 and miR-4328. While, among the significantly upregulated miRNAs in brown versus white we highlighted miR-4698, miR-4516, miR-4531, miR-29a-3p and miR-3915.
2
Chernogubova, Ekaterina. "Adrenergic stimulation of glucose uptake in brown adipocytes." Doctoral thesis, Stockholm : The Wenner-Gren institute, Stockholm university, 2005. http://urn.kb.se/resolve?urn=urn:nbn:se:su:diva-549.
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Min, So Yun. "The Origin of Human White, Brown, and Brite/Beige Adipocytes." eScholarship@UMMS, 2016. http://escholarship.umassmed.edu/gsbs_diss/878.
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During embryonic development, adipocytes emerge from microvasculature. Lineage-‐tracing studies in mice have shown that adipocyte progenitors reside in the adipose tissue capillaries. However, the direct evidence of an association between adipocyte progenitors and vasculature in humans is lacking. A specific class of adipocytes (brown and beige/brite) expresses the uncoupling protein 1 (UCP1), which consumes glucose and fatty acids to generate heat. The abundance of UCP1- containing adipocytes correlates with a lean metabolically healthy phenotype in human. However, a causal relationship between the presence of these cells and metabolic benefits in human is not clear.
In this thesis, I report human adipocyte progenitors proliferate in response to pro-angiogenic factors in association with adipose capillary networks in-vitro. The capillary-derived adipocytes transform from being UCP1-negative to positive upon adenylate cyclase activation, a defining feature of the brite/beige phenotype. Activated cells have denser, round mitochondria with UCP1 protein, and display uncoupled respiration. When implanted into NOD-scid IL2rgnull (NSG) mice, the adipocytes can form a vascularized fat pad that induces vascularization and becomes integrated into mouse circulatory system. In normal or high fat diet-fed NSG mice, activated brite/beige adipocytes enhance systemic glucose tolerance and improved hepatic steatosis, thus providing evidence for their potential therapeutic use. The adipocytes also express neuroendocrine and secretory factors such as Interleukin-33, proprotein convertase PCSK1 and proenkephalin PENK, which are correlated with human obesity. Finally, analyses on single-cell clones of capillary-sprout cells reveal the existence of diverse adipogenic progenitor populations. Further characterization of the clones will define the identifying features of the diverse adipocyte progenitor types that exist in human adipose tissue.
4
Wikström, Jakob D. "Mitochondrial form and function in pancreatic β-cells and brown adipocytes." Doctoral thesis, Stockholms universitet, Wenner-Grens institut, 2010. http://urn.kb.se/resolve?urn=urn:nbn:se:su:diva-39336.
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This thesis is focused on the role of mitochondria in pancreatic β-cells and brown adipose tissue (BAT). Two main aspects of mitochondria were explored; mitochondrial functional efficiency and the interrelationship between mitochondrial shape and function. Mitochondria in β-cells were found to exhibit heterogeneity in mitochondrial membrane potential. This functional diversity decreased when cells were challenged with glucose stimuli, suggesting that at higher fuel levels low-activity mitochondria are recruited into a pool of high-activity mitochondria. Glucolipotoxic conditions increased the functional diversity suggesting that this may be of importance for diabetes pathophysiology. To examine mitochondrial efficiency in intact islets a high throughput islet respirometry method was developed. Due to increased uncoupling, islets from a diabetic animal model exhibit lower respiratory efficiency. Glucose, free fatty acids and amino acids all decreased respiratory efficiency. A large portion of the respiratory efficiency was mediated by reactive oxygen species and the adenine nucleotide translocase. In β-cells mitochondria were found to undergo cycles of fusion and fission. During glucolipotoxicity mitochondria fragmented and lost their fusion ability. Knock down of the fission protein Fis1 rescued the β-cells from glucolipotoxic induced cell death. BAT mitochondria also showed fusion and fission. The mitochondrial dynamics proteins Mfn2 and Drp1 were shown to strongly affect BAT mitochondrial morphology. In response to a combination of adrenergic and free fatty acid stimuli mitochondria drastically changed from long filamentous structures to fragmented spheres. Inhibiting fission by the negative form of Drp1 decreased BAT response to adrenergic stimuli by half. In conclusion, mitochondrial efficiency may be of importance for normal as well as compromised β-cell and islet function. Mitochondrial morphology appears critical for mitochondrial function in β-cells and BAT.At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 3: Manuscript. Paper 4: Manuscript.
5
Rockstroh, Denise, Kathrin Landgraf, Isabel Viola Wagner, Julia Gesing, Roy Tauscher, Nicole Lakowa, Wieland Kiess, et al. "Direct evidence of brown adipocytes in different fat depots in children." Universitätsbibliothek Leipzig, 2015. http://nbn-resolving.de/urn:nbn:de:bsz:15-qucosa-161428.
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Recent studies suggested the persistence of brown adipocytes in adult humans, as opposed to being exclusively present in infancy. In this study, we investigated the presence of brown-like adipocytes in adipose tissue (AT) samples of children and adolescents aged 0 to
18 years and evaluated the association with age, location, and obesity. For this, we analysed AT samples from 131 children and 23 adults by histological, immunohistochemical and expression analyses. We detected brown-like and UCP1 positive adipocytes in 10.3% of 87 lean children (aged 0.3 to 10.7 years) and in one overweight infant, whereas we did not find brown adipocytes in obese children or adults. In our samples, the brown-like adipocytes were interspersed within white AT of perirenal, visceral and also subcutaneous depots. Samples with brown-like adipocytes showed an increased expression of UCP1
(>200fold), PRDM16 (2.8fold), PGC1α and CIDEA while other brown/beige selective markers, such as PAT2, P2RX5, ZIC1, LHX8, TMEM26, HOXC9 and TBX1 were not significantly different between UCP1 positive and negative samples. We identified a positive correlation
between UCP1 and PRDM16 within UCP1 positive samples, but not with any other brown/beige marker. In addition, we observed significantly increased PRDM16 and PAT2 expression in subcutaneous and visceral AT samples with high UCP1 expression in adults. Our data indicate that brown-like adipocytes are present well beyond infancy in subcutaneous
depots of non-obese children. The presence was not restricted to typical perirenal locations, but they were also interspersed within WAT of visceral and subcutaneous depots.
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Giroud, Maude. "Implication des microARNs dans la conversion des adipocytes blancs en adipocytes thermogéniques." Thesis, Nice, 2015. http://www.theses.fr/2015NICE4082/document.
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La découverte récente d'adipocytes bruns fonctionnels chez les humains adultes a conduit à envisager leur utilisation afin d’augmenter la dépense énergétique dans de potentiels traitements contre l'obésité et les maladies associées. Par ailleurs, des ilots d’adipocytes bruns, appelés adipocytes "brite" (brown in white), émergent dans le tissu adipeux blanc après une exposition au froid ou une stimulation des récepteurs β3-adrénergiques. En utilisant les cellules hMADS, nous avons identifié plusieurs miARNs régulés pendant le « britening ». miR-125b et let-7i ont des niveaux d’expression plus bas dans les adipocytes « brites ». Des analyses fonctionnelles utilisant un « mimic » de miR-125b ou un inhibiteur ont révélé que miR-125b agit comme un frein sur le « brunissage » des cellules hMADS en altérant leur respiration ainsi que leur contenu mitochondrial. In vivo, nous avons montré que miR-125b et let-7i sont moins exprimés dans le tissu adipeux brun par rapport au tissu adipeux blanc. La stimulation des récepteurs β3-adrénergiques ou l'exposition au froid induit une diminution d’expression des miARNs dans les deux tissus et est associée à l'activation du tissu adipeux brun et au recrutement des adipocytes « brites ». Nous avons constaté que l’injection de miR-125b ou let-7i dans le tissu adipeux blanc sous-cutané inhibait l’expression de gènes du « brunissage » induite par la stimulation de la voie β3-adrénergique. En conclusion, nos observations ont montré que miR-125b et let-7i jouaient un rôle important dans la modulation des adipocytes « brites » et des adipocytes « bruns » en ciblant l’expression de gènes mitochondriaux et en diminuant la biogenèse mitochondrialeThe recent discovery of functional brown adipocytes in adult humans has led to the consideration of their use to increase energy expenditure in the treatment of obesity and associated metabolic disorders. Furthermore, in rodents and humans, islands of thermogenic adipocytes, termed “brite” (brown in white) adipocytes, emerge within white adipose tissue after cold exposure or β3-adrenergic receptor stimulation. Using hMADS cells, we identified several miRNAs regulated during “britening” including miR-125b and let-7i which showed lower levels in brite adipocytes. Functional analysis using miR-125b mimic or miR-125b inhibitor transfection revealed that miR-125b-5p acts as a brake of the browning of hMADS cells by impairing respiration rate as well as their mitochondrial content. miR-125b and let-7i levels were lower in brown compared to white adipose tissue. In vivo, we showed that both miRNAs levels were down regulated in mice sub-cutaneous white and brown adipose tissues upon β3-adrenergic receptors stimulation or cold exposure, which is associated with BAT activation and brite adipocyte recruitment. We found that injection of both miRNA mimics in subcutaneous white adipose tissue inhibited β3-adrenergic-induced brown adipocyte markers expression. Altogether, our observations showed that miR-125b and let-7i played an important role in the modulation of brite and brown adipocytes function targeting oxygen consumption and mitochondrial gene expression
7
Kohlie, Rose [Verfasser]. "Dopamine directly increases mitochondrial mass and thermogenesis in brown adipocytes / Rose Kohlie." Lübeck : Zentrale Hochschulbibliothek Lübeck, 2018. http://d-nb.info/116222861X/34.
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Waldén, Tomas B. "Regulatory Factors that Reveal Three Distinct Adipocytes : The Brown, the White and the Brite." Doctoral thesis, Stockholms universitet, Wenner-Grens institut, 2010. http://urn.kb.se/resolve?urn=urn:nbn:se:su:diva-38362.
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Adipose tissues have long been considered to derive from a common origin. Even the functionally different brown and white adipose tissues were generalized to share a common origin. Brown adipose tissue is a highly innervated and vascularised tissue containing multilocular and multimitochondrial brown adipocytes. Brown adipose tissue expends energy through sympathetic nervous system-mediated non-shivering thermogenesis, where uncoupling protein 1 (UCP1) is the key player. In contrast, white adipose tissue consists of unilocular white adipocytes with a main role to store energy in the form of the lipid droplet. We know today that this generalisation is exaggerated since adipocytes can derive from more than one origin and not only be brown or white. We and others have demonstrated that the brown adipocyte has a dermomyotomal origin and derives from the adipomyocyte, the precursor cell that can also become a myocyte, whereas white adipocytes are suggested to derive from pericytes, cells that are embedded within the vascular vessel walls. For a long time there has been evidence that energy-expending adipocytes reside within certain white adipose tissues, based on the fact that cold exposure, by switching on the sympathetic nervous system, leads to levels of UCP1 that are not detectable in mice housed at thermoneutrality. We demonstrated that these cells have a molecular signature that is distinct from brown and white adipocytes. Since these energy-expending cells reside within certain white adipose tissues, we chose to name them brite (brown in white) adipocytes. Moreover, we also identified regulatory factors that were specifically expressed in each adipocyte type, thus, facilitating the possibility to identify the three adipocytes: the brown, the white and the brite.At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 4: Manuscript. Paper 5: Manuscript.
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Hu, Jiamiao. "The effects of short-chain fatty acid acetate on brown adipocytes differentiation and metabolism." Thesis, University of Warwick, 2016. http://wrap.warwick.ac.uk/81114/.
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Short-chain fatty acids (SCFA) are a sub-group of fatty acids including formic acid, acetic acid, propionic acid, isobutyric acid, butyric acid, isovaleric acid and valeric acid. Acetate, propionate and butyrate are three major shortchain fatty acids, which are mainly formed in the gastrointestinal tract via colonic bacteria fermentation of carbohydrates, especially resistant starches and dietary fibre. There has been increasing interest in the idea that the short-chain fatty acids play crucial roles in a range of physiological functions. Recently, increasing evidence suggested there is a strong link between short-chain fatty acids and energy homeostasis. Several studies highlighted the protective effects of the short-chain fatty acids on high-fat diet induced obesity and other harmful metabolic disorders in mice. However, the coherent understanding of the multi-level network in which short-chain fatty acids exert their effects still needs to be elucidated. Up to date, it has been demonstrated that short-chain fatty acids can mediate energy balance via affecting appetite control in brain, increasing adipogenesis in white adipocyte, and regulating insulin sensitivities in white adipose tissue and muscle, etc. However, the effects of short-chain fatty acids on brown adipocytes have not been fully investigated. In this study, we examined the roles of short-chain fatty acid acetate and its receptor(s) in the regulation of brown adipocyte differentiation and metabolism. Firstly, we identified the expression of short-chain fatty acids sensing GPR43 in brown adipose tissue and immortalized brown adipocytes by real-time PCR, Western blots and immunohistochemistry. Moreover, GPR43 expression was found to increase during the adipogenesis of cultured brown adipocytes. Pro-adipogenic reagent PPARγ agonist stimulation led to a further augment of GPR43 expression while antiadipogenic reagents such as PPARγ antagonist, RXR antagonist and STAT5 inhibitor played the opposite role on GPR43 expression. Transcription factors such as XBP1 and STAT5 were identified to be involved in GPR43 expression regulation in brown adipocytes. Furthermore, we also examined the role of acetate in the regulation of brown adipogenesis. Our results showed that acetate treatment during adipogenesis up-regulated AP2, PGC-1α and UCP1 expression and affected the morphological changes of brown adipocytes. Moreover, an increase in mitochondrial biogenesis was observed after acetate treatment. Acetate also elicited the activation of ERK and CREB, and these responses were sensitive to G(i/o)-type G-protein inactivator, Gβγ-subunit inhibitor, PLC inhibitor and MEK inhibitor, indicating a role for the G(i/o)βγ/PLC/PKC/MEK signalling pathway in these responses. These effects of acetate were mimicked by treatment with 4-CMTB, a synthetic GPR43 agonist, and were impaired in GPR43 knock-down cells, further supported the hypothesis that GPR43 mediates the pro-adipogenic effects of acetate in brown adipocytes. Furthermore, the effects of acetate treatment on brown adipose tissue were also measured in vivo. Mice fed with acetate demonstrated increased PGC-1α in brown adipose tissue, which was in agreement with the results obtained from immortalized brown adipocytes. In addition, we also measured the effects of acetate on lipid metabolism in differentiated brown adipocytes. The results showed effects of acetate treatment on lipolysis were different in white adipocytes and brown adipocytes. Acetate treatment significantly decreased the lipolysis in white adipocytes while had little effects on lipolysis in brown adipocytes. Besides, acetate treatment was also found to decrease TF2-C12 fatty acid uptake in differentiated IM-BAT cells, suggesting acetate may affect many aspects of lipid metabolism in brown adipocytes. Collectively, our results indicated that acetate might have important physiological roles in brown adipocytes. Short-chain fatty acids may serve to regulate brown adipose tissue functions and therefore improve metabolic health.
10
Schinzel, Robert [Verfasser]. "The culture and differentiation of human pluripotent cells into brown and white adipocytes / Robert Schinzel." Berlin : Freie Universität Berlin, 2012. http://d-nb.info/103029092X/34.
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Chen, Yong [Verfasser]. "miR-155 regulates differentiation of brown and beige adipocytes via a bistable circuit / Yong Chen." Bonn : Universitäts- und Landesbibliothek Bonn, 2014. http://d-nb.info/1060787113/34.
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DiStefano, Marina T. "A Role for the Lipid Droplet Protein HIG2 in Promoting Lipid Deposition in Liver and Adipose Tissue: A Dissertation." eScholarship@UMMS, 2016. http://escholarship.umassmed.edu/gsbs_diss/830.
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Chronic exposure of humans or rodents to high calorie diets leads to hypertriglyceridemia and ectopic lipid deposition throughout the body, resulting in metabolic disease. Cellular lipids are stored in organelles termed lipid droplets (LDs) that are regulated by tissue-specific LD proteins. These proteins are critical for lipid homeostasis, as humans with LD protein mutations manifest metabolic dysfunction. Identification of novel components of the LD machinery could shed light on human disease mechanisms and suggest potential therapeutics for Type 2 Diabetes.
Microarray analyses pinpointed the largely unstudied Hypoxia-Inducible Gene 2 (Hig2) as a gene that was highly expressed in obese human adipocytes. Imaging studies demonstrated that Hig2 localized to LDs in mouse hepatocytes and the human SGBS adipocyte cell line. Thus, this work examined the role of Hig2 as a LD protein in liver and adipose tissue.
Hig2 deficiency reduced triglyceride deposition in hepatocytes; conversely, ectopic Hig2 expression promoted lipid deposition. Furthermore, liver-specific Hig2-deficient mice displayed improved glucose tolerance and reduced liver triglyceride content. Hig2 deficiency increased lipolysis and -oxidation, accounting for the reduced triglyceride accumulation.
Similarly, adipocyte-specific Hig2-deficient mice displayed improved glucose tolerance, reduced adipose tissue weight and brown adipose tissue that was largely cleared of lipids. These improvements were abrogated when the animals were placed in thermoneutral housing and brown adipocyte-specific Hig2-deficient mice also displayed improved glucose tolerance, suggesting that active brown fat largely mediates the metabolic phenotype of Hig2 deletion. Thus, this work demonstrates that Hig2 localizes to LDs in liver and adipose tissue and promotes glucose intolerance.
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Lasar, David Verfasser], Angelika [Akademischer Betreuer] [Schnieke, and Martin [Akademischer Betreuer] Klingenspor. "The developmental role of brown adipose tissue and brown-like adipocytes (brite) in murine neonates / David Lasar. Gutachter: Angelika Schnieke ; Martin Klingenspor. Betreuer: Martin Klingenspor." München : Universitätsbibliothek der TU München, 2014. http://d-nb.info/105947722X/34.
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Yoo, Hyun-Tae 1973. "Quantitative analysis of carbon fluxes for fat biosynthesis in wild-type and IRS-1 knockout brown adipocytes." Thesis, Massachusetts Institute of Technology, 2005. http://hdl.handle.net/1721.1/30238.
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Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemistry, 2005.Vita.
Includes bibliographical references.
Excessive fat synthesis and the subsequent dysregulation of lipid metabolism constitute the major pathological factors of obesity and type 2 diabetes through triggering insulin resistance. Thus, controlling fat synthesis by identifying key sites for regulation of lipogenesis and modulating the lipogenic fluxes may provide novel approaches to intervention of the diseases. As a first step to quantitative investigation of lipogenic fluxes from various carbon sources as related to insulin signaling, relative contribution of glucose, glutamine, and acetoacetate to fat biosynthesis in wild-type (WT) and insulin receptor substrate-i knockout (IRS-1 KO) brown adipocytes were analyzed by stable-isotope labeling, GC/MS, and flux estimation. Glutamine contributed more to fatty acid synthesis than glucose in WT cells while glucose's contribution was heavier in IRS-1 KO cells. Unlike the straightforward pathway for lipogenesis from glucose, two possibilities for glutamine's route to fatty acid synthesis have been proposed: glutaminolysis pathway through conventional tricarboxylic acid cycle and a pathway via reductive carboxylation of a-ketoglutarate to isocitrate. These pathways were integrated into a metabolic network model for quantitative estimation of individual lipogenic fluxes. Incubation of the cells with [U-13C] glutamine for 6 hrs led to metabolic and isotopic steady state where individual fluxes of the model were estimated with 95% confidence by least-square fit method.
(cont.) Dose dependent repression of estimated net flux of reductive carboxylation by specific inhibition of NADP+-dependent isocitrate dehydrogenase and the subsequent reduction in glutamine's contribution to fatty acid synthesis in WT cells strongly indicated that reductive carboxylation is an important site of regulating glutamine's lipogenic flux. Abolition of this net flux, reduction in glutamine's lipogenic contribution, and concurrent rise in glucose's lipogenic contribution in IRS-1 KO cells were consistent with the importance of reductive carboxylation. Differential effects of lack of insulin signaling on individual lipogenic fluxes suggested that there might be specific sites at which insulin signaling regulates lipogenic utilization of carbon sources. These results revealed the importance of other carbon sources such as glutamine in fat synthesis and the means by which the flux of these carbon sources to fat synthesis can be controlled.
by Hun-Tae Yoo.
Ph.D.
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Ali, Khan Asrar [Verfasser], and Stephan [Akademischer Betreuer] Herzig. "Comparative secretome study of brown adipocytes and the role of ITIH4 in adipose biology / Asrar Ali Khan ; Betreuer: Stephan Herzig." Heidelberg : Universitätsbibliothek Heidelberg, 2017. http://d-nb.info/1180735609/34.
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Tran, Khanh-Van T. "Origin of White and Brown Adipose Cells From Vascular Endothelium: A Dissertation." eScholarship@UMMS, 2012. https://escholarship.umassmed.edu/gsbs_diss/591.
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Obesity is associated with insulin resistance, dyslipidemia, and cardiovascular disease. The current obesity epidemic is the result of surplus energy consumption. Excess energy is stored in expanding adipose tissue. Adipose tissue growth entails the enlargement of existing adipocytes, the formation of new fat cells from preexisting progenitors, and the coordinated development of supporting vasculature. Identifying adipocyte progenitors and the mechanism of adipose tissue expansion is crucial for the development of new strategies to combat obesity and its complications.
Though important progress has been made towards understanding the developmental origin of adipocytes, the identities of adipocyte progenitors are still not completely known. The main objective of this study is to determine whether endothelial cells of the adipose tissue can give rise to new adipocytes. Our results indicate that murine endothelial cells of adipose tissue are pluripotent and can potentially give rise to preadipocytes. Lineage tracing experiments using the VE-Cadherin-Cre transgenic mouse reveal localization of reporter genes in endothelial cells, preadipocytes and white and brown adipocytes. Moreover, capillary sprouts from human adipose tissue, which have predominantly endothelial cell characteristics, are found to express Zfp423, a preadipocyte determination factor. In response to PPARγ activation, endothelial characteristics of sprouting cells are progressively lost, and cells form structurally and biochemically defined adipocytes. Taken together, our data support an endothelial origin of a population of adipocytes. The ability of the vascular endothelium to give rise to adipocytes may explain how angiogenesis and adipogenesis can be temporally and spatially coordinated.
Analysis of BAT and WAT revealed that adipose depots have distinct compositions of adipocyte progenitors. Of the CD45-CD29+Sca1+CD24+ progenitor population, only 17% and 52% express VE-Cadherin in WAT and BAT, respectively. Our data show that the number of these specific progenitors in BAT and WAT are highly variable and suggest that a considerable number of adipocytes progenitors may have a non-endothelial cell origin. Differences in composition and types of adipocyte progenitors may explain the differences in the adipocytes phenotypes that we observe in discrete depots.
In brief, we find that the vascular endothelium gives rise to a population of brown and white fat cells, and that the number of endothelial-derived adipocyte progenitors residing in BAT and WAT is highly variable. These results expand our current understanding of adipose tissue growth, and, we hope, will accelerate the development of treatments for obesity-related complications.
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Schweizer, Sabine Verfasser], Martin [Akademischer Betreuer] Klingenspor, de Angelis Martin [Gutachter] [Hrabé, and Martin [Gutachter] Klingenspor. "Functional phenotype and metabolic properties of brite and brown adipocytes / Sabine Schweizer ; Gutachter: Martin Hrabé de Angelis, Martin Klingenspor ; Betreuer: Martin Klingenspor." München : Universitätsbibliothek der TU München, 2017. http://d-nb.info/1149550678/34.
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Fleckenstein-Elsen, Manuela [Verfasser], Jürgen [Akademischer Betreuer] Eckel, and Eckhard [Akademischer Betreuer] Lammert. "Impact of endocrine and nutritional factors on white-to-brown conversion of primary human adipocytes / Manuela Fleckenstein-Elsen. Gutachter: Jürgen Eckel ; Eckhard Lammert." Düsseldorf : Universitäts- und Landesbibliothek der Heinrich-Heine-Universität Düsseldorf, 2015. http://d-nb.info/1076124755/34.
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Hung, Chien-Min. "mTORC2 Promotes Lipid Storage and Suppresses Thermogenesis in Brown Adipose Tissue in Part Through AKT-Independent Regulation of FoxO1: A Dissertation." eScholarship@UMMS, 2010. http://escholarship.umassmed.edu/gsbs_diss/845.
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Recent studies suggest adipose tissue plays a critical role in regulating whole body energy homeostasis in both animals and humans. In particular, activating brown adipose tissue (BAT) activity is now appreciated as a potential therapeutic strategy against obesity and metabolic disease. However, the signaling circuits that coordinate nutrient uptake and BAT function are poorly understood. Here, I investigated the role of the nutrient-sensing mTOR signaling pathway in BAT by conditionally deleting Rictor, which encodes an essential component of mTOR Complex 2 (mTORC2) either in brown adipocyte precursors or mature brown adipocytes. In general, inhibiting BAT mTORC2 reduces glucose uptake and de novo lipogenesis pathways while increases lipid uptake and oxidation pathways indicating a switch in fuel utilization. Moreover, several key thermogenic factors (Ucp1, Pgc1α, and Irf4) are elevated in Rictor-deficient BAT, resulting in enhanced thermogenesis. Accordingly, mice with mTORC2 loss in BAT are protected from HFD-induced obesity and metabolic disease at thermoneutrality. In vitro culture experiments further suggest that mTORC2 cell-autonomously regulates the BAT thermogenic program, especially Ucp1 expression, which depends on FoxO1 activity. Mechanistically, mTORC2 appears to inhibit FoxO1 by facilitating its lysine-acetylation but not through the canonical AKT-mediated phosphorylation pathway. Finally, I also provide evidence that β-adrenergic signaling which normally triggers thermogenesis also induces FoxO1 deacetylation in BAT. Based on these data, I propose a model in which mTORC2 functions in BAT as a critical signaling hub for coordinating nutrient uptake, fuel utilization, and thermogenic gene expression. These data provide a foundation for future studies into the mTORC2-FoxO1 signaling axis in different metabolic tissues and physiological conditions.
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Hung, Chien-Min. "mTORC2 Promotes Lipid Storage and Suppresses Thermogenesis in Brown Adipose Tissue in Part Through AKT-Independent Regulation of FoxO1: A Dissertation." eScholarship@UMMS, 2016. https://escholarship.umassmed.edu/gsbs_diss/845.
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Recent studies suggest adipose tissue plays a critical role in regulating whole body energy homeostasis in both animals and humans. In particular, activating brown adipose tissue (BAT) activity is now appreciated as a potential therapeutic strategy against obesity and metabolic disease. However, the signaling circuits that coordinate nutrient uptake and BAT function are poorly understood. Here, I investigated the role of the nutrient-sensing mTOR signaling pathway in BAT by conditionally deleting Rictor, which encodes an essential component of mTOR Complex 2 (mTORC2) either in brown adipocyte precursors or mature brown adipocytes. In general, inhibiting BAT mTORC2 reduces glucose uptake and de novo lipogenesis pathways while increases lipid uptake and oxidation pathways indicating a switch in fuel utilization. Moreover, several key thermogenic factors (Ucp1, Pgc1α, and Irf4) are elevated in Rictor-deficient BAT, resulting in enhanced thermogenesis. Accordingly, mice with mTORC2 loss in BAT are protected from HFD-induced obesity and metabolic disease at thermoneutrality. In vitro culture experiments further suggest that mTORC2 cell-autonomously regulates the BAT thermogenic program, especially Ucp1 expression, which depends on FoxO1 activity. Mechanistically, mTORC2 appears to inhibit FoxO1 by facilitating its lysine-acetylation but not through the canonical AKT-mediated phosphorylation pathway. Finally, I also provide evidence that β-adrenergic signaling which normally triggers thermogenesis also induces FoxO1 deacetylation in BAT. Based on these data, I propose a model in which mTORC2 functions in BAT as a critical signaling hub for coordinating nutrient uptake, fuel utilization, and thermogenic gene expression. These data provide a foundation for future studies into the mTORC2-FoxO1 signaling axis in different metabolic tissues and physiological conditions.
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Senol-Cosar, Ozlem. "A Role for TNMD in Adipocyte Differentiation and Adipose Tissue Function: A Dissertation." eScholarship@UMMS, 2006. http://escholarship.umassmed.edu/gsbs_diss/837.
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Adipose tissue is one of the most dynamic tissues in the body and is vital for metabolic homeostasis. In the case of excess nutrient uptake, adipose tissue expands to store excess energy in the form of lipids, and in the case of reduced nutrient intake, adipose tissue can shrink and release this energy. Adipocytes are most functional when the balance between these two processes is intact. To understand the molecular mechanisms that drive insulin resistance or conversely preserve the metabolically healthy state in obese individuals, our laboratory performed a screen for differentially regulated adipocyte genes in insulin resistant versus insulin sensitive subjects who had been matched for BMI. From this screen, we identified the type II transmembrane protein tenomodulin (TNMD), which had been previously implicated in glucose tolerance in gene association studies. TNMD was upregulated in omental fat samples isolated from the insulin resistant patient group compared to insulin sensitive individuals. TNMD was predominantly expressed in primary adipocytes compared to the stromal vascular fraction from this adipose tissue. Furthermore, TNMD expression was greatly increased in human preadipocytes by differentiation, and silencing TNMD blocked adipogenic gene induction and adipogenesis, suggesting its role in adipose tissue expansion.
Upon high fat diet feeding, transgenic mice overexpressing Tnmd specifically in adipose tissue developed increased epididymal adipose tissue (eWAT) mass without a difference in mean cell size, consistent with elevated in vitro adipogenesis. Moreover, preadipocytes isolated from transgenic epididymal adipose tissue demonstrated higher BrdU incorporation than control littermates, suggesting elevated preadipocyte proliferation. In TNMD overexpressing mice, lipogenic genes PPARG, FASN, SREBP1c and ACLY were upregulated in eWAT as was UCP-1 in brown fat, while liver triglyceride content was reduced. Transgenic animals displayed improved systemic insulin sensitivity, as demonstrated by decreased inflammation and collagen accumulation and increased Akt phosphorylation in eWAT. Thus, the data we present here suggest that TNMD plays a protective role during visceral adipose tissue expansion by promoting adipogenesis and inhibiting inflammation and tissue fibrosis.
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Senol-Cosar, Ozlem. "A Role for TNMD in Adipocyte Differentiation and Adipose Tissue Function: A Dissertation." eScholarship@UMMS, 2016. https://escholarship.umassmed.edu/gsbs_diss/837.
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Adipose tissue is one of the most dynamic tissues in the body and is vital for metabolic homeostasis. In the case of excess nutrient uptake, adipose tissue expands to store excess energy in the form of lipids, and in the case of reduced nutrient intake, adipose tissue can shrink and release this energy. Adipocytes are most functional when the balance between these two processes is intact. To understand the molecular mechanisms that drive insulin resistance or conversely preserve the metabolically healthy state in obese individuals, our laboratory performed a screen for differentially regulated adipocyte genes in insulin resistant versus insulin sensitive subjects who had been matched for BMI. From this screen, we identified the type II transmembrane protein tenomodulin (TNMD), which had been previously implicated in glucose tolerance in gene association studies. TNMD was upregulated in omental fat samples isolated from the insulin resistant patient group compared to insulin sensitive individuals. TNMD was predominantly expressed in primary adipocytes compared to the stromal vascular fraction from this adipose tissue. Furthermore, TNMD expression was greatly increased in human preadipocytes by differentiation, and silencing TNMD blocked adipogenic gene induction and adipogenesis, suggesting its role in adipose tissue expansion.
Upon high fat diet feeding, transgenic mice overexpressing Tnmd specifically in adipose tissue developed increased epididymal adipose tissue (eWAT) mass without a difference in mean cell size, consistent with elevated in vitro adipogenesis. Moreover, preadipocytes isolated from transgenic epididymal adipose tissue demonstrated higher BrdU incorporation than control littermates, suggesting elevated preadipocyte proliferation. In TNMD overexpressing mice, lipogenic genes PPARG, FASN, SREBP1c and ACLY were upregulated in eWAT as was UCP-1 in brown fat, while liver triglyceride content was reduced. Transgenic animals displayed improved systemic insulin sensitivity, as demonstrated by decreased inflammation and collagen accumulation and increased Akt phosphorylation in eWAT. Thus, the data we present here suggest that TNMD plays a protective role during visceral adipose tissue expansion by promoting adipogenesis and inhibiting inflammation and tissue fibrosis.
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Chen, Fan [Verfasser], Wolfgang [Akademischer Betreuer] Eisenreich, Klaus [Gutachter] Heuner, and Wolfgang [Gutachter] Eisenreich. "Carbon fluxes and differential glucose usages in Francisella strains, Bacillus subtilis and thermogenic brown adipocytes / Fan Chen ; Gutachter: Klaus Heuner, Wolfgang Eisenreich ; Betreuer: Wolfgang Eisenreich." München : Universitätsbibliothek der TU München, 2018. http://d-nb.info/1194162622/34.
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Gantert, Thomas Uwe Robin [Verfasser], Martin [Akademischer Betreuer] Klingenspor, Stephan [Gutachter] Herzig, and Martin [Gutachter] Klingenspor. "Recruitment of brown adipocytes in visceral white adipose tissue by fibroblast growth factor 8b / Thomas Uwe Robin Gantert ; Gutachter: Stephan Herzig, Martin Klingenspor ; Betreuer: Martin Klingenspor." München : Universitätsbibliothek der TU München, 2021. http://d-nb.info/1239812477/34.
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Yao, Xi. "Un modèle en 3D d’adipocytes de type brun dérivés de cellules pluripotentes induites humaines pour le criblage in vitro de médicaments et pour la thérapie cellulaire contre l’obésité." Electronic Thesis or Diss., Université Côte d'Azur (ComUE), 2019. http://theses.univ-cotedazur.fr/2019AZUR6011.
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L'obésité est la conséquence d'un déséquilibre entre l'apport de calories et la dépense énergétique. Les thérapies basées sur la réduction de l'apport énergétique sont difficiles à suivre dans notre vie moderne et les médicaments anti obésité présentent d’importants effets secondaires. Des stratégies alternatives sont alors requises pour lutter contre l'obésité et les troubles métaboliques associés comme le diabète de type 2 et les maladies cardiovasculaires. Les adipocytes bruns et de type brun, encore appelés beige ou brite (BA), stockent la graisse, mais contrairement aux adipocytes blancs, les BA sont équipés pour brûler les lipides et consommer le glucose afin de dissiper l'énergie stockée. Les BA sécrètent également des adipokines qui vont cibler d'autres organes et pour participer à la régulation des paramètres métaboliques. Ainsi, les BA représentent des cibles cellulaires prometteuses pour lutter contre l'obésité en favorisant la dépense énergétique. Cependant, la rareté des BA chez l’homme adulte, qui est accentuée chez les patients obèses, est une limitation majeure pour un traitement de l’obésité basé sur le BA. La notion d’augmenter la masse de BA en greffant des progéniteurs de BA (BAP) chez des patients obèses a récemment émergée. La preuve de concept a été faite dans des modèles murins. Le prochain défi consiste à identifier une source abondante et fiable de BAP humains. Nous décrivons dans cette thèse la capacité des cellules souches pluripotentes induites humaines (hiPSCs) à générer des BAP et capables de se différencier avec une grande efficacité dans un modèle en 3D en adiposphères. Les hiPSC- adiposphères ont un profil d'expression de la matrice extracellulaire et des récepteurs couplés à la protéine G (GPCR) similaires aux adiposphères humaines dérivées de progéniteurs adipeux abdominaux sous-cutanés. Ces résultats montrent la pertinence physiologique du modèle hiPSC-adiposphères. De plus, les hiPSC-adiposphères contiennent plus de cellules UCP1 positives que les adiposphères abdominales. L’expression de UCP1 dans les hiPSC-adiposphères est augmentée suite à la stimulation par le 8-CPT-AMPc ou du 8-Br-GMPc de manière aiguë et chronique. Ceci indique que notre modèle 3D présente les caractéristiques métaboliques des adipocytes de type bruns et peut répondre à un criblage de molécules visant à augmenter la dépense énergétique.Enfin, l'enrichissement du modèle 3D en cellules endothéliales humaines (HDMEC) a été réalisé via une co-culture en suspension. La fonctionnalité des HDMECs intégrées dans les hiPSC-adiposhères a été testée in vitro par la visualisation de l’absorption de LDL. Nous avons aussi montré que les hiPSC-BAs et les HDMEC pouvaient générer des structures de type vascularisées dans le core de la sphère.En conclusion, le modèle hiPSC-adiposphère représente une source illimitée d’adipocytes d’intérêt thérapeutique qui pourrait, dans un avenir proche constituer un nouvel outil approprié à la fois pour la transplantation chez les patients atteint d’obésité morbide et pour le criblage de médicaments. Le potentiel thérapeutique des hiPSC-adiposphères sera tester prochainement dans un modèle de souris obèsesObesity results from an imbalance between calorie intake and energy expenditure. Therapies based to reduce energy intake are difficult to follow in our modern life, and drugs can display adverse effects. Alternative strategies are urgently required to fight obesity and associated metabolic disorders. Brown and brown-like adipocytes (BAs) store fat, but in contrast to white adipocytes, BAs are equipped to burn glucose and lipids to dissipate energy stored. BAs also secrete adipokines that signal other organs and regulate metabolism. Therefore, BAs represent promising cell targets to promote energy expenditure and counteract obesity. However, the scarcity of BAs in human adults is a major limitation for a BA-based therapy of obesity, and the notion to increase the BA mass by transplanting BA progenitors (BAPs) in obese patients recently emerged. The proof of concept has been done in murin models. The next challenge is to identify an abundant and reliable source of human BAPs. We recently described the capacity of human induced pluripotent stem cells (hiPSCs) to generate BAPs. During my thesis, we established a procedure to generate hiPSC-BAP spheroids and a method for their differentiation at a high efficiency in hiPSC-brown-like adipospheres. The model was then enriched with Human Dermal Microvascular Endothelial Cells (HDMECs) to better mimic the adipose tissue microenvironment and to improve its therapeutic potential. BAPs derived from human iPSCs were maintained in suspension to form spheroids able to different into adipospheres. The structure of adipospheres was analysed by confocal microscopy and adipocytes were characterized at the molecular and metabolic levels. We generated adipospheres from two different hiPSC-BAP clones, which are able to fully differentiate from the surface to the core. We compared hiPSC-brown-like adipospheres with the ones generated by hanging drop method, and our model displays comparable pattern regarding to extracellular matrix and adipogenesis, despite the sizes are not defined. We also proved hiPSC-brown-like adipospheres promotes accumulation of brown-like adipocytes that are more biologically active compared to cells maintained in conventional monolayer cell cultures. In addition, hiPSC-brown-like adipospheres have a similar expression profile of extracellular matrix and G Protein-Coupled Receptors (GPCRs) compared with human adipospheres derived from subcutaneous abdominal adipose progenitors, suggested the physiological relevance of the hiPSC-adiposphere model. Moreover, hiPSC-adipospheres display a more brown-like adipogenic potential than abdominal adipospheres opening the opportunity and advantages for anti-obesity drug testing and cell based therapy to increase the BA mass in patients. Furthermore, hiPSC-adipospheres express UCP1 that can response to the stimulation of 8-CPT-cAMP or 8-Br-cGMP acutely and chronically, which indicated that our 3D model display metabolic characteristics of brown-like adipocytes. Finally, enrichment with HDMECs was performed via co culture in suspension. HDMECs functionality was tested in vitro by LDL-uptake. We proved that hiPSC-BAPs and HDMECs can co-culture in 3D and differentiate into vascularized hiPSC-brown-like adipospheres with functional tubular-like structure formed inside. Moreover, our co-cultured 3D model can secrete factors like VEGF and FGF2 to support vascularization which mimic in vivo situation.Altogether, the hiPSC-brown-like adipposphere model represents an unlimited source of human BAPs that in a near future may be a suitable tool for both therapeutic transplantation and for drug screening allowing discovery of novel and safe anti-obesity drugs
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Li, Yongguo [Verfasser], Martin [Akademischer Betreuer] Klingenspor, Hannelore [Akademischer Betreuer] Daniel, Michael [Akademischer Betreuer] Schemann, and Susanne [Akademischer Betreuer] Klaus. "Characterization of brown-like adipocytes differentiated in primary culture: thermogenic function, molecular basis of variation between strains and transcriptome analysis / Yongguo Li. Betreuer: Martin Klingenspor. Gutachter: Hannelore Daniel ; Michael Schemann ; Susanne Klaus ; Martin Klingenspor." München : Universitätsbibliothek der TU München, 2015. http://d-nb.info/1079655115/34.
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Paré, Martin. "Étude sur les mécanismes moléculaires impliqués dans l’auto-renouvellement, la différenciation et la conversion thermogénique des cellules adipocytaires dans différentes situations pathologiques." Electronic Thesis or Diss., Université Côte d'Azur (ComUE), 2019. http://www.theses.fr/2019AZUR4022.
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Il existe deux types de tissus adipeux (TA). Le tissu adipeux blanc stocke les lipides sous forme de triglycérides. Le tissu adipeux brun possède une signature thermogénique via la protéine UCP1 utilisant les lipides pour former de la chaleur. Il existe aussi des adipocytes qui ont des caractéristiques similaires aux adipocytes bruns (adipocytes beiges) au sein du TA blanc. Le TA sécrète également des hormones lui conférant une fonction endocrinienne. Il maintient l’homéostasie énergétique et peut être altéré de différentes façons, ce qui conduit à des dysfonctionnements métaboliques : Une perte importante du TA dans les lipoatrophies est observée lors d’un traitement antirétroviral hautement actif contre le VIH (thérapie HAART). Ceci amène à des modifications métaboliques graves, dues à des niveaux élevés de lipides circulants et à une résistance à l’insuline systémique. Cette thérapie HAART est composée d’inhibiteurs de la protéase du VIH (IPs) ou de la transcriptase inverse (INTI). Les effets inhibiteurs des IPs sur le processus de différenciation adipocytaire blanche sont bien connus. Cependant, les mécanismes spécifiques qui affectent les différents dépôts adipeux humains distinctement ainsi que la différenciation adipocytaire brune le sont moins. Le cancer est une pathologie caractérisée par la prolifération dérégulée de cellules capables de former des métastases. Les cellules tumorales interagissent activement avec leur microenvironnement, notamment avec le TA qui est présent autour de nombreux organes et qui peut favoriser la progression tumorale (tissu adipeux associé au cancer). Le TA promeut la prolifération des cellules cancéreuses par la sécrétion d’adipocytokines. De plus, les cellules tumorales modifient le TA pour tirer leur énergie des lipides ce qui favorise leur expansion et leur dissémination. Nous avons étudié les interactions entre adipocytes et cellules tumorales de sein puisque le TA fait partie intégrante de la glande mammaire. Mon travail de thèse a consisté à identifier de nouveaux mécanismes moléculaires importants pour le développement physiopathologique et/ou l’altération du TA. Nous avons d’abord étudié les effets des IPs sur la perte de l’auto-renouvellement des progéniteurs adipeux (PAs) (1) et sur les modifications métaboliques des adipocytes (2). Nous étudions aussi les interactions entre les cellules de cancer du sein et le microenvironnement adipeux (3). Tout d’abord, les IPs inhibent l’auto-renouvellement des PAs en diminuant IER3 ce qui déstabilise en aval la boucle autocrine de l’Activine A. Les IPs bloquent la différenciation des PAs en adipocytes. La perte de ces deux processus indique que les IPs induisent des lipoatrophies retrouvées au cours de la thérapie HAART. Par la suite, nous observons que les IPs réduisent l’expression des marqueurs thermogéniques dans les adipocytes beiges et bruns par l’inhibition de la transcription d’UCP1. Ils altèrent aussi l’expression des sirtuines, enzymes antivieillissement. L’utilisation d’un activateur de la sirtuine 1 permet de renverser partiellement les effets des IPs sur l’expression d’UCP1. Enfin, nos résultats démontrent que des mammosphères de cancer de sein induisent la protéine UCP1 dans les adipocytes adjacents. L’adrénomedulline produite par les mammosphères participe à ce processus et nous avons pu caractériser son mécanisme d’action. En conclusion, les travaux réalisés pendant ma thèse ont permis de mieux comprendre les mécanismes par lesquels les IPs inhibent l’auto-renouvellement des progéniteurs adipeux ainsi que l’altération de la signature thermogénique via la perte d’UCP1 dans les adipocytes bruns. Les cellules tumorales, quant à elles, induisent l’expression d’UCP1 résultant en une conversion métabolique des adipocytes blancs en adipocytes brunsThere are two types of adipose tissues (AT). White adipose tissue stocks lipids in the form of triglycerides. Brown adipose tissue possesses a thermogenic signature through the protein UCP1 in order to generate heat by using lipids. Some adipocytes have brown-like adipocyte characteristics (beige adipocytes) and are localized in the white adipose tissue. AT also secrete hormones giving it an endocrine function. AT maintains energetic balance and can be altered in many ways, leading to metabolic dysfunctions: Important loss of AT in lipoatrophy are observed during highly active antiretroviral therapy against HIV (HAART therapy). This leads to severe metabolic modifications resulting in high levels of circulating fatty acids and systemic insulin resistance. The HAART therapy is composed of HIV protease inhibitors (PIs) or reverse transcriptase inhibitors (NRTI). PIs inhibitory effects on white adipocyte differentiation are well known. However, specific mechanisms distinctly altering different human adipose depots or brown adipocyte differentiation are less known. The pathology of cancer is characterized by upregulated proliferation of cells capable of metastasis. Tumor cells interact with their microenvironment, especially the AT surrounding numerous organs and can promote cancer progression (cancer-associated adipose tissue). AT induces cancer cells proliferation through secretion of adipocytokines. Furthermore, tumor cells modify the AT in order to gain energy from their lipids resulting in tumoral expansion and invasion. We have studied the interactions between adipocytes and breast cancer cells because AT is an integral part of the mammary gland. My thesis work consists of identifying new molecular mechanisms implicated in the physiopathological development and/or alteration of the AT. We have first studied the PIs effects on the loss of adipose progenitors (APs) self-renewal (1) and the metabolic modifications of adipocytes (2). We also studied the interactions between breast cancer cells and the adipose microenvironment (3). First, PIs inhibit self-renewal of APs by decreasing IER3 which disrupts the activin A autocrine loop downstream. PIs also block the differentiation of APs into adipocytes. The loss of both processes shows that PIs induce lipoatrophy observe during HAART therapy. After, we observed that PIs decrease the expression of thermogenic markers in beige and brown adipocytes through inhibition of UCP1 transcription. They also impair the expression of sirtuins, anti-aging enzymes. The use of a sirtuin 1 activator can partially reverse the PIs effects on UCP1 expression. Finally, our results show that breast cancer mammospheres increase UCP1 protein expression in adjacent adipocytes. Adrenomedullin is produced by the mammospheres and participated in this process and we were able to characterize its mechanism of action. In conclusion, the work done during my thesis have allowed us to better understand the mechanisms by which PIs inhibit self-renewal of APs as well as the impairment of the thermogenic signature through the loss of UCP1 in beige and brown adipocytes. Tumor cells, however, induce UCP1 expression resulting in the metabolic conversion of white adipocytes into brown adipocytes
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Rau, Verena [Verfasser]. "Identification of brown adipocyte progenitors / Verena Rau." Ulm : Universität Ulm, 2020. http://d-nb.info/1207927643/34.
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Cantwell, Marc. "STAT3 in the Regulation of Brown Adipocyte Differentiation." VCU Scholars Compass, 2018. https://scholarscompass.vcu.edu/etd/5507.
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Thermogenic fat is a promising target for new therapies in diabetes and obesity. Understanding how thermogenic fat develops is important to develop rational strategies to treat obesity. Previously, we have shown that Tyk2 and STAT3, part of the JAK-STAT pathway, are necessary for proper development of classical brown fat. Using primary preadipocytes isolated from newborn mice we demonstrate that STAT3 is required for differentiation and robust expression of Uncoupling Protein 1. We also confirm that STAT3 is necessary during the early induction stage of differentiation and is dispensable during the later terminal differentiation stage. Without STAT3, the brown preadipocytes have increased apoptosis early in the terminal differentiation phase. We also show that the block in differentiation is caused by an inability of STAT3 knockouts to down regulate β-catenin by the end of the induction phase. Application of Wnt/β-catenin inhibitors or knockdown of β-catenin during the induction phase is sufficient to fully rescue differentiation of brown adipocytes from the Myf5+ lineage, including reduction in apoptosis, restoration of histone acetylation in the UCP1 promoter and enhancer regions, and full restoration of the expression of brown fat genes. Finally, we show that in the beige lineage, STAT3 is also necessary during the induction phase and can be rescued by Wnt/β-catenin inhibitors, although the rescue is not as robust as it is in the Myf5+ lineage.
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Bagchi, Mandrita. "Role of Vascular Endothelial Growth Factor Signaling in Brown Adipocyte Survival, Proliferation and Function." Thesis, Harvard University, 2012. http://dissertations.umi.com/gsas.harvard:10713.
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Both white and brown adipose tissues exhibit extensive vascularity. Increased angiogenesis in brown adipose tissue (BAT) is crucial for brown fat activation and thermogenesis in animals during cold acclimation. BAT can be similarly activated by food intake to generate heat through cellular respiration, in a process known as diet induced thermogenesis. Vascular endothelial growth factor (VEGF) is a potent angiogenic factor that regulates both pathological and physiological angiogenesis and can stimulate cell proliferation, migration, survival and vessel permeability. However, VEGF has also been shown to affect an increasing number of non-vascular cells such as skeletal muscle and kidney podocytes. The expression and function of VEGF in white and brown adipocytes are not fully understood. We have previously shown that the expression of VEGF is concomitantly regulated with skeletal muscle differentiation. Here we show that VEGF is expressed in BAT and all major white adipose depots in mice. VEGF expression was increased during white and brown adipocyte differentiation and was regulated in cultured brown adipocytes by the \(PPAR\gamma\) agonist troglitazone and by \(PGC1\alpha\) in BAT in vivo. Systemic VEGF neutralization led to brown adipocyte apoptosis in vivo, loss of mitochondrial cristae and increased mitophagy and was associated with increased inflammation and fibrosis. VEGFR2 was expressed in both brown preadipocytes and adipocytes. Blockade of VEGF signaling using anti-VEGFR2 antibody DC101 increased brown adipocyte apoptosis in vitro. VEGF also functioned as a mitogen and survival factor for brown preadipocytes. VEGF 164 and VEGF 188, isoforms that can bind heparan sulfate proteoglycans, comprise >98% of total VEGF in BAT, subcutaneous and perigonadal fat depots. Embryos that lacked VEGF 164 and 188 displayed abnormal BAT development with fewer brown adipocytes, lower levels of mitochondrial uncoupling protein 1 and Cox IV. These results indicate a direct role for VEGF signaling in brown adipocytes and preadipocytes and suggest the importance of heparan sulfate binding VEGF isoforms in BAT development. Elucidation of the role of VEGF signaling in adipocytes is vital to understanding adipose tissue expansion and activation and may reveal novel therapeutic targets for the activation of brown fat in humans.
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McDonald, Meghan Elizabeth. "Identification of novel regulators of mesenchymal stem cell commitment to the brown adipocyte lineage." Thesis, Boston University, 2013. https://hdl.handle.net/2144/12817.
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Thesis (Ph.D.)--Boston University
PLEASE NOTE: Boston University Libraries did not receive an Authorization To Manage form for this thesis or dissertation. It is therefore not openly accessible, though it may be available by request. If you are the author or principal advisor of this work and would like to request open access for it, please contact us at open-help@bu.edu. Thank you.Obesity is associated with an imbalance resulting from increased caloric intake and decreased energy expenditure. Humans have two types of adipose tissue: white adipose tissue (WAT), specialized for the storage of excess energy as lipid; and brown adipose tissue (BAT), which catabolizes lipid, releasing heat. Enhancing the development and/or activity of brown adipose tissue (BAT) or brown-like (beige) adipocytes within WAT is proposed as a means to enhance energy expenditure in obese individuals. Brown adipocyte progenitors share common origins with vascular cells; however, the mechanisms regulating commitment to these lineages are not understood. Bone Morphogenic Protein 7 (BMP7), a member of the Transforming Growth Factor β (TGFβ) superfamily, promotes the development of brown adipocytes. The goal of this study was to identify novel mechanisms regulating the commitment of mesenchymal stem cells (MSCs) to the brown adipocyte lineage, and to characterize the contrasting effects of BMP7 and TGFβ1 on cell fate. To address these questions, we used MSC culture models and identified several genes that are selectively regulated by BMP7 during BAT lineage commitment. These include the transcription factor Zinc Finger Protein of the Cerebellum 1 (Zinc1), Gremlin1, a secreted BMP antagonist, and regulators of cell shape, the Rho-associated protein kinases, Rock1/2. Repression of Gremlin1 and Zic1 expression are necessary for MSCs to undergo brown adipogenesis. It is well-established that TGFβ1 activates ROCK, and induces elongated, myofibroblast morphology in MSCs. We demonstrate that BMP7, in contrast, represses ROCK activity, altering actin dynamics and promoting a broadened morphology. Consistent with these findings, inhibition of ROCK activity or the downstream transcription factor Serum Response Factor (SRF), promotes brown adipocyte development. We conclude from these results that changes in cell shape and gene expression programs that are responsive to the status of the actin cytoskeleton are critical mediators of BAT lineage commitment. Our study has identified multiple genes involved in a brown fat/myofibroblast phenotypic switch. Modulation of ROCK or SRF activity may provide a novel means of promoting the development of brown/beige adipocytes in obese individuals. Further delineation of mechanisms regulating BAT development will lead to the identification of novel targets for anti-obesity therapeutics.
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de, Jong Jasper. "Who is Who in the Adipose Organ : A look at the Heterogeneity of Adipocyte Biology." Doctoral thesis, Stockholms universitet, Institutionen för molekylär biovetenskap, Wenner-Grens institut, 2017. http://urn.kb.se/resolve?urn=urn:nbn:se:su:diva-140884.
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The increasing prevalence of obesity and related health complications, such as type 2 diabetes, cardiovascular disease and cancer, demands thorough investigation of the underlying processes. One of the key tissues investigated in this context is adipose tissue. It is becoming increasingly clear that adipose tissue is a very dynamic and heterogenic organ. This thesis provides an overview of various aspects of adipose biology that illustrate its heterogenic nature and describes my own scientific contributions to this field. We typically distinguish between thermogenic, energy-expending brown adipocytes and energy-storing white adipocytes that are located in anatomically distinct adipose depots. In addition, brite (or beige) adipocytes are functionally thermogenic, but are located among white adipocytes. Related to functional variation, adipocytes and adipose tissues display a wide range of morphological appearances. An additional property that illustrates the heterogeneity among adipose cells and depots is the variation of cellular responses to physiological cues, such as changes in diet or environmental temperature. Furthermore, the developmental origins of various adipose types display great heterogeneity, which may explain some of the functional and dynamic differences that are observed. In line with the complexity of developmental origins, molecular markers that were initially proposed to distinguish between brown, brite/beige and white adipose subtypes have added to the notion that the composition of the adipose organ is much more complex than has long been appreciated. My own work has contributed to the enhancement of our understanding of the heterogeneity of adipose subtypes. In particular, my findings related to marker gene expression patterns have led to increased appreciation of the complex nature of adipose gene expression patterns and the complications of translating results obtained in mice to humans. Some of my other contributions have increased the understanding of the differences and similarities in thermogenic adipose tissue functionality and dynamics. With cell culture studies, I have revealed new characteristics of pre-adipose cells from various depots that further add to the appreciation of the adipose heterogeneity. Overall, this thesis provides an overview of important characteristics of the adipose organ, illustrating its heterogenic nature. Realization of this heterogeneity is of importance in order to properly study the adipose organ to ultimately understand how the adipose organ can be therapeutically targeted to effectively treat adipose-related diseases.At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 3: Manuscript. Paper 7: Manuscript. Paper 8: Manuscript.
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Ye, Li. "Identification of TRPV4 as a Regulator of Adipose Oxidative Metabolism, Inflammation and Energy Homeostasis by a Chemical Biology Approach." Thesis, Harvard University, 2012. http://dissertations.umi.com/gsas.harvard:10350.
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\(PGC1\alpha\) is a key transcriptional coregulator of mitochondrial biogenesis, oxidative metabolism and thermogenesis. We developed a quantitative high throughput screen to identify small molecules that can induce \(PGC1\alpha\) expression in adipocytes. Small molecules antagonizing the TRPVs (Transient Receptor Potential Vanilloid), a family of ion channels, induced \(PGC1\alpha\) expression in adipocytes. In particular, inhibition of TRPV4 increased expression of \(PGC1\alpha\), UCP1 and cellular respiration; conversely, chemical activation of TRPV4 repressed this pathway. Blocking TRPV4 in cultured adipocytes also reduced the expression of multiple proinflammatory genes that are involved in the development of insulin resistance. These effects of TRPV4 were mediated by the activation of ERK1/2. Finally, mice with a null mutation for TRPV4 showed higher energy expenditure with no change in movement or food intake, and were protected from diet-induced obesity, adipose inflammation and insulin resistance. This study links TRPV4 to robust pathways that offer therapeutic potential in obesity and related metabolic diseases.
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Boeuf, Stéphane. "Comparative study of gene expression during the differentiation of white and brown preadipocytes." Phd thesis, Universität Potsdam, 2002. http://opus.kobv.de/ubp/volltexte/2005/51/.
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EinleitungSäugetiere haben zwei verschiedene Arten von Fettgewebe: das weiße Fettgewebe, welches vorwiegend zur Lipidspeicherung dient, und das braune Fettgewebe, welches sich durch seine Fähigkeit zur zitterfreien Thermogenese auszeichnet. Weiße und braune Adipozyten sind beide mesodermalen Ursprungs. Die Mechanismen, die zur Entwicklung von Vorläuferzellen in den weißen oder braunen Fettzellphenotyp führen, sind jedoch unbekannt. Durch verschiedene experimentelle Ansätze konnte gezeigt werden, daß diese Adipocyten vermutlich durch die Differenzierung zweier Typen unterschiedlicher Vorläuferzellen entstehen: weiße und braune Preadipozyten. Von dieser Hypothese ausgehend, war das Ziel dieser Studie, die Genexpression weißer und brauner Preadipozyten auf Unterschiede systematisch zu analysieren.
Methoden
Die zu vergleichenden Zellen wurden aus primären Zellkulturen weißer und brauner Preadipozyten des dsungarischen Zwerghamsters gewonnen. „Representational Difference Analysis“ wurde angewandt, um potentiell unterschiedlich exprimierte Gene zu isolieren. Die daraus resultierenden cDNA Fragmente von Kandidatengenen wurden mit Hilfe der Microarraytechnik untersucht. Die Expression dieser Gene wurde in braunen und weißen Fettzellen in verschiedenen Differenzierungsstadien und in braunem und weißem Fettgewebe verglichen.
Ergebnisse
12 Gene, die in braunen und weißen Preadipozyten unterschiedlich exprimiert werden, konnten identifiziert werden. Drei Komplement Faktoren und eine Fettsäuren Desaturase werden in weißen Preadipozyten höher exprimiert; drei Struktur Gene (Fibronectin, Metargidin und a Actinin 4), drei Gene verbunden mit transkriptioneller Regulation (Necdin, Vigilin und das „small nuclear ribonucleoprotein polypeptide A“) sowie zwei Gene unbekannter Funktion werden in braunen Preadipozyten höher exprimiert. Mittels Clusteranalyse (oder Gruppenanalyse) wurden die gesamten Genexpressionsdaten charakterisiert. Dabei konnten die Gene in 4 typischen Expressionsmuster aufgeteilt werden: in weißen Preadipozyten höher exprimierte Gene, in braunen Preadipozyten höher exprimierte Gene, während der Differenzierung herunter regulierte Gene und während der Differenzierung hoch regulierte Gene.
Schlußfolgerungen
In dieser Studie konnte gezeigt werden, daß weiße und braune Preadipozyten aufgrund der Expression verschiedener Gene unterschieden werden können. Es wurden mehrere Kandidatengene zur Bestimmung weißer und brauner Preadipozyten identifiziert. Außerdem geht aus den Genexpressionsdaten hervor, daß funktionell unterschiedliche Gruppen von Genen eine wichtige Rolle bei der Differenzierung von weißen und braunen Preadipozyten spielen könnten, wie z.B. Gene des Komplementsystems und der extrazellulären Matrix.
Introduction
Mammals have two types of adipose tissue: the lipid storing white adipose tissue and the brown adipose tissue characterised by its capacity for non-shivering thermogenesis. White and brown adipocytes have the same origin in mesodermal stem cells. Yet nothing is known so far about the commitment of precursor cells to the white and brown adipose lineage. Several experimental approaches indicate that they originate from the differentiation of two distinct types of precursor cells, white and brown preadipocytes. Based on this hypothesis, the aim of this study was to analyse the gene expression of white and brown preadipocytes in a systematic approach.
Experimental approach
The white and brown preadipocytes to compare were obtained from primary cell cultures of preadipocytes from the Djungarian dwarf hamster. Representational difference analysis was used to isolate genes potentially differentially expressed between the two cell types. The thus obtained cDNA libraries were spotted on microarrays for a large scale gene expression analysis in cultured preadipocytes and adipocytes and in tissue samples.
Results
4 genes with higher expression in white preadipocytes (3 members of the complement system and a fatty acid desaturase) and 8 with higher expression in brown preadipocytes were identified. From the latter 3 coded for structural proteins (fibronectin, metargidin and a actinin 4), 3 for proteins involved in transcriptional regulation (necdin, vigilin and the small nuclear ribonucleoprotein polypeptide A) and 2 are of unknown function. Cluster analysis was applied to the gene expression data in order to characterise them and led to the identification of four major typical expression profiles: genes up-regulated during differentiation, genes down-regulated during differentiation, genes higher expressed in white preadipocytes and genes higher expressed in brown preadipocytes.
Conclusion
This study shows that white and brown preadipocytes can be distinguished by different expression levels of several genes. These results draw attention to interesting candidate genes for the determination of white and brown preadipocytes (necdin, vigilin and others) and furthermore indicate that potential importance of several functional groups in the differentiation of white and brown preadipocytes, mainly the complement system and extracellular matrix.
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Pramme-Steinwachs, Ines [Verfasser], Matthias [Akademischer Betreuer] Tschöp, Matthias [Gutachter] Tschöp, and Martin [Gutachter] Klingenspor. "The Role of Calcium and its Transporter P2RX5 in Brown Adipocyte Function / Ines Pramme-Steinwachs ; Gutachter: Matthias Tschöp, Martin Klingenspor ; Betreuer: Matthias Tschöp." München : Universitätsbibliothek der TU München, 2019. http://d-nb.info/1203799306/34.
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Yoo, Hyuntae, Maciek Antoniewicz, Joanne K. Kelleher, and Gregory Stephanopoulos. "Differential effects of insulin signaling on individual carbon fluxes for fatty acid synthesis in brown adipocytes." 2004. http://hdl.handle.net/1721.1/7478.
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Considering the major role of insulin signaling on fatty acid synthesis via stimulation of lipogenic enzymes, differential effects of insulin signaling on individual carbon fluxes for fatty acid synthesis have been investigated by comparing the individual lipogenic fluxes in WT and IRS-1 knockout (IRS-1 KO) brown adipocytes. Results from experiments on WT and IRS-1 KO cells incubated with [5-¹³C] glutamine were consistent with the existence of reductive carboxylation pathway. Analysis of isotopomer distribution of nine metabolites related to the lipogenic routes from glucose and glutamine in IRS-1 KO cells using [U-¹³C] glutamine as compared to that in WT cells indicated that flux through reductive carboxylation pathway was diminished while flux through conventional TCA cycle was stimulated due to absence of insulin signaling in IRS-1 KO cells. This observation was confirmed by quantitative estimation of individual lipogenic fluxes in IRS-1 KO cells and their comparison with fluxes in WT cells. Thus, these results suggest that glutamine’s substantial contribution to fatty acid synthesis can be directly manipulated by controlling the flux through reductive carboxylation of alpha-ketoglutarate to citrate using hormone (insulin).Singapore-MIT Alliance (SMA)
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Diallo, Kadidia. "14-3-3ζ overexpression improves tolerance to acute and chronic cold exposure in male mice." Thèse, 2019. http://hdl.handle.net/1866/23660.
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La thermogenèse adaptative est un mécanisme de production de chaleur médié par les adipocytes bruns. En réponse au froid, ou à un stimulus adrénergique, les adipocytes blancs peuvent être convertis en adipocytes beiges lors d’un processus que l’on nomme le « beiging ». Contrairement aux adipocytes blancs, les adipocytes beiges et bruns expriment des taux élevés de la protéine de découplage 1 (UCP1) et dissipent l'énergie sous forme de chaleur grâce à l'oxydation des lipides. Il a été démontré chez les rongeurs que l’activation des adipocytes bruns et beiges entraîne une réduction significative du poids corporel et l’activation de ces adipocytes chez l’humain semble être un traitement prometteur contre l’obésité et le diabète. Nous avons précédemment identifié un rôle essentiel de la protéine d’échafaudage 14-3-3ζ dans l'adipogenèse, mais son rôle dans d'autres processus adipocytaires reste incertain. Une des premières fonctions identifiées de la 14-3-3ζ est sa capacité à réguler l'activité enzymatique de la tyrosine hydroxylase, indispensable à la production de norépinephrine pour la thermogenèse. Notre étude vise donc à déterminer si la 14-3-3ζ influence le développement et la fonction des adipocytes beiges et bruns.
Nos données montrent que la délétion d’un allèle du gène de la 14-3-3ζ n’affecte pas la tolérance au froid aiguë. Comparées aux souris de type sauvage (WT), les souris transgéniques mâles surexprimant la 14-3-3ζ (TAP) ont une meilleure tolérance au froid aiguë (3 heures, 4 °C) et chronique (3 jours, 4 °C). On observe chez les TAP une augmentation du beiging due à une élévation significative de l'ARNm et de la protéine UCP1 dans le tissu adipeux blanc inguinal (iWAT). Par ailleurs, les souris TAP présentent également une réduction significative de la conductance thermique lors d’exposition au froid leur permettant de mieux conserver la chaleur. Collectivement, nos résultats soulignent le rôle novateur de la 14-3-3ζ dans le beiging et nous permettent de mieux comprendre comment la thermogenèse adaptative est régulée.Adaptive thermogenesis is a mechanism of heat production primarily mediated by brown fat. In some instances, cold exposure or adrenergic stimuli can convert white adipocytes into brown-like or beige adipocytes during a process termed “beiging”. Both beige and brown adipocytes express higher levels of uncoupling protein 1 (UCP1) and can release energy in the form of heat following lipid oxidation. The activation of these thermogenic adipocytes increases energy expenditure to reduce body weight in rodents, and it has been postulated to be a promising therapy for the treatment of obesity and diabetes. We previously identified an essential role of the molecular scaffold, 14-3-3ζ, in adipogenesis, but its roles in other adipocyte processes is uncertain. An early identified function of 14-3-3 was its ability to regulate the enzymatic activity of tyrosine hydroxylase, which is indispensable in the production of norepinephrine for thermogenesis. Thus, our study aims to investigate whether 14-3-3ζ influences the development and function of beige and brown adipocytes. We report here that one allele deletion of the gene of 14-3-3ζ did not affect acute cold tolerance. On the other hand, transgenic overexpression of 14-3-3ζ in male mice (TAP) improves cold tolerance due to enhanced beiging with a remarkable increase in Ucp1 mRNA and protein in inguinal white adipose tissue (iWAT). Interestingly, beiging is increased in the TAP mice without any changes in sensitivity to beta-adrenergic stimuli, sympathetic innervation, or norepinephrine content being detected between WT and TAP mice. TAP mice also displayed significantly lower thermal conductance decreasing heat loss during the chronic cold challenge. Collectively, our results point to a novel role of 14-3-3ζ in beiging and increases our understanding of how adaptive thermogenesis is regulated.
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Čajková, Michaela. "Úloha receptorů spřažených s Gq proteiny v hnědých adipocytech." Master's thesis, 2015. http://www.nusl.cz/ntk/nusl-331783.
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Charles university in Prague, Pharmaceutical faculty in Hradci Králové, Department of biological and medical sciences Rheinische Friedrich-Wilhelms-University Bonn, Institute of Pharmacology and Toxicology Candidate: Michaela Čajková Supervisor: PharmDr. Miroslav Kovařík, Ph.D. Consultant: Dr. Linda Sarah Hoffmann Title of diploma thesis: Role of Gq-coupled receptors in brown adipocytes In my diploma thesis, we focused on four Gq-coupled receptors (F2R, LPHN1, α1DAR, TSHR) in brown adipocytes (BAs), which were identified in the screen as the highest expressed in immature and mature BAs. Our goal was to validate suggestion, that Thyroid stimulating hormone receptor (TSHR) plays a key role in differentiation of BAs and that F2R, LPHN1, α1D-AR might be important for BAs. In our study, we investigated gene expression of these four receptors in BAs, using analytical methodsquantitative reverse-transcriptase polymerase chain reaction (qRT-PCR) and Western blot. Results from analysis revealed, that expression of TSHR was increased in mature BAs, it means, that TSHR induce differentiation of BAs. The BAs transduced with short hairpin RNA (sh-RNA) against TSHR were less differentiated, this we proved also with Oil Red-O staining. Expression of adipocyte Protein 2 (aP2), peroxisome proliferator-activated...
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Long, Adam. "Analysis of brown adipocyte-derived VEGF-A." Thesis, 2016. https://hdl.handle.net/2144/19489.
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OBJECTIVE: While it has long been known that vascular endothelial growth factor A (VEGF-A) plays a role in vascular homeostasis, only recently have its effects been explored in adipose tissue. As perivascular adipose tissue (PVAT) is in close proximity with the aorta and coronary arteries and is known to contribute to vasodilation, it may influence vascular function via secretion of VEGF-A. The objective of this study is to analyze the effects of brown-adipocyte deletion of VEGF-A on circulating VEGF-A levels and distribution of VEGF-A isoforms. We hypothesize that ablation of VEGF-A in brown adipocytes will affect perivascular adipocyte and vascular function.
MATERIALS/ METHODS: Mice harboring a brown adipose-specific VEGF deficiency, UCP1cre.VEGFflox/flox mice, were maintained on a chow diet. Primary adipocytes were isolated from brown adipose tissue (BAT) and thoracic PVAT by collagenase digestion and culturing. Gene expression was measured by RT-PCR from RNA extracted from tissues of UCP1cre.VEGFflox/flox mice. Circulating and tissue VEGF-A levels were quantified by ELISA.
RESULTS: While VEGF-A ablation using the UCP1 promoter decreases VEGF- protein A levels in BAT and PVAT, it does not affect VEGF-A levels in the circulation.
CONCLUSION: This study confirms the functional utility of the UCP1cre.VEGFflox/flox mouse model, as it selectively reduces VEGF-A levels in BAT and PVAT without affecting other tissues or circulating levels. As previous studies using VEGF ablation in all adipose tissues demonstrate an impaired thermogenic response and brown-adipocyte dysfunction, further study of the brown adipose-specific mouse model is warranted. Because PVAT provides protection against vascular stiffness, modulation of VEGF-A in PVAT may be a viable treatment for obesity-associated vascular complications.
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Manolescu, Daniel-Constantin. "Impacts métaboliques et thérapeutiques de la vitamine A, sous forme d’acide rétinoïque, dans l’obésité, la résistance à l’insuline et le diabète de type 2 chez la souris ob/ob = Metabolic and Therapeutic Impacts of Vitamin A as Retinoic Acid on Obesity, Insulin Resistance, and Type 2 Diabetes in ob/ob Mice." Thèse, 2018. http://hdl.handle.net/1866/21808.
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YI, Liu LI, and 留立穎. "The Role of CCL5 Mediated Signal in the Development of Brown-like Adipocyte And Its Underlying Mechanism." Thesis, 2014. http://ndltd.ncl.edu.tw/handle/62841630859236437590.
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碩士國防醫學院
生理學研究所
102
Obesity caused by energy imbalance is a worldwide public health problem in the modern societies. Adipocytes play an important role in energy regulation. White adipocytes can store energy and brown adipocyte can deplete energy. The aim of current study is to investigate the role of CCL5 mediated signal in the development of brown-like adipocyte and its underlying mechanism. The in vitro experiment were conducted with human SGBS pre-adipocytes, mouse 3T3-L1 cell, primary pre-adipocytes isolated from inguinal, epididymis adipose tissue to evaluate the role of CCL5 in regulation of adaptive thermogenesis and lipolysis. The result showed that adipocyte UCP-1 expression was higher in low glucose medium than in high glucose medium in SGBS and 3T3-L1 cells. However, adipocyte UCP-1 expression in low and high glucose medium were in reverse order when coculture with isoproterenol. CCL5 treated could suppress UCP-1 expression in culture medium The result of oil red was increased when treated CCL5 in SGBS cells but it was decreases in 3T3-L1 adipocyte. The glycerol in low glucose medium was higher than high glucose medium in SGBS cells but it was decreases in 3T3-L1 adipocyte. When adipocytes treated CCL5, SGBS cells increased and 3T3-L1 decreased secretion of glycerol. However, pHSL ser660/ tHSL was increased when treated CCL5 in SGBS and 3T3-L1. On the other hand, primary culture of subcutaneous and visceral adipocyte secreted different level CCL5 and also showed different responses about glycerol when treated CCL5. This study suggests that CCL5 could decrease adaptive thermogenesis and regulate lipolysis to affect energy homeostasis.
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Goh, Ted. "Novel approaches to white adipose browning and beige adipose activation for the treatment of obesity." Thesis, 2017. https://hdl.handle.net/2144/26568.
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Brown and beige fat are specialized adipose tissues found in almost all mammals that can increase energy expenditure and produce heat. Cold exposure and b3-adrenergic stimulation has been extensively shown to activate brown adipose tissue (BAT) in rodents, which promotes uncoupled respiration of glucose and lipid substrates via uncoupling protein 1 (UCP1). Prolonged stimulation can induce white adipose browning, which leads to the emergence of thermogenic cells within white fat depots, called beige adipocytes. The beige adipocyte possesses a unique molecular signature, yet shares several characteristics of brown adipocytes, including high mitochondrial content. When activated, beige fat can be induced to initiate a thermogenic transcriptional program similar to that of BAT. Recent human studies have identified brown and/or beige fat in the supraclavicular region using various radiation imaging modalities. This remarkable discovery has reinvigorated scientific interest in adipose browning and brown/beige fat activation as possible therapeutic targets for obesity. Like in rodents, several groups have previously tested the potential impact of cold exposure and b3-adrenergic agonism on BAT-mediated thermogenesis in humans. However, even though these approaches were shown to significantly increase energy expenditure and promote weight loss in obese individuals, they are not ideal clinical interventions. Cold exposure is uncomfortable and requires prolonged treatment, while b3-adrenergic agonists may lead to many adverse effects like cardiovascular problems. This thesis will evaluate the therapeutic potential and clinical relevance of alternative anti-obesity approaches that target adipose browning and beige adipose activation.
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Zhao, Shangang. "Monoacylglycerol, alpha/beta-hydrolase domain-6, and the regulation of insulin secretion and energy metabolism." Thèse, 2015. http://hdl.handle.net/1866/13533.
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Le cycle glycérolipides/acides gras libres (GL/FFA) est une voie métabolique clé qui relie le métabolisme du glucose et des acides gras et il est composé de deux processus métaboliques appelés lipogenèse et lipolyse. Le cycle GL/FFA, en particulier la lipolyse des triglycérides, génère diverses molécules de signalisation pour réguler la sécrétion d'insuline dans les cellules bêta pancréatiques et la thermogenèse non-frissonnante dans les adipocytes. Actuellement, les lipides provenant spécifiquement de la lipolyse impliqués dans ce processus sont mal connus.
L’hydrolyse des triglycérides dans les cellules β est réalisée par les actions successives de la triglycéride lipase adipocytaire pour produire le diacylglycérol, ensuite par la lipase hormono-sensible pour produire le monoacylglycérol (MAG) et enfin par la MAG lipase (MAGL) qui relâche du glycerol et des acides gras. Dans les cellules bêta, la MAGL classique est très peu exprimée et cette étude a démontré que l’hydrolyse de MAG dans les cellules β est principalement réalisée par l'α/β-Hydrolase Domain-6 (ABHD6) nouvellement identifiée. L’inhibition d’ABHD6 par son inhibiteur spécifique WWL70, conduit à une accumulation des 1-MAG à longues chaines saturées à l'intérieur des cellules, accompagnée d’une augmentation de la sécrétion d'insuline stimulée par le glucose (GSIS). Baisser les niveaux de MAG en surexprimant ABHD6 dans la lignée cellulaire bêta INS832/13 réduit la GSIS, tandis qu’une augmentation des niveaux de MAG par le « knockdown » d’ABHD6 améliore la GSIS. L'exposition aiguë des monoacylglycérols exogènes stimule la sécrétion d'insuline de manière dose-dépendante et restaure la GSIS supprimée par un inhibiteur de lipases appelé orlistat. En outre, les souris avec une inactivation du gène ABHD6 dans tous les tissus (ABHD6-KO) et celles avec une inactivation du gène ABHD6 spécifiquement dans la cellule β présentent une GSIS stimulée, et leurs îlots montrent une augmentation de la production de monoacylglycérol et de la sécrétion d'insuline en réponse au glucose. L’inhibition d’ABHD6 chez les souris diabétiques (modèle induit par de faibles doses de streptozotocine) restaure la GSIS et améliore la tolérance au glucose. De plus, les résultats montrent que les MAGs non seulement améliorent la GSIS, mais potentialisent également la sécrétion d’insuline induite par les acides gras libres ainsi que la sécrétion d’insuline induite par divers agents et hormones, sans altération de l'oxydation et l'utilisation du glucose ainsi que l'oxydation des acides gras. Nous avons démontré que le MAG se lie à la protéine d’amorçage des vésicules appelée Munc13-1 et l’active, induisant ainsi l’exocytose de l'insuline. Sur la base de ces observations, nous proposons que le 1-MAG à chaines saturées agit comme facteur de couplage métabolique pour réguler la sécrétion d'insuline et que ABHD6 est un modulateur négatif de la sécrétion d'insuline.
En plus de son rôle dans les cellules bêta, ABHD6 est également fortement exprimé dans les adipocytes et son niveau est augmenté avec l'obésité. Les souris dépourvues globalement d’ABHD6 et nourris avec une diète riche en gras (HFD) montrent une faible diminution de la prise alimentaire, une diminution du gain de poids corporel et de la glycémie à jeun et une amélioration de la tolérance au glucose et de la sensibilité à l'insuline et ont une activité locomotrice accrue. En outre, les souris ABHD6-KO affichent une augmentation de la dépense énergétique et de la thermogenèse induite par le froid. En conformité avec ceci, ces souris présentent des niveaux élevés d’UCP1 dans les adipocytes blancs et bruns, indiquant le brunissement des adipocytes blancs. Le phénotype de brunissement est reproduit dans les souris soit en les traitant de manière chronique avec WWL70 (inhibiteur d’ABHD6) ou des oligonucléotides anti-sense ciblant l’ABHD6. Les tissus adipeux blanc et brun isolés de souris ABHD6-KO montrent des niveaux très élevés de 1-MAG, mais pas de 2-MAG. L'augmentation des niveaux de MAG soit par administration exogène in vitro de 1-MAG ou par inhibition ou délétion génétique d’ABHD6 provoque le brunissement des adipocytes blancs. Une autre évidence indique que les 1-MAGs sont capables de transactiver PPARα et PPARγ et que l'effet de brunissement induit par WWL70 ou le MAG exogène est aboli par les antagonistes de PPARα et PPARγ. L’administration in vivo de l’antagoniste de PPARα GW6471 à des souris ABHD6-KO inverse partiellement les effets causés par l’inactivation du gène ABHD6 sur le gain de poids corporel, et abolit l’augmentation de la thermogenèse, le brunissement du tissu adipeux blanc et l'oxydation des acides gras dans le tissu adipeux brun. L’ensemble de ces observations indique que ABHD6 régule non seulement l’homéostasie de l'insuline et du glucose, mais aussi l'homéostasie énergétique et la fonction des tissus adipeux.
Ainsi, 1-MAG agit non seulement comme un facteur de couplage métabolique pour réguler la sécrétion d'insuline en activant Munc13-1 dans les cellules bêta, mais régule aussi le brunissement des adipocytes blancs et améliore la fonction de la graisse brune par l'activation de PPARα et PPARγ. Ces résultats indiquent que ABHD6 est une cible prometteuse pour le développement de thérapies contre l'obésité, le diabète de type 2 et le syndrome métabolique.The glycerolipid/ free fatty acid (GL/FFA) cycle is a key metabolic pathway that links glucose and fatty acid metabolism and it consists of lipogenesis and lipolysis. GL/FFA cycling, especially in its lipolysis arm, generates various lipid signaling molecules to regulate insulin secretion in pancreatic ß-cells and non-shivering thermogenesis in adipocytes. Currently, the lipolysis-derived lipid signals involved in this process are uncertain. Triglyceride hydrolysis in mammalian cells is accomplished by the sequential actions of adipose triglyceride lipase to produce diacylglycerol, by hormone sensitive lipase to produce monoacylglycerol (MAG) and by MAG lipase (MAGL) that releases free fatty acid and glycerol. Our work shows that in pancreatic ß-cell, the classical MAGL is poorly expressed and that MAG hydrolysis is mainly conducted by the newly identified α/β-Hydrolase Domain-6 (ABHD6). Inhibition of ABHD6 by its specific inhibitor WWL70, leads to long-chain saturated 1-MAG accumulation inside the cells, accompanied by enhanced glucose-stimulated insulin secretion (GSIS). Decreasing the MAG levels by overexpression of ABHD6 in the ß-cell line INS832/13 reduces GSIS, while increasing MAG levels by ABHD6 knockdown enhances GSIS. Acute exposure of INS832/13 cells to various MAG species dose-dependently stimulates insulin secretion and restores GSIS suppressed by the pan-lipase inhibitor orlistat. Also, various biochemical and pharmacological experiments show that saturated 1-MAG levels species rather than unsaturated or 2-MAG species best correlate with insulin secretion. Furthermore, whole-body and β-cell-specific ABHD6-KO mice exhibit enhanced GSIS in vivo, and their isolated islets show elevated MAG production and GSIS. Inhibition of ABHD6 in low dose streptozotocin diabetic mice restores GSIS and improves glucose tolerance. Results further show that ABHD6-accessible MAGs not only enhance GSIS, but also potentiate fatty acid and non-fuel-induced insulin secretion without alteration in glucose oxidation and utilization as well as fatty acid oxidation. We have identified that MAG binds and activates the vesicle priming protein Munc13-1, thereby inducing insulin exocytosis. Based on all these observations, we propose that lipolysis-derived saturated 1-MAG acts as a metabolic coupling factor to regulate insulin secretion and ABHD6 is a negative modulator of insulin secretion. Besides its role in ß-cells, ABHD6 is also highly expressed in adipocytes and its level is increased with obesity. Mice globally lacking ABHD6 on high fat diet (HFD) show modestly reduced food intake, decreased body weight gain, insulinemia and fasting glycemia and improved glucose tolerance and insulin sensitivity and enhanced locomotor activity. In addition, ABHD6-KO mice display increased energy expenditure and cold-induced thermogenesis. In accordance with this, these mice show elevated UCP1 level in white and brown adipocytes, indicating browning of white adipocytes. The browning phenotype is reproduced in the mice either chronically treated with the ABHD6 inhibitor WWL70 or an antisense oligonucleotides targeting ABHD6. White and brown adipose tissues isolated from whole body ABHD6 KO mice show greatly elevated levels of 1-MAG, but not 2-MAG. Increasing MAG levels by either exogenous administration of 1-MAG or ABHD6 inhibition or genetic deletion induces browning of white adipocytes in a cell-autonomous manner. Further evidence indicates that 1-MAGs can transactivate PPARα and PPARγ and the browning effect induced by WWL70 or exogenous MAG is abolished by PPARα and PPARγ antagonists. In vivo administration of the PPARα antagonist GW6471 to ABHD6 KO mice partially reversed the ABHD6-KO effects on body weight gain, and abolishes the enhanced thermogenesis, white adipose browning and fatty acid oxidation in brown adipose tissue. All these observations indicate that ABHD6 regulates not only insulin and glucose homeostasis but also energy homeostasis and adipose tissue function. Thus, ABHD6-accessible 1-MAG not only acts as a metabolic coupling factor to regulate fuel and non-fuel induced insulin secretion by activating Munc13-1 in beta cells, but also regulates glucose, insulin and energy homeostasis. The latter effects are mediated at least in part via browning of white adipocytes and enhanced brown fat function through the activation of PPARα and PPARγ. Collectively these findings suggest that ABHD6 is a promising target for developing therapeutics against obesity, type 2 diabetes and metabolic syndrome.