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1
Eriksson, Maria. „Adipocyte-derived hormones and cardiovascular disease“. Doctoral thesis, Umeå universitet, Institutionen för folkhälsa och klinisk medicin, 2010. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-36679.
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Obesity is increasing globally and related to major changes in lifestyle. This increase is associated with an increased risk of cardiovascular disease (CVD). Knowledge about adipose tissue as a metabolic-endocrine organ has increased during the last few decades. Adipose tissue produces a number of proteins with increased body weight, many of which are important for food intake and satiety, insulin sensitivity, and vessel integrity, and aberrations have been related to atherosclerosis. Notably, the risk for developing CVD over the course of a lifetime differs between men and women. In Northern Sweden, men have a higher risk for myocardial infarction (MI). However, the incidence is declining in men but not in women. These sex differences could be due to functional and anatomical differences in the fat mass and its functions. The primary aim of this thesis was to evaluate associations between the adipocyte-derived hormones leptin and adiponectin, and fibrinolysis and other variables associated with the metabolic syndrome, and particularly whether these associations differ between men and women. Another aim was to evaluate these associations during physical exercise and pharmacological intervention (i.e. enalapril). Finally, whether leptin and adiponectin predict a first MI or sudden cardiac death with putative sex differences was also investigated. The first study used a cross-sectional design and included 72 men and women recruited from the WHO MONICA project. We found pronounced sex differences in the associations with fibrinolytic variables. Leptin was associated with fibrinolytic factors in men, whereas insulin resistance was strongly associated with all fibrinolytic factors in women. The second study was an experimental observational study with 20 men exposed to strenuous physical exercise. During exercise, leptin levels decreased and adiponectin levels increased, and both were strongly associated with an improved fibrinolytic capacity measured as decreased PAI-1 activity. Changes in insulin sensitivity were not associated with changing adiponectin levels. The third study was a randomised, double-blind, single centre clinical trial including 46 men and 37 women who had an earlier MI. The study duration was one year, and participating subjects were randomised to either placebo or ACE inhibitor (i.e. enalapril). Circulating leptin levels were not associated with enalapril treatment. During the one-year study, changes in leptin levels were associated with changes in circulating levels of tPA mass, PAI-1 mass, and tPA-PAI complex in men, but not vWF. These associations were found in all men and men on placebo treatment. In women on enalapril treatment there was an association between changes in leptin and changes in vWF. In the fourth study, the impact of leptin, adiponectin, and their ratio on future MI risk or sudden cardiac death was tested in a prospective nested casecontrol study within the framework of the WHO MONICA, Västerbotten Intervention Project (VIP), and Västerbotten Mammary Screening Program (MSP). A total 564 cases (first-ever MI or sudden cardiac death) and 1082 matched controls were selected. High leptin, low adiponectin, and a high leptin/adiponectin ratio independently predicted a first-ever MI, possibly with higher risk in men in regards to leptin. The association was found for non-fatal cases with ST-elevation MI. Subjects with low adiponectin levels had their MI earlier than those with high levels. In conclusion, the adipocyte-derived hormones leptin and adiponectin are related to the development of CVD with a sex difference, and fibrinolytic mechanisms could be possible contributors to CVD risk.
2
Lu, Buyu. „Hormones of stress and control of adipocyte biological "colour"“. Thesis, University of Warwick, 2011. http://wrap.warwick.ac.uk/46849/.
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The family of “stress” peptides that includes CRH and UCNs are emerging as important regulators of the homeostatic mechanisms regulating energy balance and metabolism. These peptides exert well documented central anorectic and thermogenic actions in controlling food uptake and optimise energy losses. Furthermore, CRH acting through specific G-protein coupled receptors, CRH-R1 and R2 can target multiple peripheral tissues such as skeletal muscle and adipose tissue to influence important metabolic pathways. Two types of adipose tissue exist in mammals: WAT and BAT. Since WAT is the largest energy reserve in mammals and BAT can utilize energy through adaptive thermogenesis, one of the goals in this study was to identify the presence of CRH system components in adipose tissue. Real time RT-PCR and immunofluorescence demonstrated that CRH-Rs as well as CRH, UCN-I, and UCN-II are expressed in both WAT and BAT, raising the possibility that CRH and UCNs are important regulators of energy storage and adaptive thermogenesis. Also the functional roles of CRH-Rs in adipose tissue were investigated. Using an experimental paradigm the T37i fibroblast that can differentiate into brown adipocyte, it was demonstrated that CRH at low (nanomolar) but not high (submicromolar) concentrations stimulated a signaling pathway involving the AC/cAMP/PKA/AMPK signaling cascade that regulates downstream phosphorylation of HSL. This was associated with a significant translocation of HSL toward lipid droplets and association with perilipin, as demonstrated with immunofluorescence. Studies applying quantitative RT-PCR also suggested that CRH-R1 appears to regulate genes important for adaptive thermogenesis, whereas CRH-R2 likely regulates brown adipocyte formation. Further analysis using an experimental paradigm the 3T3L1 fibroblast that can differentiate into white adipocyte showed that exposure of 3T3L1 cells to UCN-II (a specific CRH-R2 agonist) or NBI-27914 (a CRH-R1 specific antagonist) were able to induce morphological and biochemical characteristics suggesting adipocyte differentiation to a “beige” phenotype in white preadipocytes/adipocytes. Thus, CRH-R1 and R2 could be of potential importance in maintenance of energy homeostasis. Moreover, in vivo analysis showed that CRH system seems to demonstrate a certain degree of plasticity in response to stress perturbation. For instance, HFD significantly repressed the expression of CRH-Rs and their agonists, whereas food deprivation dramatically increased their expression. The analysis of quantitative RTPCR demonstrated that this activation of CRH system might be associated with induction of ‘beige’ cells in white fat depots. Since CRH-R1 KO mice displayed a lean phenotype and resistance to HFD-induced fat accumulation and these phenotypes can be reversed by supplementation of corticosterone, role of CRH-R2 in adipose tissue of these KO mice was investigated. Data showed that CRH-R2 activation likely induced BAT activity and transdifferentiation from WAT to BAT in CRH-R1 KO mice. Corticosterone reversed these changes in KO mice via potential suppression of CRH-R2.
3
Auffret, Julien. „Impact des hormones lactogènes sur la cellule β pancréatique et l’adipocyte“. Thesis, Paris 11, 2012. http://www.theses.fr/2012PA11T087/document.
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Pour étudier l’impact de la signalisation de la prolactine (PRL), une hormone impliquée dans la proliférationcellulaire sur l’adipocyte et la cellule β pancréatique, deux types cellulaires impliqués dans la balanceénergétique, nous avons caractérisé le phénotype de souris déficientes en récepteur de la PRL (R PRL-/-) sousdifférentes conditions physiopathologiques. Dans un premier temps, nous avons étudié l’impact du R PRL sur ledéveloppement d’une obésité induite par un régime obésogène. Dans un deuxième temps, nous nous sommesintéressés à l’impact du R PRL sur l’ontogenèse des cellules β durant les adaptations périnatales. Nous avonsaussi évalué son rôle sur la sécrétion d’insuline à l’âge adulte.Notre première étude montre que les souris R PRL-/- sous régime obésogène ont une prise de poids réduite etune augmentation de la dépense énergétique comparées à celles des souris sauvages. Nous montrons que desadipocytes beiges, une nouvelle classe d’adipocytes thermoactifs récemment caractérisés et exprimant laprotéine découplante UCP1, émergent dans le tissu adipeux blanc périrénal des souris R PRL-/- soumises à unrégime gras. Nous avons démontré que le R PRL contribue à l’apparition des adipocytes beiges en modulant lavoie de signalisation pRb/FoxC2 permettant la résistance à l’obésité induite par le régime gras.Notre deuxième étude montre que la souris R PRL-/- et le rat GK, un modèle de diabète de type 2, ont un défautd’adaptation de la masse des cellules β en période périnatale. Cette altération est corrélée à un défautd’expression d’igf2 (Insulin-like Growth Factor 2), une cible de la PRL. A partir d’îlots de Langherans de sourisadultes, nous avons confirmé que le R PRL est essentiel à la sécrétion d’insuline.Les résultats obtenus ont permis de mieux comprendre le rôle de la PRL sur la balance énergétique. Ces travauxouvrent des perspectives nouvelles pour le développement de stratégies thérapeutiques dans la lutte contrel’obésité et le diabète de type IIIn order to study the impact of prolactin (PRL) signaling on pancreatic β-cell and adipocyte, two cell typesinvolved in energy balance, we characterized the phenotype of PRL receptor deficient mice (PRL R-/-) underdifferent physiopathological conditions. First, we studied the impact of PRL R on the development of obesityinduced by a high fat diet. Second, we investigated the impact of PRL R on β-cell ontogenesis during perinataladaptation and its role in insulin secretion during adulthood.Our first study shows that PRL R-/- mice under obesogenic diet have a reduced weight gain and an increase ofenergy expenditure as compared to those of wild-type mice. We showed that beige adipocytes, a new class ofthermogenic adipocytes recently characterized expressing uncoupling protein UCP1, emerged in the perirenalwhite adipose tissue of PRL R-/- mice challenged with a high fat diet. Altered expression of pRb/FoxC2 suggeststhat PRL R contributes to the development of beige adipocytes modulating this signaling pathway for resistanceto high fat diet induced obesity.Our second study shows that PRL R-/- mice do not adapt β-cell mass in perinatal period and this alteration isassociated with a lack of igf2 (Insulin-like Growth Factor 2) expression, a PRL target. We confirmed that R PRL isessential for insulin secretion using b islets in adult animals.These results lead to a better understanding of the PRL role on energy balance, and open new perspectives forthe development of therapeutic strategies in obesity and type II diabetes
4
Ortega, Delgado Francisco José. „Mecanismos de regulación del anabolismo lipídico en el tejido adiposo del paciente obeso“. Doctoral thesis, Universitat de Girona, 2012. http://hdl.handle.net/10803/83713.
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Obesity is one of the most important public health problems facing the world today. Gene expression studies applied to fat depots from obese subjects have provided important clues about the pathophysiology of adipose tissue. The data collected in this thesis show that the synthesis of fatty acids (lipogenesis) is decreased in the adipose tissue of obese subjects, and describe the behavior of a new lipogenic factor. We also demonstrate that subcutaneous fat (beneath the skin of the buttocks, thighs and abdomen) is characterized by a greater responsiveness to thyroid hormones than the visceral (around the omentum, the intestines and the perirenal areas), and describe the increased activity of enzymes that activate thyroid hormones in adipose tissue of obese patients and the effects on the metabolism. According to these results, the local activation of thyroid hormone and the ability to synthesize fat are altered in adipose tissue from obese patients, and indicate significant differences between visceral and subcutaneous adipose tissue depots.La obesidad es uno de los problemas de salud pública más importante. Los estudios de expresión aplicados a los depósitos de grasa en sujetos obesos han aportado importantes indicios sobre la fisiopatología del tejido adiposo. Los datos recogidos en esta tesis doctoral demuestran que la síntesis de grasa (lipogénesis) está disminuida en el tejido adiposo del paciente obeso, y describen el comportamiento de un nuevo factor lipogénicos. Se demuestra además que el tejido adiposo subcutáneo (situado bajo la piel de las nalgas , muslos y abdomen) está caracterizado por una mayor capacidad de respuesta a las hormonas tiroideas respecto al adiposo visceral (alrededor del epiplón, los intestinos y las áreas perirrenal) y se describe un incremento en la actividad de las enzimas que activan las hormonas tiroideas en el tejido adiposo del paciente obeso y los posibles efectos de esta eventualidad sobre el metabolismo. Según los resultados recopilados en esta tesis doctoral, la activación local de hormonas tiroideas y la capacidad para sintetizar acidos grasos del tejido adiposo del paciente obeso están alteradas, e indican importantes diferencias entre los depósitos de grasa visceral y subcutáneo.
L’obesitat és un dels problemes de salut pública més important. Els estudis d'expressió aplicats als dipòsits de greix en subjectes obesos han aportat importants indicis sobre la fisiopatologia del teixit adipós. Les dades recollides a aquesta tesi doctoral demostren que la síntesis de greix (lipogènesis) està disminuïda al teixit adipós del pacient obès, i descriuen el comportament d'un nou factor lipogènic. Es demostra, a més a més, que el teixit adipós subcutani (situat sota la pell de les natges, cuixes i abdomen) està caracteritzat per una major capacitat de resposta a les hormones tiroidees respecte a l'adipós visceral (al voltant de l’epipló, els intestins i las àrees perirenals) i es descriu un increment en l’activitat dels enzims que activen les hormones tiroidees al teixit adipós del pacient obès i els possibles efectes d'aquesta eventualitat sobre el metabolisme. Segons els resultats recopilats a aquesta tesi doctoral, l’activació local d'hormones tiroidees i la capacitat per sintetitzar greixos del teixit adipós del pacient obès estan alterades, i indiquen importants diferències entre els dipòsits de greix visceral i subcutani.
5
Plee-Gautier, Emmanuelle. „Regulation par les hormones et les nutriments de l'expression de deux genes du metabolisme intermediaire de l'adipocyte ; la lipase hormono-sensible et l'aspartate aminotransferase“. Paris 11, 1997. http://www.theses.fr/1997PA11T034.
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6
Christianson, Jennifer L. „Defining the Importance of Fatty Acid Metabolism in Maintaining Adipocyte Function: A Dissertation“. eScholarship@UMMS, 2009. https://escholarship.umassmed.edu/gsbs_diss/415.
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Although once considered a simple energy storage depot, the adipose tissue is now known to be a powerful regulator of whole body insulin sensitivity and energy metabolism. This metabolically dynamic organ functions to safely store excess fatty acid as triglyceride, thereby preventing lipotoxicity in peripheral tissues and the development of insulin resistance. In addition, the adipose tissue acts as an endocrine organ and secretes factors, called adipokines, which influence whole body insulin sensitivity and glucose homeostasis. Therefore, understanding adipose tissue development and biology is essential to understanding whole body energy metabolism.
A master regulator of adipose tissue development and whole body insulin sensitivity is the nuclear receptor, PPARγ. Due to the importance of this nuclear receptor in maintaining adipocyte function, disruptions in PPARγ activity result in severe metabolic abnormalities, such as insulin resistance and type 2 diabetes. Conversely, PPARγ activation by synthetic agonists ameliorates these conditions, demonstrating the potent control this nuclear receptor has on whole body metabolism. Therefore, understanding how PPARγ expression and activity are regulated, particularly in the adipose tissue, is paramount to understanding the pathogenesis of type 2 diabetes.
While there are several synthetic PPARγ agonists available, identifying the endogenous ligand or ligands is still an area of intense investigation. Since fatty acids can induce PPARγ activation, in the first part of this thesis, I screened several fatty acid metabolizing enzymes present in the adipocyte to identify novel modulators of PPARγ activity. These studies revealed that the fatty acid Δ9 desaturase, Stearoyl CoA Desaturase 2 (SCD2), is absolutely required for 3T3-L1 adipogenesis and to maintain adipocyte-specific gene expression in fully differentiated cells. Although SCD2 does not appear to regulate PPARγ ligand production, it does potently regulate PPARγ activity by maintaining the synthesis of PPARγ protein. Surprisingly, this effect was found only with SCD2 and not with the highly homologous protein, SCD1. Therefore, these findings identify separate cellular functions for these SCD isoforms and reveal a novel and essential role for fatty acid desaturation in the adipocyte.
Equally important to understanding PPARγ regulation is identifying the downstream mechanisms by which PPARγ activation improves insulin sensitivity. Evidence suggests that the PPARγ target gene, Cidea, is involved in mediating insulin sensitivity by binding to lipid droplets and promoting lipid storage in the adipocyte. Therefore, the second part of thesis provides mechanistic detail into Cidea function by showing that the carboxy terminal 104 amino acids is necessary and sufficient for lipid droplet targeting and the stimulation of triglyceride storage. However, these studies also identified a novel function for Cidea, which requires both the carboxy and amino termini: to induce larger and fewer droplets from smaller dispersed droplets, indicating the possible fusion of droplets. Perhaps this striking change in lipid droplet morphology allows tighter packing and more efficient storage of triglyceride and identifies a novel role for Cidea in lipid metabolism.
The results presented in this thesis elucidate key aspects of lipid metabolism that maintain adipocyte function: SCD2 is required to maintain PPARγ protein expression in the mouse; Cidea is a downstream effector of PPARγ activity by promoting efficient triglyceride storage. Therefore, these findings enhance our understanding of adipocyte biology.
7
Liu, Jing, und 刘静. „Investigation of the molecular mechanisms underlying the anti-breast cancer activity of an adipocyte-derived hormone, adiponectin“. Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2011. http://hub.hku.hk/bib/B46503237.
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8
Lau, Tik-yan Ivy. „Macrophage-adipocyte cross-talk in the initiation of obesity-related insulin resistance and type 2 diabetes : role of adiponectin /“. Click to view the E-thesis via HKUTO, 2008. http://sunzi.lib.hku.hk/hkuto/record/B4129046X.
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9
Hoong, Isabelle Yoke Yien. „Expression of 11β-hydroxysteroid dehydrogenases in mice and the role of glucocorticoids in adipocyte function“. Monash University, Dept. of Biochemistry and Molecular Biology, 2003. http://arrow.monash.edu.au/hdl/1959.1/9473.
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10
Lau, Tik-yan Ivy, und 劉荻茵. „Macrophage-adipocyte cross-talk in the initiation of obesity-related insulin resistance and type 2 diabetes: roleof adiponectin“. Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2008. http://hub.hku.hk/bib/B4129046X.
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11
Auffret, Julien. „Impact des hormones lactogènes sur la cellule β pancréatique et l'adipocyte“. Phd thesis, Université Paris Sud - Paris XI, 2012. http://tel.archives-ouvertes.fr/tel-00915468.
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Pour étudier l'impact de la signalisation de la prolactine (PRL), une hormone impliquée dans la proliférationcellulaire sur l'adipocyte et la cellule β pancréatique, deux types cellulaires impliqués dans la balanceénergétique, nous avons caractérisé le phénotype de souris déficientes en récepteur de la PRL (R PRL-/-) sousdifférentes conditions physiopathologiques. Dans un premier temps, nous avons étudié l'impact du R PRL sur ledéveloppement d'une obésité induite par un régime obésogène. Dans un deuxième temps, nous nous sommesintéressés à l'impact du R PRL sur l'ontogenèse des cellules β durant les adaptations périnatales. Nous avonsaussi évalué son rôle sur la sécrétion d'insuline à l'âge adulte.Notre première étude montre que les souris R PRL-/- sous régime obésogène ont une prise de poids réduite etune augmentation de la dépense énergétique comparées à celles des souris sauvages. Nous montrons que desadipocytes beiges, une nouvelle classe d'adipocytes thermoactifs récemment caractérisés et exprimant laprotéine découplante UCP1, émergent dans le tissu adipeux blanc périrénal des souris R PRL-/- soumises à unrégime gras. Nous avons démontré que le R PRL contribue à l'apparition des adipocytes beiges en modulant lavoie de signalisation pRb/FoxC2 permettant la résistance à l'obésité induite par le régime gras.Notre deuxième étude montre que la souris R PRL-/- et le rat GK, un modèle de diabète de type 2, ont un défautd'adaptation de la masse des cellules β en période périnatale. Cette altération est corrélée à un défautd'expression d'igf2 (Insulin-like Growth Factor 2), une cible de la PRL. A partir d'îlots de Langherans de sourisadultes, nous avons confirmé que le R PRL est essentiel à la sécrétion d'insuline.Les résultats obtenus ont permis de mieux comprendre le rôle de la PRL sur la balance énergétique. Ces travauxouvrent des perspectives nouvelles pour le développement de stratégies thérapeutiques dans la lutte contrel'obésité et le diabète de type II.
12
Hagan, G. Nana. „Adipocyte Insulin-Mediated Glucose Transport: The Role of Myosin 1c, and a Method for in vivo Investigation: A Dissertation“. eScholarship@UMMS, 2008. https://escholarship.umassmed.edu/gsbs_diss/403.
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The importance of insulin delivery and action is best characterized in Type 2 Diabetes, a disease that is becoming a pandemic both nationally and globally. Obesity is a principal risk factor for Type 2 Diabetes, and adipocyte function abnormalities due to adipose hypertrophy and hyperplasia, have been linked to obesity. Numerous reports suggest that the intracellular and systemic consequences of adipocyte function abnormalities include adipocyte insulin resistance, enhanced production of free fatty acids, and production of inflammatory mediators. A hallmark of adipocyte insulin sensitivity is the stimulation of glucose transporter isoform 4 (GLUT4) trafficking events to promote glucose uptake. In the Type 2 diabetic and insulin resistant states the mechanism behind insulin-stimulated GLUT4 trafficking is compromised. Therefore, understanding the role of factors involved in glucose-uptake in adipose tissue is of great importance.
Studies from our laboratory suggest an important role for the unconventional myosin, Myo1c, in promoting insulin-mediated glucose uptake in cultured adipocytes. Our observations suggest that depletion of Myo1c in cultured adipocytes results in a significant reduction in the ability of adipocytes to take up glucose following insulin treatment, suggesting Myo1c is required for insulin-mediated glucose uptake. A plausible mechanism by which Myo1c promotes glucose uptake in adipocytes has been suggested by further work from our laboratory in which expression of fluorescently-tagged Myo1c in cultured adipocytes induces significant membrane ruffling at the cell periphery, insulin-independent GLUT4 translocation to the cell periphery, and accumulation of GLUT4 in membrane ruffling regions. Taken together Myo1c seems to facilitate glucose uptake through remodeling of cortical actin.
In the first part of this thesis I, in collaboration with others, uncovered a possible mechanism through which Myo1c regulates adipocyte membrane ruffling. Here we identified a novel protein complex in cultured adipocytes, comprising Myo1c and the mTOR binding partner, Rictor. Interestingly our studies in cultured adipocytes suggest that the Rictor-Myo1c complex is biochemically distinct from the Rictor-mTOR complex of mTORC2. Functionally, only depletion of Rictor but not Myo1c results in decreased Akt phosphorylation at serine 473, but depletion of either Rictor or Myo1c results in compromised cortical actin dynamic events. Furthermore we observed that whereas the overexpression of Myo1c in cultured adipocytes causes remarkable membrane ruffling, Rictor depletion in cells overexpressing Myo1c significantly reduces these ruffling events. Taken together our findings suggest that Myo1c, in conjunction with Rictor, modulates cortical actin remodeling events in cultured adipocytes. These findings have implications for GLUT4 trafficking as GLUT4 has been previously observed to accumulate in Myo1c-induced membrane ruffles prior to fusion with the plasma membrane.
During our studies of adipocyte function we noticed that current siRNA electroporation methods present numerous limitations. To silence genes more effectively we employed a lentivirus-mediated shRNA delivery system, and to standardize this technology in cultured adipocytes we targeted Myo1c and MAP4K4. Using this technology we were able to achieve clear advantages over siRNA oligonucleotide electroporation techniques in stability and permanence of gene silencing. Furthermore we showed that the use of lentiviral vectors in cultured adipocytes did not affect insulin signaling or insulin-mediated glucose uptake events. Despite our inability to use lentiviral vectors to achieve gene silencing in mice we were able to achieve adipose tissue-specific gene silencing effects in mice following manipulation of the lentiviral conditional silencing vector, and then crossing resulting founders with aP2-Cre mice. Interestingly however, only founders from the MAP4K4 conditional shRNA vector, but not founders from the Myo1c conditional shRNA vector, showed gene knockdown, possibly due to position-effect variegation. Taken together, findings from these studies are important because they present an alternative means of achieving gene silencing in cultured adipocytes, with numerous advantages not offered by siRNA oligonucleotide electroporation methods. Furthermore, the in vivo, adipose tissue-specific RNAi studies offer a quick, inexpensive, and less technically challenging means of achieving adipose tissue-specific gene ablations relative to traditional gene knockout approaches.
13
Morigny, Pauline. „Etude des mécanismes liant l'inhibition de la lipase hormono-sensible et l'amélioration de la sensibilité à l'insuline“. Thesis, Toulouse 3, 2017. http://www.theses.fr/2017TOU30267.
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Le développement d'une résistance à l'action de l'insuline est fréquemment observée au cours de l'obésité et est à l'origine du diabète de type 2. L'amélioration du signal insulinique au sein de la cellule adipeuse (i.e adipocyte) est une stratégie thérapeutique intéressante en vue d'améliorer la sensibilité à l'insuline systémique de patients pré-diabétiques et diabétiques. Dans cette optique, l'inhibition de la lipase hormono-sensible (LHS) adipocytaire (enzyme responsable de la libération d'acides gras par le tissu adipeux) protège de l'insulino-résistance. Les mécanismes impliqués dans l'amélioration de la sensibilité à l'insuline n'étaient cependant pas encore connus. Mon travail de thèse a donc été axé sur l'identification des mécanismes liant l'inhibition de la LHS et l'amélioration de la sensibilité à l'insuline. Dans des adipocytes humains, l'invalidation de la LHS augmente le transport du glucose, la voie de la lipogenèse de novo (synthèse d'acides gras à partir du glucose) et le signal insulinique. Parmi les enzymes lipogéniques, l'élongase des acides gras à longue chaîne ELOVL6 voit son expression très fortement induite in vitro et in vivo lors d'une déficience pour la LHS, conduisant à un enrichissement en oléate des phospholopides et des triglycérides. L'invalidation d'ELOVL6 dans des adipocytes humains a permis de démontrer le rôle clé de l'élongase dans la médiation des effets bénéfiques de l'invalidation de la LHS. In vivo, une déficience pour ELOVL6 conduit également à une détérioration du signal insulinique dans le tissu adipeux. Dans des études cliniques, l'expression d'ELOVL6 s'effondre au cours de l'insulino-résistance et est restaurée après une chirurgie bariatrique. L'enrichissement en oléate dans les phospholipides par ELOVL6 est responsable des effets protecteurs de l'inhibition de la LHS sur le signal insulinique. Des adipocytes surexprimant ELOVL6 présentent d'ailleurs une augmentation de la fluidité membranaire associée à une amélioration du signal insulinique. Dans le foie, ELOVL6 est une cible du facteur de transcription ChREBP. ChREBP adipocytaire, notamment l'isoforme ChREBPß, a récemment été mis en évidence pour son rôle déterminant sur la sensibilité à l'insuline systémique. Chez l'Homme, nous avons observé in vitro et in vivo d'étroites corrélations positives entre les expressions adipocytaires de ChREBPß et d'ELOVL6. L'inhibition simultanée de la LHS et ChREBP réduit fortement l'expression d'ELOVL6 et annule l'enrichissement en oléate des phospholipides ainsi que l'amélioration du signal insulinique. De manière particulièrement intéressante, nous avons mis en évidence qu'une interaction physique entre la LHS et ChREBP inhibe la translocation nucléaire du facteur et son activité transcriptionnelle. L'activité catalytique de la LHS n'est pas requise pour assurer l'interaction. Nous avons aussi montré que cette interaction est spécifique de la LHS et est restreinte à l'adipocyte. En conclusion, notre travail a mis au jour une nouvelle voie déterminante pour la sensibilité à l'insuline adipocytaire, liant la LHS au facteur de transcription ChREBP et à sa cible, l'élongase des acides gras ELOVL6. L'enrichissement consécutif en oléate des phospholipides conduit à une augmentation de la fluidité membranaire et à une amélioration du signal insulinique. L'inhibition de l'interaction entre la LHS et ChREBP dans le tissu adipeux pourrait donc être bénéfique dans la prise en charge de l'insulino-résistance associée à l'obésitéInsulin resistance is a feature frequently associated to obesity and an early defect in the development of type 2 diabetes. Improvement of fat cell insulin signaling may favor recovery of whole body systemic insulin sensitivity in pre-diabetic and diabetic states. In this context, inhibition of hormone-sensitive lipase (HSL) in adipocytes (an enzyme responsible for fatty acid release by adipose tissue) was demonstrated to be protective against insulin resistance. However, the mechanisms remained unclear. Consequently, my PhD work aimed at understanding the mechanisms linking HSL inhibition and improvement of insulin sensitivity. In human adipocytes, HSL gene silencing increased glucose transport, de novo lipogenesis and insulin signaling. Among de novo lipogenesis enzymes, ELOVL6 was preferentially induced in vitro and in vivo during HSL partial deficiency, resulting in enrichment of phospholipids and triglycerides in oleic acid. ELOVL6 gene silencing in human adipocytes provided the direct demonstration of the role of the enzyme in the beneficial effect of HSL inhibition. Fat cell insulin signaling was also impaired in adipose tissue of Elovl6 null mice. In clinical studies, ELOVL6 expression was blunted in insulin resistant states and restored after bariatric surgery. ELOVL6-mediated oleic acid enrichment of phospholipids was responsible for the positive effect of HSL inhibition on insulin signaling. FRAP studies revealed an increase in plasma membrane fluidity and insulin signaling in adipocytes overexpressing ELOVL6. In the liver, ELOVL6 is a target of ChREBP. Adipose ChREBP, notably the constitutively active isoform ChREBPß, recently emerged as a major determinant of systemic insulin action on glucose metabolism. In humans, we observed in several in vitro models and in vivo studies a strong positive association between adipose ChREBPß and ELOVL6. Dual HSL-ChREBP inhibition blunted adipose ELOVL6 expression in vivo and in vitro and mirrored ELOVL6 gene silencing on fatty acid profile and insulin signaling. Importantly, we found that physical interaction between HSL and ChREBP impairs ChREBP translocation into the nucleus and its transcriptional activity. A naturally short form of HSL devoid of catalytic activity retained the capacity to bind ChREBP. We also demonstrated that ChREBP-HSL interaction was specific of the lipase and restricted to adipocyte. To conclude, our work identifies a novel pathway critical for optimal insulin signaling in fat cells which links the neutral lipase HSL to the glucose-responsive transcription factor ChREBP and its target gene, the fatty acid elongase, ELOVL6. ELOVL6-mediated oleate enrichment in phospholipids increases membrane fluidity and improves insulin signaling. Inhibition of HSL/ChREBP interaction in adipose tissue may be beneficial in the treatment of obesity-associated insulin resistance
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Al-Jafari, A. A. „Adipocytes in vitro : some aspects of their response to hormones“. Thesis, Cardiff University, 1985. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.304755.
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15
Crowley, John J. „Cholesterol and Phospholipid Modulation of BK[subscript Ca] Channel Activity and Ethanol Sensitivity: a dissertation“. eScholarship@UMMS, 2003. https://escholarship.umassmed.edu/gsbs_diss/107.
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The large conductance Ca++-activated K+ channel (BKCa) regulates neuronal excitability through the efflux of K+, in response to membrane depolarization and increases in intracellular Ca++. The activity of the BKCa channel is increased by acute exposure to ethanol (EtOH), which is thought to underlie, in part, the influence of the drug on peptide hormone release from neurohypophysial nerve terminals (Dopico et al., 1996, 1998). Moreover, chronic EtOH exposure attenuates acute drug action on hormone release, and reduces the sensitivity of BKCa channels to acute EtOH exposure (Knott et al., 2002). The factors regulating EtOH action on BKCa channels are not well understood. Several lines of evidence suggest, however, that the lipid composition of the plasma membrane may influence channel sensitivity to the drug. The plasma membrane is highly complex in its organization (Welti and Glaser, 1994; Brown and London, 1998). There is a growing body of literature indicating that the local lipid composition of the membrane can influence the function of ion channels, including BKCa (Chang et al., 1995a, b; Moczydlowski et al., 1985; Park et al., 2003; Turnheim et al., 1999). Interestingly, chronic exposure to EtOH in animal models results in alterations in the composition of synaptic plasma membranes, including changes in the amount and distribution of membrane cholesterol (CHS) (Chin et al., 1978; Chin et al., 1979; Wood et al., 1989). The significance of these alterations is unclear. Here, we set out to determine the ability of membrane lipids to modulate BKCa channel activity and EtOH sensitivity. To address this, we implement the planar lipid bilayer technique, allowing control of both the protein and lipid components of the membrane. Native BKCa channels retain EtOH sensitivity in this reductionist preparation (Chu et al., 1998), and we extend the study here to examine cloned human brain (hslo) BKCachannels.
We show here that hslo channels maintain their characteristic large conductance, voltage and Ca++-dependent gating, and sensitivity to 50 mM EtOH in bilayers cast from a 3:1 mixture of 1-pamiltoyl-2-oleoyl-phosphatidylethanolamine (POPE) and 1-pamiltoyl-2-oleoyl-phosphatidylserine (POPS). The addition of CHS to the bilayer decreases both the basal activity and EtOH sensitivity of the channels, in a concentration-dependent manner. This lends support to the notion that alterations in plasma membrane CHS levels following chronic EtOH exposure may reflect adaptations to the acute actions of the drug on ion channels. Furthermore, the EtOH sensitivity and CHS modulation of these reconstituted hslo channels are greatly reduced in the absence of negatively charged POPS in the bilayer (pure POPE). Based on these findings, we look to gain mechanistic insight into the lipid headgroup and acyl chain properties that may regulate BKCa channel modulation by EtOH and CHS. When POPS is replaced with the uncharged lipid 1-palmitoyl-2-oleoyl-phosphatidylcholine (POPC), the hslo response to EtOH and CHS is restored, suggesting that the loss of negative surface charge or PS headgroup structure itself cannot explain the lack of channel modulation by these agents in POPE bilayers. Moreover, increases in the proportion of unsaturated acyl chains in the bilayer cannot significantly influence the hslo response to EtOH. The loss of EtOH sensitivity in pure POPE and CHS-containing bilayers may, therefore, reflect the propensity of POPE and CHS to form nonlamellar (nonbilayer) structures. Regarding the basal activity of the channel, we demonstrate that decreases in negative surface charge, increases in the proportion of unsaturated acyl chains, and increases in the complexity of head group interactions can all influence the steady-state activity of reconstituted hslochannels, relative to control POPE/POPS (3:1) bilayers. Overall, these data further suggest the ability of the local lipid environment to regulate the basal function and EtOH sensitivity of an ion channel protein.
Parts of this dissertation have appeared in separate publications:
Treistman, S.N., O'Connell, R.J., and Crowley, J.J. (2002). Artificial Bilayer Techniques in Ion Channel Study. In Methods in Alcohol-Related Neuroscience Research, D. Lovinger and Y. Liu, eds. (Boca Raton, Florida: CRC Press)
Crowley, J.J., Treistman, S.N., and Dopico, A.M. (2003). Cholesterol antagonizes ethanol potentiation of human BKCA channels in binary phospholipid bilayers. Mol. Pharma. 64(2):364-372.
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Yip, Rupert G. „Signal Transduction Mechanisms for the Stimulation of Lipolysis by Growth Hormone: A Dissertation“. eScholarship@UMMS, 1994. https://escholarship.umassmed.edu/gsbs_diss/108.
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The purpose of this study was to investigate the mechanism of action of lipolysis by growth hormone in rat adipocytes. GH-induced lipolysis, in contrast to that of isoproterenol (ISO), is slow in onset (lag time >1h), small in magnitude (~2X basal). and requires corticosteroid. Evidence for direct coupling between GH receptors and adenylyl cyclase or G-proteins is lacking, and although we could detect no measurable change in cAMP content after treatment with GH + dexamethasone (Dex), it is likely that cAMP activation of protein kinase A is a central event in GH-induced lipolysis. Rp-cAMPS, a competitive antagonist of cAMP was equally effective in decreasing lipolysis in tissues treated with GH/Dex or a comparably lipolytic dose of ISO. Incorporation of 32P from γ-32P-ATP into kemptide, a synthetic oligopeptide substrate for protein kinase A, was increased in homogenates of GH/Dex-treated tissue. This increase was correlated with increased lipolysis. Earlier estimates based upon 32P-ribosylation of Gi catalysed by pertussis toxin (PTx) suggested that the abundance of Gi in adipocyte membranes was decreased 4h after treatment of hypophysectomized rats with GH. We therefore examined the possibility that changes in amount or distribution of G-proteins in adipocyte membranes might account for the lipolytic action of GH. Homogenates of GH/Dex-treated and control adipocytes were subjected to differential centrifugation and the abundance of G-proteins in low speed, l6k x g (16k), pellets and high speed, 100k x g (100k), pellets were determined by quantitative Western analysis with densitometry. A 35% loss of Giα2 from the l6k pellet compared from tissues treated with GH/Dex was associated with a 70% increase of Giα2 in the 100k pellet. No change in Gsα was observed in the l6k pellet but a 35% loss of Gsα was seen in the 100k pellet. The G proteins in the l6k pellet were fractionated on a continuous sucrose gradient followed by quantitation with Western analysis or autoradiography after 32P-NAD ribosylation. Giα2 was consistently shifted from heavier to lighter fractions of the l6k pellet after treatment with GH/Dex. Similar shifts of Gsα were not seen. The distribution of 32P-labelled proteins was comparably altered after incubation of homogenates of control and GH/Dex treated adipocytes with PTx and 32P-NAD. These shifts were blocked by treatment of adipocytes with 100μM colchicine which also blocked the lipolytic action of GH/Dex. We propose that an action of GH/Dex on the cytoskeleton of fat cells may change the cellular distribution of G-proteins in a manner that produces a relative decrease in the tonic inhibitory influence of Gi on adenylyl cyclase.
17
Kamel, Ashraf Fawzy. „Insulin and growth hormone : regulation of adipocyte metabolism during infancy and childhood /“. Stockholm, 1999. http://diss.kib.ki.se/1999/91-628-3485-1/.
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18
Østerlund, Torben. „Structure-function relationships of hormone-sensitive lipase“. Lund : Section for Molecular Signalling, Dept. of Cell and Molecular Biology, Lund University, 1998. http://catalog.hathitrust.org/api/volumes/oclc/39103640.html.
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Saulnier-Blache, Jean-Sébastien. „Régulations neuro-humorales de l'expression du récepteur alpha2-adrénergique : étude sur l'adipocyte mature et le préadipocyte chez le hamster : [thèse en partie soutenue sur un ensemble de travaux]“. Toulouse 3, 1990. http://www.theses.fr/1990TOU30199.
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La surexpression du recepteur alpha2-adrenergique antilipolytique de la cellule adipeuse est associee a une diminution de la lipomobilisation des reserves lipidiques du tissu adipeux sous l'action des catecholamines. Nous avons donc recherche, dans le tissu adipeux de hamster dore, les facteurs neuro-humoraux impliques dans cette surexpression de l'alpha2-adrenocepteur adipocytaire. Dans une premiere partie, le recepteur a ete caracterise grace a l'utilisation de nouveaux radioligands agonistes et antagonistes (3h-uk14304 et 3h-rx821002). Ces outils pharmacologiques nous ont ensuite permis, dans une deuxieme partie, d'explorer la regulation du recepteur in vivo. Nous avons tout d'abord montre que l'alpha2-recepteur n'etait pas regule de facon homologue par le niveau d'innervation orthosympathique du tissu adipeux. Nous avons ensuite mis evidence l'existence d'une regulation hautement specifique de l'alpha2-recepteur par la photoperiode selon un mecanisme testosterone dependant. Nous avons enfin revele l'existence d'une regulation de l'alpha2-recepteur induite par un traitement chronique a l'insuline. Dans la troisieme partie, nous avons developpe un modele de precurseurs adipocytaires en culture. Ce modele est capable de se convertir en adipocytes dans un milieu chimiquement defini et d'exprimer l'alpha2-recepteur dans les phases tardives de differenciation. Nous disposons donc d'un modele de cellules adipeuses en culture sur lesquelles il sera possible, dans l'avenir, d'etudier directement la regulation de l'alpha2-recepteur in vitro
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Clifford, Gary. „The translocation of hormone-sensitive lipase and perilipin during lipolysis“. Thesis, University of Newcastle Upon Tyne, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.285397.
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21
Shi, Xiarong. „Mitochondrial Dysfunction and AKT Isoform-Specific Regulation in 3T3-L1 Adipocytes: A Dissertation“. eScholarship@UMMS, 2010. https://escholarship.umassmed.edu/gsbs_diss/505.
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Excess food consumption and/or lack of exercise have dramatically contributed to the prevalence of overweight (BMI≥25) and obesity (BMI≥30) in modern society. The obesity epidemic has been linked to the rise in type 2 diabetes. In recent years, evidence has pointed to a close association between mitochondrial dysfunction in white adipose tissue (WAT) and insulin resistance, a key feature of type 2 diabetes. In order to dissect the cause and effect relationship between WAT mitochondrial dysfunction and insulin resistance, we established an in vitro cell line system to investigate this issue. We artificially introduced mitochondrial dysfunction in 3T3-L1 adipocytes by depleting the mitochondrial transcription factor A (Tfam) during adipogenesis, without changing the overall adipocyte differentiation program. We found that these Tfam-depleted 3T3-L1 adipocytes showed symptoms of insulin resistance, evidenced by impaired insulin stimulated GLUT4 translocation and glucose uptake. This result suggested that mitochondrial dysfunction could be a primary contributor to insulin resistance in fat tissue. However, the exact mechanism underlying this finding remains unclear.
As part of a comprehensive understanding of insulin signaling in fat cells, we also investigated the involvement of the endosomal protein WDFY2 in the regulation of Akt isoform-specific effect on glucose uptake. In 3T3-L1 adipocytes, both Akt1 and Akt2 isoforms are expressed, but only Akt2 plays an indispensible role in insulin-stimulated GLUT4 translocation and glucose uptake. Previous studies implied that endosomal proteins may take a part in determining Akt substrate specificity. Here we found that WDFY2 preferentially co-localized with Akt2 and that knockdown of WDFY2 inhibited insulin-stimulated glucose uptake in 3T3-L1 adipocytes, suggesting that endosomes are involved in this regulation. The effect of WDFY2 knockdown on insulin-stimulated glucose uptake worked through the down-regulation of Akt2, but not Akt1, protein level. We concluded that, endosomal protein WDFY2, by preferentially interacting with Akt2, regulates insulin signaling in glucose uptake in 3T3-L1 adipocytes. Our findings may help to develop specific therapeutic interventions for treatment of insulin resistance and type 2 diabetes.
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Schneider, Laëtitia. „Implication et expression des récepteurs hormonaux nucléaires de la triiodothyronine et du calcitriol dans la différenciation de la lignée préadipocytaire murine Ob17“. Aix-Marseille 2, 2001. http://theses.univ-amu.fr.lama.univ-amu.fr/2001AIX20684.pdf.
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L'hormone thyroïdienne (T3) et le calcitriol (1,25-(OH)2 vitamine D3) agissent sur leurs tissus cibles principalement en activant des récepteurs nucléaires voisins appartenant à la superfamille des récepteurs hormonaux nucléaires stéroïdes/thyroïde-rétinoïdes : les récepteurs de T3 (T3Rα1,-β1,-β2) et de vitamine D3 (VDR). Ces récepteurs, après activation par la liaison de leur ligand respectif, régulent la transcription de différents gènes dans ces tissus cibles. Dans notre modèle cellulaire, la lignée préadipocytaire murine Ob17, il était établi que T3 et le calcitriol peuvent induire individuellement, dans des conditions de culture nonadipogéniques et à des concentrations physiologiques, la différenciation adipocytaire. De plus, T3 et le calcitriol interféraient dans leur action adipogénique. Ces effets pouvaient impliquer leurs récepteurs respectifs, T3R et VDR. Des T3R de type α1 étaient alors identifiés dans les cellules Ob17 et les sites liant T3 étaient trouvés modulés négativement par des concentrations adipogéniques de T3 et de calcitriol. Ce travail définit maintenant dans ces cellules l'expression du VDR (ARNm, protéine, sites liants) et analyse les modalités et les niveaux moléculaires de régulation d'expression des T3R et VDR. Il est mis en évidence des modulations négatives croisées des sites récepteurs par des concentrations adipogéniques de ces ligands et mettant en jeu des mécanismes moléculaires différents pour chaque type de récepteur : pré-traductionnel dans la diminution des sites VDR par T3, post-traductionnel dans la diminution des sites T3Rα1 par le calcitriol. Cette étude a aussi montré que les cellules Ob17, et plus largement la souris, expriment, comme cela a été décrit chez le rat, un variant ARNm du VDR produit par un épissage alternatif dans sa partie 3’-codante. La protéine traduite à partir de cet ARNm ne lie pas le calcitriol et pourrait, comme le VDR variant du rat, exercer une activité antagoniste sur l'activité transcriptionnelle médiée par le VDR canonique. Par ailleurs, ce travail a mis en évidence une expression transitoire du sous-type T3Rβ1 à un stade préadipocytaire précoce. Cette expression β1 (ARNm, protéine, sites liants) précède l'augmentation séquentielle d'expression de gènes codant pour des facteurs transcriptionnels de l'adipogenèse, appelée cascade adipogénique. L'expression transitoire des transcrits T3Rβ1, comme celle des facteurs de la cascade adipogénique, disparaît dans des conditions de culture non-adipogéniques et elle est restaurée par l'ajout précoce de T3. Elle est également restaurée par l'ajout de calcitriol, cela établissant un niveau complémentaire dans le dialogue mis ici en évidence entre les voies d'action du calcitriol et de T3. Ces différents résultats appuient ainsi les notions d'interchangeabilité et d'interférences d'action entre T3 et le calcitriol dans leur action adipogénique au travers de leurs voies de signalisation nucléaire respectives. Le dialogue existant entre ces voies de signalisation peut impliquer différents mécanismes. Ce travail apporte également des arguments en faveur d'un rôle de T3Rβ1 lors d'une étape préadipocytaire précoce.
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Amri, Ez-Zoubir. „Evénements précoces et tardifs de la conversion adipocytaire : effet modulateur de l'insuline, rôle des polyamines“. Nice, 1986. http://www.theses.fr/1986NICE4025.
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Melrose, Shona E. „Chronic hormonal control of lipid synthesis and hydrolysis in adipocytes“. Thesis, University of Glasgow, 1999. http://theses.gla.ac.uk/6192/.
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The aim of this study was to. further elucidate the mechanisms whereby growth .. . hormone (GH) exerts its ~hronic effect on adipose tissue metabolism, and in particular the effects of GH on lipolysis. Previous studies had shown that turnout necrosis factor alpha (TNFa.) chronically increases basal lipolysis in rat epididymal cidipocytes: an effect that is similar to that of GH. Other research had implicated a protein with a halflife of less than 3 hours in the regulation of lipolysis and lipogenesis by GR. This led to the investigation if TNFa. might be this putative protein involved in mediating the chronic metabolic effects of GH. Initial studies used ovine adipose tissue explants. TNFa. caused a small increase in basal lipolysis and attenuated insulin effects on lipogenesis. However, the effects ofTNFa. were smaller than those ofGH and TNFa. did not appear to mimic the effects of GH on isoproterenol-stimulated lipolysis in this system. Therefore TNFa. was not the protein involved in GH regulation of lipolysis and lipogenesis. Previous studies in the laboratory on the mechanism of GH action had used inhibition of signal transduction components in an ex.plant system. More specific effects could be observed by using an antisense approach, but this required the use of a cell culture system rather than adipose tissue explants. The suitability of an ovine cell culture system was established for investigating the molecular basis of the lipolytic effects of GH; in particular the inhibitory effects of GH on adenosine inhibition of lipolysis. The lipolytic system partially developed in primary ovine adipocytes, but the antilipolytic system did not appear. to develop. However, by. manipulating the differentiation conditions, I significantly improved both cell differentiation and the lipolytic response and sensitivity to isoproterenol, but there· was no improvement in response to adenosine. As an alternative, the suitability of the murine cell line, 3T3-F442A, was .. . investigat.ed ·for determining the molecular basis of the lipolytic effects of GH. However, although the lipolytic system did· develop in differentiated 3T3-F442A adipocytes and response to isoproterenol was observed, the antilipolytic system did not appear io develop either. This line of investigation was not pursued further. Therefore, I decided to investigate the effects of GH and insulin on the lipogenic system in 3T3-F442A adipocytes i.nstead, with a view to extending previous observations by others (Millar, 1998) in the laboratory on the roles of specific isoforms of protein kinase C (PKC) on the modulation of lipogenesis by insulin and GH. The main objective was to determine the role of PKC isoforms in the modulation of the effect of insulin and GH on activation' and expression (mRNA) of the lipogenic enzyme . acetyl CoA carboxylase (ACC). However, the effect of the hormones on lipogenesis, and especially ACC, was considered to be too small to investigate the roles of specific PKC isoforms, despite trying many different ways of improving the hormone effects. A possible explanation for the poor response to insulin was that the lipogenic system was not "switching off' in the absence of insulin, so isoproterenol was added to the 3T3-F442A adipocytes to decrease lipogenesis. Isoproterenol did reduce the rate of lipogenesis, but the effect of insulin was still small. Therefore, modulation of the effect of specific phosphodiesterase (POE) isoforms on lipogenesis was explored as an alternative. The use of specific POE inhibitors showed that both POE3 and PDE4 enzymes were involved in the modulation of lipogenesis in 3T3-F442A adipocytes.
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Moftah, Souad A. M. „The effects of growth hormone receptor-associated ERK activation on adipocyte differentiation and function“. Thesis, Cardiff University, 2012. http://orca.cf.ac.uk/46265/.
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Growth hormone (GH) modulates adipocyte function to promote lipolysis via a cell surface GH receptor (GHR) which activates multiple signalling cascades including STAT5 and p42/44 MAP kinase (MAPK) pathways. The growth promoting effects of GH are mediated primarily by STAT5 activation but little is known about pathways mediating the effects of GH on adipocyte function. We therefore studied the effect of GH on STAT5 and MAPK (ERK) activation in the 3T3-L1 mouse pre-adipocyte cell line during adipogenesis. Cells were plated, allowed to reach confluence and cultured in adipogenic medium containing the PPARg agonist, pioglitazone. GH induced activation (10 minutes exposure) of STAT5 and MAPK was analysed on days 0, 2, 5 and 8 during adipogenesis by phospho-specific western blotting and densitometry. During adipogenesis, GH progressively loses the ability to activate p42/44 MAPK despite elevated GHR and unaltered total ERK levels. In contrast, GH-stimulated STAT5 activation increases as 3T3-L1 differentiation proceeds. Subsequently we investigated possible explanations for the altered GHR signalling. The adapter protein p66Shc is thought to be necessary to link GHR activation to the ERK pathway. However levels of this protein, measured by western blotting and densitometry, did not decrease as 3T3-L1 cells underwent adipocyte differentiation. GHR levels increase with adipogenic differentiation of 3T3-L1 cells leading us to hypothesize that this may lead to preferential association with JAK2-STAT5. This was tested by overexpressing the GHR in 3T3-L1; similar GH-stimulated ERK pathway activation was obtained in cells transfected with the GHR vector and in those transfected with the empty vector. Finally, we have investigated whether changes in GHR signalling also occur during adipogenesis of primary pre-adipocytes from mice and various human depots. There was minimal GH-induced phosphorylation of ERK at all-time points before and during differentiation (required up to 15 days in primary cells) and no depot, either murine or human, demonstrated a reduction in p ERK, suggesting that this feature is unique to 3T3-L1. Furthermore, ERK phosphorylation may be the stimulus for mitotic clonal expansion which occurs in the cell line but not in human primaries. GH-stimulated STAT5 activation increases as human and mouse primary pre-adipocytes differentiation progresses, as in the 3T3-L1 cell-line, and may be the result of increased GHR transcript levels as differentiation proceeds. Future studies could investigate the mechanisms responsible for these similarities and differences.
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Li, Aiyun. „GROWTH HORMONE (GH) INFLUENCES ADIPOCYTE SIZE IN MOUSE MODELS WITH VARYING LEVELS OF GH SIGNALING“. Ohio University / OhioLINK, 2006. http://rave.ohiolink.edu/etdc/view?acc_num=ohiou1162411912.
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Landron, Dorothée. „Interactions de l'hormone de croissance humaine avec les adipocytes de rats zucker genetiquement obeses : relations entre la liaison et les effets biologiques“. Paris 6, 1988. http://www.theses.fr/1988PA066344.
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L'objectif de ce travail est de comparer la liaison et les effets biologiques de l'hormone de croissance (gh) 1) dans les adipocytes du tissu inguinal de jeunes rats zucker obeses fa/fa et minces fa/fa; 2) dans les preadipocytes de rats zucker en culture primaire au cours de la differenciation adipocytaire. 1. Les etudes de liaison de la gh et les courbes dose-reponse pour le transport et le metabolisme du glucose sont realisees avec des adipocytes soit fraichement isoles (f) soit preincubes 3 h (p)
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Sarkissian, Gaïané. „Récepteur C-ErbA bêta des hormones thyroïdiennes : expression, fonctions, pathologies moléculaires associées“. Aix-Marseille 2, 1999. http://theses.univ-amu.fr.lama.univ-amu.fr/1999AIX20665.pdf.
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Les hormones thyroïdiennes (HT) agissent principalement par l'intermédiaire de récepteurs nucléaires qui sont les produits homologues de deux gènes c-erb Aα et c-crb Aβ. Nous nous sommes particulièrement intéressée aux récepteurs de type β (TRβ). Le syndrome de résistance aux hormones thyroïdiennes (RHT) est associé à la présence de mutations de TRβ. Nous avons recherché des mutations chez des patients atteints de ce syndrome et identifié seize mutations différentes dans 22 familles. Huit de ces mutations étaient nouvelles et six d'entre elles ont fait l'objet d'une étude des altérations fonctionnelles du TRβ muté produit in vitro par mutagénèse dirigée. Nous avons mis en évidence une nouvelle région de mutations dans TRβ (Q374K, R383C) et montré qu'il était possible de dissocier l'effet dominant négatif des TR mutés de leur capacité à s'hétérodimériser avec RXR (1280V). La mutation T329N est associée à un phénotype inhabituel dans les RHT. Une autre mutation (V444A) est par contre associée à un état d'hypersensibilité aux HT. Les caractéristiques fonctionnelles du Trβ muté sont en accord avec la symptomatologie du patient et étayent l'hypothèse d'une hypersensibilité constitutionnelle aux HT. Par ailleurs, dans la lignée préadipocytaire Ob17, qui requiert T3 pour se différencier en culture, nous avons mis en évidence une expression transitoire de TRβ à un stade précoce de la différenciation. Cette expression est concomitante à, ou précède, celle d'autres marqueurs de l'adipogenèse qui ne se produit pas en son absence. Ceci suggère fortement l'implication de TRβ dans la transition préadipocyte-adipocyte. Les résultats obtenus ont apporté un certain nombre d'informations concernant l'existence de nouvelles mutations associées à des pathologies avec troubles de sensibilité aux HT et les particularités d'altérations fonctionnelles, en particulier dans le cadre d'effet dominant négatif exercé par les TR mutés. L’existence d'un rôle spécifique de l’isoforme TRβ est étayée.
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Millar, Iona M. „Investigation of the functional roles of specific protein kinase C isoforms in 3T3-F442A adipocyte development and function“. Thesis, University of Glasgow, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.266679.
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Durand, Jason AJ. „Regulation of Adipocyte Lipolysis by TSH and its Role in Macrophage Inflammation“. Thèse, Université d'Ottawa / University of Ottawa, 2012. http://hdl.handle.net/10393/22694.
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Elevated Thyroid-Stimulating Hormone (TSH) is associated with an increased risk of cardiovascular disease (CVD). We hypothesized that TSH-stimulated FA release from adipocytes contributes to macrophage inflammation. 3T3-L1 and human subcutaneous differentiated adipocytes were treated with TSH for 4 hours under various conditions and lipolysis assessed via glycerol secretion. Optimal conditions were determined and protein expression of ATGL, HSL and perilipin remained stable. TSH-stimulated 3T3-L1 or human adipocyte-conditioned medium (T-ACM) was placed on murine J774 or human THP-1 macrophages, respectively, and macrophage cytokine mRNA levels (IL-1β, IL-6, MCP-1, and TNFα) were measured by real-time RT-PCR. T-ACM did not change cytokine mRNA expression in J774 macrophages or THP-1 macrophages when compared to ACM. Absence of BSA in the medium may have hindered release of FA from differentiated adipocytes into the medium, BSA may be required to permit adequate FA accumulation in the medium to then evaluate the effect of T-ACM on macrophages. Further investigation is required to determine the effect of FA on J774 and THP-1 inflammatory response.
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Ranjit, Srijana. „Role and Regulation of Fat Specific Protein (FSP27) in Lipolysis in 3T3-L1 Adipocytes: A Dissertation“. eScholarship@UMMS, 2010. https://escholarship.umassmed.edu/gsbs_diss/484.
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The alarming rate of increase in incidence and prevalence of the type 2 diabetes mellitus has prompted intense research on understanding the pathogenesis of the type 2 diabetes. It is observed that the development of type 2 diabetes is preceded by a state of insulin resistance and obesity. Previous studies have suggested that the obesity induced insulin resistance may be mediated by elevated levels of circulating free fatty acids (FFAs). The increase in circulating levels of FFAs may be contributed by the release of FFAs from stored triglycerides (TG) in adipocytes via lipolysis. It is hypothesized that the decrease in levels of circulating FFAs by sequestration and storage of FFAs in adipocytes may prevent deleterious effects of FFAs on insulin sensitivity. Recently our lab and others have shown that the storage of TG in adipocytes is promoted by a novel protein, Fat Specific Protein 27 (FSP27). Although, these studies also revealed FSP27 to be a lipid droplet associated protein that suppresses lipolysis to enhance TG accumulation in adipocytes, the role of FSP27 in lipolysis remains largely undetermined. Therefore, this study investigates the role and regulation of FSP27 in adipocytes in both the basal state, as well as during lipolysis.
The studies presented here show FSP27 to be a remarkably short-lived protein (half-life=15 min) due to its rapid ubiquitination and proteasomal degradation. Thus, I tested the hypothesis that lipolytic agents like the cytokine, TNF-α and the catecholamine isoproterenol modulate FSP27 protein levels to regulate FFA release. Consistent with this concept, TNF-α markedly decreased FSP27 mRNA and protein along with lipid droplet size as it increased lipolysis in cultured adipocytes. Similarly, FSP27 depletion using siRNA mimicked the effect of TNF-α to enhance lipolysis, while maintaining stable FSP27 protein levels by expression of HA epitope-tagged FSP27 blocked TNF-α mediated lipolysis. In contrast, the robust lipolytic action of isoproterenol is paradoxically associated with increases in FSP27 protein and a delayed degradation rate that corresponds to decreased ubiquitination. This catecholamine-mediated increase in FSP27 abundance, probably a feedback mechanism to restrain excessive lipolysis by catecholamines, is mimicked by forskolin or 8-Bromo-cAMP treatment, and prevented by Protein Kinase A (PKA) inhibitor KT5720 or PKA depletion using siRNA. These results show that isoproterenol stabililizes FSP27 via the canonical PKA pathway and increased cAMP levels. However, the work presented here also suggests that FSP27 does not get phosphorylated in response to isoproterenol treatment, and the stabilization of FSP27 is independent of isoproterenol mediated lipolysis.
The data presented in this thesis not only identifies the regulation of FSP27 as an important intermediate in mechanism of lipolysis in adipocytes in response to TNF-α and isoproterenol, but also suggests that FSP27 may be a possible therapeutic target to modulate lipolysis in adipocytes.
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Saule, Pasquine. „L'interleukine-7 : cytokine-clé du métabolisme énergétique du parasite Schistosoma mansoni et de son hôte vertébré“. Lille 2, 2003. http://www.theses.fr/2003LIL2MT11.
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Kartchner, Laurel Brianne. „Role of the Endoplasmic Reticulum Chaperone dsbA-L Gluthathione S-Transferase Activity in the Assembly of Adipocyte Hormone Adiponectin“. Thesis, The University of Arizona, 2011. http://hdl.handle.net/10150/144537.
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34
Mehebik-Mojaat, Nadia. „Régulations hormonales non génomiques de la production du monoxide d'azote (no) dans les adipocytes de rat“. Paris 7, 2007. http://www.theses.fr/2007PA077015.
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Le tissu adipeux sécrète différents facteurs comme la leptine, les oestrogènes et du monoxyde d'azote (NO). Le NO dans le tissu adipeux peut être produit par deux isoformes de monoxyde d'azote synthases, la NOS II et la NOS ÏÏI. Le NO intervient dans le métabolisme adipocytaire. Dans ce travail, nous avons recherché si la leptine et les oestrogènes, ayant pour cible le tissu adipeux, peuvent réguler de façon non génomique la production du NO adipocytaire. Premièrement, nous avons montré que la leptine stimule la production du NO et la phosphorylation de la NOS III sur la Ser1179, par une voie dépendante de Jak2, PKA et de p42/p44 MAPK. Deuxièmement, nous avons testé les effets sur la production du NO d'une forte concentration de leptine et de l'insuline à concentration physiologique. Nous montrons que ces deux hormones, simultanément, n'induisent ni l'activité NOS ni la phosphorylation de la NOS III sur la Ser 7 de la NOS III, suggérant une interférence négative entre la leptine et l'insuline. Finalement, nous avons montré que le 17-ß oestradiol (E2) et une autre forme d'oestradiol couplé à l'albumine bovine, ne traversant pas la membrane plasmique E2-BSA, induisent la phosphorylation de la Ser1179 ainsi que l'activité NOS. Ces effets sont dépendants de l'activation de PI-3 kinase et de PKA pour les deux formes d'oestrogènes. Cependant l'action de E2-BSA sur l'activité NOS et sur la phosphorylation de la NOS in est dépendante de l'activation de p42/p44 MAPK contrairement à E2. En conclusion, la production du NO adipocytaire peut être régulée la leptine, l'insuline et les oestrogènes via des mécanismes non génomiques ayant pour cible la phosphorylation de la NOS IIIAdipose tissue produces many factors like leptin, estrogens and nitric oxide (NO). In adipose tissue NO can be produced by two nitric oxide isoforms: NOS II and NOS III. NO is implicated in adipocyte metabolism. In this work, we have tested if leptin and estrogens which act on adipose tissue, can regulate NO production by non genomic pathways. Firstly, we showed that leptin activated NO production and NOS III phosphorylation at Ser1179 and it is mediated through Jak2, PKA and p42/p44 MAP kinases activation. Secondly, we tested high concentration of leptin and normally concentration of insulin on NO production. We found that treatment with thèse two hormons at the same time did not induce NOS activity and phosphorylation at Ser1179. This resuit suggests a negative interaction between leptin and insulin. Thirdly, we showed 17-beta oestradiol (E2) and its membrane impermeant albumine conjugated forrn (E2-BSA) induced NOS activity and NOS III phosphorylation at Ser1179. These effects involved PI-3 kinase and PKA activations. We also found that E2-BSA effects were dépendent of p42/p44 MAP kinases in contrats to E2. In conclusion, NO production in adipocytes could be regulated by leptin, insulin and estrogens through non genomic pathway which act on NOS III phosphorylation
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Hirsch, David J. „Hormonal regulation of long chain fatty uptake by adipocytes and studies of FATP gene family“. Thesis, Massachusetts Institute of Technology, 2000. http://hdl.handle.net/1721.1/50631.
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Thesis (Ph.D.)--Massachusetts Institute of Technology, Dept. of Biology, June 2001.Includes bibliographical references.
Long chain fatty acids (LCFA) are an important source of energy for most organisms. Serum fatty acid (FA) levels are dynamically regulated by hormones. We show that insulin directly stimulates adipocyte fatty acid influx suggesting that the decrease in serum FA levels seen after meals is partially mediated by an insulin-stimulated increase in FA uptake by adipocytes. We also find that TNF-ax directly inhibits FA uptake by 3T3-L1 adipocytes providing a physiologic link between the increased serum levels of TNF-oa and FA seen in Type II diabetes. Transport of LCFA across the plasma membrane is facilitated by FATP, a plasma membrane protein that increases LCFA uptake when expressed in cultured mammalian cells (Schaffer and Lodish, 1994). We report the identification of family of evolutionarily conserved FATPs. In addition to the gene first isolated by Schaffer and Lodish, humans have five additional FATP homologues (designated FATP1-5). All of the mammalian FATPs increase fatty acid uptake when overexpressed in COS cells. FATPs are also found in such diverse organisms as F. rubripes, C. elegans, D. melanogaster, S. cerevisiae, and M. tuberculosis. The function of the FATP gene family is conserved throughout evolution as the C. elegans and mycobacterial FATPs facilitate LCFA uptake when over-expressed in COS cells or E. coli, respectively. Among the mammalian FATPs, several are expressed in a highly tissue specific manner. We show that FATP4 is expressed at high levels on the apical side of mature enterocytes in the small intestine. Furthermore, reduction of FATP4 expression in primary enterocytes by anti-sense oligonucleotides inhibits FA uptake by 50% suggesting that FATP4 is the principal fatty acid transporter in enterocytes. FATP5 is expressed only in adult liver. We have isolated the FATP5 promoter and find that tissue specific expression can be recapitulated in vitro and requires a single GC box in conjunction with two novel ten nucleotide motifs. Additional study of the FATP gene family may provide a better understanding of the mechanisms whereby LCFAs traverse the lipid bilayer as well as yield insight into the control of energy homeostasis and its dysregulation in diseases such as diabetes and obesity.
by David J. Hirsch.
Ph.D.
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GLORIAN, MARTINE. „Controle hormonal et nutritionnel de l'expression du gene codant la phosphoenolpyruvate carboxykinase dans les adipocytes“. Paris 6, 2001. http://www.theses.fr/2001PA066108.
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La phosphoenolpyruvate carboxykinase (pepck) est une enzyme exprimee dans le foie et le tissu adipeux (ta). Dans le foie, elle est l'enzyme cle de la neoglucogenese et joue un role crucial dans l'homeostasie glucidique. Dans le ta, elle est impliquee dans la neoglycerogenese et fournit le glycerol-3-phosphate necessaire a la re-esterification partielle des acides gras (ag) d'origine lipolytique sous forme de triglycerides. La pepck du ta participant au controle du taux d'ag circulants, nous avons etudie l'effet de molecules hypolipemiantes sur son expression. Dans les adipocytes 3t3-f442a et dans des explants de ta de rat, les fibrates et les thiazolidinediones (tzds) antidiabetiques augmentent de 7 fois les transcrits pepck en 4 heures. Cet effet est purement transcriptionnel et implique l'element pck2 du promoteur du gene. Les glucocorticoides exercent un effet inhibiteur sur l'expression du gene pepck induite par l'oleate, les fibrates et les tzds dans les adipocytes. L'effet inhibiteur des glucocorticoides sur la stimulation induite par les fibrates et les tzds ne necessite pas de synthese de proteines, est au moins en partie transcriptionnel et requiert le recepteur des glucocorticoides. L'element af1 du promoteur du gene est specifiquement implique dans cette repression. Dans le foie, cet element intervient dans la stimulation de la transcription du gene par les glucocorticoides. Ainsi, af1 est implique dans l'effet oppose des glucocorticoides sur la transcription du gene pepck dans le foie et le ta. De nombreux arguments suggerent qu'une concentration elevee d'ag circulants est susceptible de conduire au diabete de type ii. Aussi, les enzymes controlant le metabolisme des ag constituent des candidats potentiellement impliques dans l'apparition de cette pathologie. Le fait que l'expression du gene pepck corresponde a l'une des cibles des tzds suggere que leur action antidiabetique pourrait s'exercer, au moins en partie, sur la neoglycerogenese adipocytaire.
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Langille, Melanie L. „Mechanisms of the pro-inflammatory action of the thyroid stimulating hormone on human abdominal subcutaneous differentiated adipocytes“. Thesis, University of Ottawa (Canada), 2009. http://hdl.handle.net/10393/28380.
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Subclinical hypthyroidism characterized by elevated thyroid stimulating hormone (TSH) levels with normal thyroid hormone levels, is associated with an increased risk for cardiovascular disease. Human adipocytes express the TSH receptor and may be a bystander target of TSH action. Treatment of human differentiated adipocytes with TSH stimulates interleukin (IL)-6 release through activation of the nuclear factor-kappa B (NF-kappaB) pathway. I identified intermediates implicated in TSH-induced activation of NF-kappaB and is upstream regulator, inhibitor of kappa B (IkappaB) kinase (IKK)beta. My results also suggest that TSH-induced NFkappaB activation and IL-6 production are not dependent on protein kinase A (PKA) activity. Studies demonstrate that protein kinase Cdelta and reactive oxygen species are upstream of IKKbeta/NF-kappaB activation. Furthermore, TSH induces monocyte chemoattractant protein-1 production in an IKKbeta- and PKA-dependent manner. Further analysis of the TSH-induced inflammatory response in human adipocytes will broaden our understanding of TSH action in subclinical hypothyroidism.
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Lundgren, Magdalena. „Interplay between hormones, nutrients and adipose depots in the regulation of insulin sensitivity : an experimental study in rat and human adipocytes“. Doctoral thesis, Umeå : Public Health and Clinical Medicine, 2006. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-677.
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Shtayer, Meytal. „Potential Role of NADPH Oxidase Subunit Neutrophil Cytosolic Factor 1 (NCF1) in Regulation of Adipocyte Hormone Adiponectin and Aging-Associated Lipodystrophy“. Thesis, The University of Arizona, 2011. http://hdl.handle.net/10150/144961.
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Iliou, Jean-Pierre. „Contribution a l'étude des mécanismes de régulation de la lipolyse du tissu adipeux au cours de la gestation et de la lactation : étude bibliographique, étude expérimentale "in vitroe sur adipocytes isolés de brebis“. Paris 7, 1985. http://www.theses.fr/1985PA077129.
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Chez la Brebis, au cours de la gestation et de la lactation, l'évolution du métabolisme lipidique du tissu adipeux est caractérisée par 2 phases métaboliques successives et opposées. La prmière est une phase d'accumulation des réserves lipidiques (lipogénèse élevée, lipolyse aibl), elle correspond aux 2 premiers tiers de la gestation. La seconde est une phase de mobilisation des réserves lipidiques (lipogénèse faible, lipolyse élvée), elle englobe les périodes du dernier tiers de la gestation et du début de la lactation. Ce profil d'évolution du métabolism lipidique doit permettre à l'organisme maternel de subvenir d'une part aux besoins énergétiques importants du foetus en fin de gestation et d'autre part, de préparer et de aire face au coût énergétique très élevé de la lactation. En utilisant un système d'incubation d'adipocytes isolés maintenus en survie, ces derniers étant prélevés sur des Brebis en cours de gestation et de lactation, l'étude expérimental a porté sur l'évolution de la réponse cellulaire à l'action de différents effecteurs de la lipolyse. La sensibilité des adipocytes aux stimuli lipolytiques de l'isoprénaline (caté¬cholamine de synthèse) et de la théophylline (méthylxanthine) croît au cours de la gestation pour tendre vers un maximum à quelques jours "pré-partum". Pendant la 3ème semaine de lactation, les cellules demeurent à un niveau élevé de sensibilité. Le niveau de l'effet antilipolytique de l'adénosine est proportionnel à la sensibilité des cellules isolées au stimulus lipolytique de l'isoprénaline. Cet effet rétro-régulateur a été mis en évidence de manière directe en présence d'adé-nosine et d'isoprénaline et de manière indirecte en présence d'adénosine désaminase. Les actions sur la lipolyse de 2 hormones, l'hormone placentaire lactogène ovine (oPL) et l'hormone de croissance bovine (bGh) ont été testées. L'oPL ne présente aucun effet, la bGh présente en début de gestation un effet de potentialisation sur l'action lipolytique du couple isoprénaline-théophylline. La réorientation complète du métabolisme lipidique à partir de la fin du second tiers de la gestation se reflète dans l'évolution de la sensibilité cellulaire aux stimuli lipolytiques de l'isoprénaline et de la théophylline. Les rôles suggérés dans la littérature pour la bGh et l'oPL au sujet de leur action lipolytique demeurent très controversés.
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Dace, Alexandra. „Recepteurs de triiodothyronine, produits de genes c-erb a, dans la differenciation adipocytaire des cellules ob 17 : interactions avec des recepteurs apparentes dans la famille des recepteurs nucleaires (doctorat)“. Aix-Marseille 2, 1997. http://www.theses.fr/1997AIX20654.
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Doglio, Alain. „Controle multi-hormonal de l'expression de genes impliques dans le processus de differenciation adipocytaire“. Nice, 1987. http://www.theses.fr/1987NICE4122.
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MacIntyre, Terence M. „Acetyl CoA carboxylase, adipocyte P2, lipoprotein lipase, and hormone-sensitive lipase mRNA levels in the ovine adipose tissues and their relationship with carcass fat“. Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1999. http://www.collectionscanada.ca/obj/s4/f2/dsk2/ftp01/MQ49399.pdf.
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Lesende, Vivian A. „RNA Expression of Receptors for Growth Hormone, Insulin-like Growth Factor 1, and Insulin in Mouse Whole Adipose Tissue, Stromal Vascular Fraction, and Adipocytes“. Ohio University / OhioLINK, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=ohiou1440105877.
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Young, James L. „Innate Immunity in Type 2 Diabetes Pathogenesis: Role of the Lipopolysaccharide Signaling Cascade: A Dissertation“. eScholarship@UMMS, 2008. https://escholarship.umassmed.edu/gsbs_diss/400.
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Once seen as a disease of wealthy nations, type 2 diabetes mellitus is now showing unprecedented growth throughout the world, fueling increases in microvascular and macrovascular complications. A compelling and growing body of evidence suggests that glucose intolerance and insulin resistance, hallmarks of the diabetic patient, may be driven by chronic inflammation. In particular, a predominance of visceral fat has been associated with enhanced inflammatory cytokine secretion that may contribute to enhanced risk of diabetes and comorbid cardiovascular disease in these individuals. As a function of its potency and wide environmental and biological distribution, we hypothesized that bacterial lipopolysaccharide (LPS, also known as endotoxin) may promote adipose inflammation and concomitant metabolic dysfunction.
Indeed, expression of the LPS receptor CD14 is enhanced on visceral adipocytes of ob/ob mice, paralleling enhanced IL-6 secretion ex vivo. Furthermore, rosiglitazonefed ob/obmice demonstrated a reduction in CD14 that coordinated with diminished IL-6 secretion, suggesting a basis for the touted anti-inflammatory effects of this commonly employed type 2 diabetes medication. Mice deficient in components of the LPS signaling cascade, namely CD14, TLR4, and MyD88, yielded adipocytes with markedly attenuated IL-6 secretion, corroborating the central importance of LPS in adipocyte inflammation and supporting the role of this signaling pathway in depot-specific inflammation.
Despite the prominent role of LPS signaling in adipocyte inflammation, CD14-, TLR4-, and MyD88-deficient mice failed to show resistance to diet induced obesity. Surprisingly, cd14-/- and tlr4-/- mice had marked glucose intolerance without alteration in total weight or adipose accumulation. In contrast, myd88-/- mice revealed minor glucose intolerance only with high fat diet challenge at an advanced age despite being overtly obese. In cd14-/- and tlr4-/-, but not myd88-/-, mice, an exaggerated rebound to hypoglycemia was associated with enhanced norepinephrine secretion, which could be abrogated by the adrenergic β-blocker propranolol. The overlay of these mouse models reveals a divergence of phenotypes that demonstrate LPS signaling disruption may lead to glucose intolerance and insulin resistance in part due to enhanced sympathoadrenal tone, uncovering an essential role of innate immunity in physiological stress and its impact upon glucose homeostasis.
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Levacher, Christine. „Controle de la differentiation adipocytaire au cours du developpement chez le rat“. Paris 7, 1988. http://www.theses.fr/1988PA077106.
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Abrão, Ricardo Marcelo. „A interferência dos hormônios sexuais no tempo de esqueletização. Estudo experimental em ratos Wistar“. Universidade de São Paulo, 2006. http://www.teses.usp.br/teses/disponiveis/17/17143/tde-13022007-160018/.
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Pesquisas têm documentado como é variável a decomposição corporal e o intervalo de tempo verificado entre as diversas fases do processo de decomposição do cadáver e o momento em que se verificou a morte. Fatores ambientais como temperatura, umidade, condições aeróbica e anaeróbica, presença de microrganismos e condições do solo são considerados como fatores que interferem no processo que envolve a preservação ou não do cadáver. As circunstâncias que detêm a putrefação, uma vez iniciada, estão representadas pelos processos naturais conservadores dos cadáveres. A formação da adipocera foi investigada para confirmar a sua relação com o tempo de esqueletização relacionado ao sexo. O trabalho teve os seguintes objetivos: 1) registrar e comparar as variáveis ambientais temperatura, umidade relativa do ar, chuvas e as variáveis corporais peso e teor de gordura dos animais; 2) investigar se o processo de esqueletização sofre interferência hormonal, descrevendo, macroscopicamente, a esqueletização comparando-se os grupos conforme o sexo e a fase hormonal e 3) identificar a composição da massa cadavérica dos restos da decomposição corpórea através do método da cromatografia gasosa. Trata-se de trabalho experimental com ratos Wistar sendo utilizados 30 ratos divididos em três grupos: 10 machos castrados sem reposição de testosterona (MCST), 10 machos castrados com reposição de testosterona (MCCT) e 10 machos controles da testosterona (MCoT). Para a formação do grupo das fêmeas foram utilizadas 60 ratas divididas em seis grupos: 10 fêmeas controles na fase diestro (FCoD), 10 fêmeas controles na fase estro (FCoE), 10 fêmeas controles na fase proestro (FCoP), 10 fêmeas castradas sem reposição de hormônio (FCSH), 10 fêmeas castradas com reposição de estrógeno (FCCE) e 10 fêmeas castradas com reposição de progesterona (FCCP). Estes animais foram cuidados até atingirem o peso entre 350 e 450g, quando foram mortos em câmara de CO2 e depois envolvidos individualmente em gaze e algodão e colocados em urnas de madeira e depois sepultados dentro de uma caixa de cimento enterrada no solo. As análises realizadas para verificar a variação dos fatores ambientais e dos fatores corporais não interferiram no processo de esqueletização. Após as exumações, apenas o grupo MCoT apresentou esqueletização completa com o esqueleto visível livre de quaisquer restos remanescentes. Os grupos MCST e MCCT apresentaram esqueletização mínima com massa cadavérica recobrindo todo o corpo e alguns ainda apresentando órgãos e vísceras conservados. Todos os grupos das fêmeas apresentaram esqueletização parcial. Toda massa cadavérica analisada confirmou ser adipocera. Considerando-se que os dois grupos de animais foram sepultados no mesmo local, sob as mesmas condições ambientais e corporais, simultaneamente durante o mesmo intervalo de tempo, foi possível apontar a variável hormônio como o fator responsável pela diferença observada na decomposição corpórea.Researches have been documenting as it is variable the corporal decomposition and the interval of time verified between the several phases of the process of decomposition of the corpse and the moment in which the death was verified. Environmental factors as temperature, humidity, aerobic and anaerobic conditions, presence of microorganisms and conditions of the soil are considered as factors that interfere in the process that involves the preservation or not of the corpse. The circumstances that stop the rotting, once initiated, are represented by the natural processes conservative of the corpses. The formation of the adipocere was investigated to confirm its relation to the time of skeletization related to the sex. The research had the following objectives: 1) to register and to compare the environmental temperature variables, relative humidity of the air, rain and the corporal weight variables and rate of fat of the animals; 2) to investigate if the skeletization process suffers hormonal interference, describing, macroscopically, the skeletization being compared to the groups according to the sex and the hormonal phase and 3) to identify the composition of the cadaverous mass of the remains of the corporal decomposition through the method of gas chromatography. It deals with experimental work with 30 Wistar rats divided into three groups: 10 castrated males no testosterone replacement (CMNT), 10 castrated males with testosterone replacement (CMWT) and 10 males control of testosterone (MCoT). For the formation of the group of the females, 60 female rats were used divided into six groups: 10 females control in the phase diestrus (FCoD), 10 females control in the phase estrus (FCoE), 10 females control in the phase proestrus (FCoP), 10 castrated females no hormone replacement (CFNH), 10 castrated females with estrogen replacement (CFWE) and 10 castrated females with progesterone replacement (CFWP). These animals were taken care of until they reached the weight between 350 and 450g, when they were killed in camera of CO2 and later involved individually in gauze and cotton and put in wood urns and later buried in a cement box placed in the soil. The analyses did to verify the variation of the environmental factors and of the corporal factors didn\'t interfere in the skeletization process. After the exhumations, just the group MCoT presented complete skeletization with the visible skeleton free from any remaining remains. The groups CMNT and CMWT presented minimum skeletization with cadaverous mass covering the whole body and some still presenting conserved organs and viscera. All of the groups of females presented partial skeletization. Every analyzed cadaverous mass was confirmed to be adipocere. Considering that the two groups of animals were buried in the same place, under the same environmental and corporal conditions, simultaneously during the same interval of time, it was possible to point out the variable hormone as the responsible factor for the difference observed in the corporal decomposition.
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Capel, Émilie. „Formes monogéniques de lipomatose de Launois-Bensaude : étude clinique et moléculaire, et modélisation cellulaire“. Thesis, Sorbonne université, 2019. http://www.theses.fr/2019SORUS501.
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Ce travail initié en lien avec le centre de référence des Pathologies Rares de la Résistance à l’Insuline et de l’Insulino-Sensibilité, s’intéresse à l’étude de la physiopathologie de formes rares de syndromes lipodystrophiques. Parmi ceux-ci, la lipomatose de Launois-Bensaude (LLB) est caractérisée par la présence de masses lipomateuses associées à des troubles métaboliques. Nous avons investigué la plus grande cohorte de patients atteints de LLB due au variant p.Arg707Trp du gène MFN2, codant la mitofusine 2, une protéine de la fusion mitochondriale. Nous avons également étudié une patiente présentant des symptômes compatibles avec une LLB porteuse d’un nouveau variant p.Glu943Glyfs*22 de LIPE, codant la lipase hormono-sensible, enzyme-clé de la lipolyse adipocytaire. Les caractéristiques de ces patients porteurs de variants de MFN2 et LIPE sur le plan clinico-biologique et tissulaire, permettent de mieux définir les particularités de la LLB au sein des syndromes lipodystrophiques. Nous avons isolé les cellules souches adipocytaires (ASC) des lipomes et utilisé ce modèle pour évaluer le retentissement des variants sur la différenciation et les fonctions adipocytaires. Les études morphologiques (microscopie optique et électronique) et fonctionnelles (immuno-histochimie, expression génique et protéique, lipolyse et respiration mitochondriale) des lipomes et/ou des ASC, montrent des altérations adipocytaires multiples avec un phénotype thermogénique des adipocytes LLB-MFN2. La lipodystrophie associée à MFN2 pourrait provenir d’une altération de la balance de différenciation adipocytaire blanche/beigeThis work, initiated in cooperation with the rare diseases reference center ‘Pathologies de la Résistance à l’Insuline et de l’Insulino-Sensibilité’, focuses on the pathophysiology of rare lipodystrophic syndromes. Among them, Launois-Bensaude lipomatosis, also called multiple symmetric lipomatosis (MSL), is characterized by upper-body lipomatous masses and frequent metabolic alterations. We have investigated the largest reported series of patients with MSL due to the MFN2 p.Arg707Trp variant. MFN2 encodes mitofusin 2, a protein involved in mitochondrial fusion. Additionally, a patient with clinical symptoms consistent with MSL, harboring a new p. Glu943Glyfs*22 variant of LIPE, encoding hormone-sensitive lipase, a key enzyme in the lipolysis pathway, has also been studied. The clinical, biological and adipose tissue characteristics of patients carrying MFN2 and LIPE variants, allow for a better definition of MSL within the lipodystrophic syndromes. We have isolated adipose-derived stem cells (ASC) from lipomas and used this cellular model to assess the impact of variants on adipocyte differentiation and functions. Morphological (optic and electronic microscopy) and functional studies (immunohistochemistry, gene and protein expression, lipolysis, and mitochondrial respiration) on pseudo-lipomas and/or on ASC show numerous adipose dysfunctions and highlight the thermogenic phenotype of adipocytes from MFN2-MSL patients. This MFN2-related lipodystrophy could result from a misbalance of white and beige adipocyte differentiation
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„The role of glucose-dependent insulinotropic peptide in adipocyte“. 2012. http://library.cuhk.edu.hk/record=b5549650.
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糖尿病是一种呈现流行趋势的代谢紊乱综合症，现如今，全球大约有3.46亿糖尿病患者， 这庞大的数字给各国的公共健康安全支出带来了严重的财政负担。 其中，二型糖尿病（T2DM）占90%。其特点是周围组织的胰岛素抵抗以及后期损伤的胰岛β细胞的功能。在饮食后，小肠会分泌两种肠促胰岛素，葡萄糖依赖性促胰岛素多肽（GIP）和胰高血糖素样肽-1（GLP-1）。两种多肽的主要功能是促进餐后胰岛细胞中胰岛素的分泌，另外他们还可以通过其自身的G蛋白偶联受体，GIPR和GLP-1R发挥其他作用，如葡萄糖依赖性的刺激胰岛素的生成，刺激胰岛β细胞的增殖，抑制细胞的凋亡等。这些功能也使肠促胰岛素成为糖尿病治疗的一种手段，比如Exendin-4和DPP4抑制剂。 然而，除了在胰岛中的作用，肠促胰岛还可能和脂质代谢相关，其中GIP和脂质代谢的报导研究的更加深入。在肥胖的状态下，血液中GIP含量高于正常水平；GIPR基因敲除老鼠和GIPR的抑制剂喂养的小鼠可以抵抗高脂饮食诱导的肥胖和2型糖尿病；GIP还可以直接调节脂肪细胞的脂肪生成和脂解。这些数据表明GIP在肥胖和糖尿病的发生过程中可能存在促进作用,这使得GIP治疗药物的开发需要谨慎的对待。为了进一步研究GIP在脂肪细胞中发挥的生物学效应，在本研究中，我们利用腺病毒介导技术通过在脂肪细胞中过表达GIPR来增加GIP的活性，然后检查GIP在脂肪细胞中所起的作用。实验结果表明,GIP可以通过cAMP-PKA信号通路迅速并且长期的刺激脂肪细胞的炎症反应，增强IKKβ-NFκB信号通路和增加炎症基因的表达。更深入的机制研究表明，JNK 信号通路也参与GIP诱导的炎症反应，抑制JNK通路可以大部分恢复GIP增加的炎症因子的表达和IKKβ的磷酸化水平。由于长期的炎症反应，脂肪细胞的胰岛素信号通路受到GIP的损伤，在GIPR过表达的脂肪细胞中，胰岛素刺激的AKT磷酸化水平和葡萄糖吸收能力都被GIP降低，葡萄糖转运蛋白4（Glut-4）的表达水平也同时减少。因此，本研究结果表明GIP可能在肥胖的发展过程中，通过诱导脂肪细胞的炎症反应来损伤胰岛素敏感性而最终导致2型糖尿病的发生。
Diabetes mellitus is a type of metabolic syndrome that has prevailed all over the world with the development of economic and over-nutrient lifestyle. It is estimated to 346 million diabetes patients in the worldwide most recently. The huge population put a major burden on the cost of public health care to all the countries. Among the types of diabetes, type 2 diabetes (T2DM) makes up 90% of recorded cases. The characteristics of T2DM are insulin resistance of peripheral tissues and impaired pancreatic cell function and mass. Two major incretins GIP (glucose-dependent insulinotropic peptide) and GLP-1 (glucagon-like peptide 1) are secreted from gut in response to food ingestion. The prominent role of GIP and GLP-1 is to stimulate glucose-dependent insulin release in pancreatic β cell. In addition, they both exert multiple biological effects via their relative G-protein coupled receptors, GIPR and GLP-1R, including glucose-stimulated insulin production, cell proliferation and anti-apoptosis in pancreatic β cells. The beneficent effects of incretins potentiate them as targets for the treatment of diabetes. GLP-1 analog, exendin-4 and DDP4 (dipeptidyl peptidase-4) inhibitors (to prevent GIP and GLP-1 from degradation) have been already used in clinical research. However, in addition to their effects on pancreatic β cell, both peptides are also related to lipid metabolism. The role of GIP has been studied more extensively. In obese state, the circulating level of GIP is elevated. GIPR knockout (KO) mice are resistant to high fat diet (HFD) induced obesity, a similar phenotype is found in GIPR antagonist administrated HFD-mice. Moreover, GIP also directly promotes lipogenesis and lipolysis in adipocytes. The rising evidence suggests a potential role of GIP in adipocyte biology and lipid metabolism, which diminishes the enthusiasm of GIP as a candidate therapeutic reagent for T2DM.
In order to further understand the biological effects of GIP in adipocytes, here, we over-expressed GIPR in 3T3-L1 CAR adipocytes via adenovirus-mediated gene transfer technology to enhance the activity of GIP. The results demonstrate that GIP impairs the physiological functions of adipocytes as a consequence of increasing the production of inflammatory cytokines, chemokines, and phosphorylation of IkB kinase (IKK) β through activation of the cyclic AMP-protein kinase A (cAMP-PKA) pathway. Activation of Jun N-terminal Kinase (JNK) pathway is also observed in GIP-induced inflammatory responses in adipocytes. An inhibitor of JNK blocks GIP-stimulated secretion of inflammatory cytokines and chemokines, as well as phosphorylation of IKKβ. The chronic inflammatory response eventually impairs insulin signaling in adipocytes, as demonstrated by reduction of protein kinase B (PKB/AKT) phosphorylation. The subsequently physiological analysis also indicates that GIP inhibits insulin-stimulated glucose uptake, and gene expression analysis reveals a decrease of glucose transporter 4 (Glut-4) in the meanwhile. The results suggest that GIP may be one of stimuli attributable to obesity induced insulin resistance via induction of adipocyte inflammation.
Detailed summary in vernacular field only.
Detailed summary in vernacular field only.
Nie, Yaohui.
Thesis (Ph.D.)--Chinese University of Hong Kong, 2012.
Includes bibliographical references (leaves 95-111).
Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web.
Abstract also in Chinese.
Abstract --- p.i
摘要 --- p.iii
Acknowledgements --- p.v
INTRODUCTION --- p.1
Chapter Part 1 --- Obesity and Type 2 diabetes --- p.1
Chapter 1.1 --- Introduction to diabetes --- p.1
Chapter 1.1.2 --- Physiology of adipocyte --- p.4
Chapter 1.1.3 --- Mechanism of obesity induced diabetes --- p.10
Chapter Part 2 --- Incretins and T2DM --- p.12
Chapter 2.1 --- History of incretins --- p.12
Chapter 2.2 --- Physiological actions of incretins --- p.14
Chapter 2.3 --- Molecular mechanism of incretin actions in pancreas --- p.16
Chapter 2.4 --- Incretins and T2DM --- p.19
Chapter Part 3 --- Incretins and lipid metabolism --- p.23
Objective --- p.26
Methods and materials --- p.28
Chapter 1 --- Cell culture --- p.28
Chapter 1.1 --- 3T3-L1 culture and differentiation --- p.28
Chapter 1.2 --- 3T3-L1 CAR culture and differentiation --- p.29
Chapter 2 --- Cloning and recombinant adenovirus construction --- p.30
Chapter 2.1 --- Plasmid construct --- p.30
Chapter 2.2 --- Construct of recombinant adenoviruses --- p.30
Chapter 2.3 --- Generation and infection of the adenoviruses --- p.31
Chapter 3 --- Physiological and morphological assays --- p.32
Chapter 3.1 --- Lipolysis assay --- p.32
Chapter 3.2 --- TUNEL assay --- p.32
Chapter 3.3 --- Glucose uptake --- p.33
Chapter 3.4 --- Glut-4 localization --- p.33
Chapter 4 --- Gene expression analysis --- p.35
Chapter 4.1 --- Quantitative real-time PCR --- p.35
Chapter 4.2 --- Immunoblot analysis --- p.35
Chapter 4.3 --- ELISA assay --- p.36
Chapter 5 --- Isolation of primary adipocytes --- p.37
Results --- p.38
Chapter Part 1 --- Role of GIP in 3T3-L1 cells --- p.38
Chapter 1.1 --- Differentiation of 3T3-L1 adipocytes --- p.38
Chapter 1.2 --- GIP slightly stimulates phosphorylation of p-CREB and lipolysis in 3T3-L1 cells. --- p.40
Chapter 1.3 --- Analysis of gene expression in GIP-treated adipocytes --- p.42
Chapter 1.4 --- Discussion --- p.44
Chapter Part 2 --- Role of GIP in GIPR over-expressing 3T3-L1 CAR adipocytes --- p.46
Chapter 2.1 --- Differentiation of 3T3-L1 CAR adipocytes --- p.46
Chapter 2.2 --- Functional tests in GIPR over-expressing 3T3-L1 CAR adipocytes. --- p.48
Chapter 2.3 --- Effect of GIP on cell viability --- p.50
Chapter 2.4 --- Analysis of gene expression in GIP-treated adipocytes --- p.52
Chapter 2.5 --- GIP activates inflammatory responses in GIPR over-expressing adipocytes --- p.54
Chapter 2.6 --- Inhibition of IKKb pathway restores GIP-induced inflammatory responses --- p.56
Chapter 2.7 --- Effects of GIP on adipocytes are partially dependent on the cAMP-PKA pathway --- p.58
Chapter 2.8 --- Activation of cAMP-PKA pathway induces adipocyte inflammation. --- p.60
Chapter 2.9 --- cAMP-Epac pathway is not involved in GIP-induced inflammation --- p.62
Chapter 2.10 --- GIP stimulates cell stress activated kinases --- p.64
Chapter 2.11 --- JNK partially mediates GIP-induced adipocyte inflammation --- p.65
Chapter 2.12 --- Inhibition of JNK pathway partially restores GIP-induced inflammatory responses --- p.67
Chapter 2.13 --- GIP impairs insulin signaling in GIPR over-expressing 3T3-L1 CAR adipocytes via inducing inflammatory response --- p.69
Chapter 2.14 --- GIP enhances basal glucose uptake but impairs insulin stimulated glucose uptake in 3T3-L1 CAR GIPR over-expressing adipocytes --- p.71
Chapter 2.15 --- Discussion --- p.73
Chapter Part 3 --- Role of GIP in primary adipocytes --- p.78
Chapter 3.1 --- GIPR expression level in primary adipocytes --- p.78
Chapter 3.2 --- Analysis of gene expression in primary adipocytes after GIP treatment --- p.80
Chapter 3.3 --- Discussion --- p.81
SUMMARY --- p.82
Chapter Future investigation --- p.83
Chapter Appendix 1: --- Abbreviations --- p.86
Chapter Appendix 2: --- Protocols --- p.90
Preparation of competent cells --- p.90
Outlines of recombinant adenovirus preparation --- p.91
Virus titering (TCID50) --- p.92
Primers for real-time PCR --- p.93
Chapter Publications and Scientfic activities --- p.94
Thesis related publication: --- p.94
Other pubiliations: --- p.94
Scientific activities: --- p.94
References --- p.95
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Blum, Robert M. „Metabolic signals are more important than adipocyte, pancreatic and adrenal hormones in control of reproduction /“. Diss., 2004. http://gateway.proquest.com/openurl?url_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation&res_dat=xri:pqdiss&rft_dat=xri:pqdiss:3154553.
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