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Molecular mechanisms of insulin-induced rat brown adipose tissue structural remodelling

dc.contributor.advisorKorać, Aleksandra
dc.contributor.otherStančić, Ana
dc.contributor.otherKorać, Bato
dc.contributor.otherJanković, Aleksandra
dc.contributor.otherBuzadžić, Biljana
dc.creatorMarkelić, Milica B.
dc.date.accessioned2016-01-05T11:46:10Z
dc.date.available2016-01-05T11:46:10Z
dc.date.available2020-07-03T08:08:28Z
dc.date.issued2012-05-04
dc.identifier.urihttp://eteze.bg.ac.rs/application/showtheses?thesesId=17
dc.identifier.urihttps://nardus.mpn.gov.rs/handle/123456789/2051
dc.identifier.urihttps://fedorabg.bg.ac.rs/fedora/get/o:2208/bdef:Content/download
dc.identifier.urihttp://vbs.rs/scripts/cobiss?command=DISPLAY&base=70036&RID=
dc.description.abstractU svetlu sve većeg broja dokaza koji ukazuju na prisustvo metabolički aktivnog mrkog masnog tkiva (BAT – brown adipose tissue, engl.) kod odraslih ljudi, kao i na njegovu potencijalnu ulogu u sprečavanju razvoja gojaznosti, insulinske rezistence i metaboličkog sindroma uopšte, sve je više studija o rasvetljavanju metaboličkog značaja ovog tkiva, kao i njegovoj termogenoj stimulaciji u svrhu terapije navedenih poremećaja. Insulin se, kao važan anabolički hormon, smatra značajnim modulatorom strukturne organizacije i funkcije BAT. Cilj ovog istraživanja bio je rasvetljavanje molekulskih osnova insulinomindukovanog strukturnog remodeliranja BAT putem identifikacije mehanizama koji regulišu insulinom-stimulisanu proliferaciju i diferencijaciju ćelija, kao i identifikacije mehanizama koji učestvuju u oštećenjima ćelija i njihovom umiranju. Pacovi soja Wistar su jednom dnevno tretirani fiziološkom (0.4 IU/kg telesne mase) i suprafiziološkom (4 IU/kg telesne mase) dozom insulina, jedan (akutan tretman) ili tri (hroničan tretman) dana. Kao fiziološka kontrola, dve grupe pacova su u istom trajanju tretirane fiziološkim rastvorom (akutna i hronična kontrola). Tri sata nakon poslednje doze, životinje su žrtvovane, a interskapularni depo BAT je izolovan, izmeren i pripremljen za tehnike svetlosne i elektronske mikroskopije. Analiza tkiva izvršena je korišćenjem metoda histohemijskog i imunohistohemijskog bojenja, metoda konfokalne i transmisione elektronske mikroskopije i elektron-disperzivne analize X-zracima (EDX) hemijskog sastava tkiva kao i metoda stereološke i morfometrijske analize. Rezultati su pokazali postojanje strukturnog i funkcijskog remodeliranja BAT, gde dominiraju procesi hipertrofije i hiperplazije ćelija, praćene povećanjem termogenog kapaciteta mrkih adipocita (raste ekspresija dekuplujućeg proteina 1 (UCP1 – uncoupling protein 1, engl.), udeo mitohondrija, procesi mitohondriogeneze). S druge strane, primetno je da se, naročito pri hroničnim i tretmanima visokom dozom insulina, javljaju citotoksični i inhibitorni efekti na pojedine ćelije ili klastere ćelija: raste učestalost ćelijske smrti, ekstravazacija eritrocita i njihovo uklanjanje od strane mrkih adipocita i makrofaga, (evidentno toksično po adipocite sudeći po rastu: ekspresije enzima antioksidativne odbrane; lipidne peroksidacije i nitrozilacije proteina, učestalosti lipofuscinogeneze). Takođe se pri hronično visokoj hiperinsulinemiji smanjuje ekspresija regulatora termogeneze (PGC-1α - peroxisome proliferator-activated receptor – γ coactivator - 1α, engl.) ukazujući da produženo izlaganje visokim dozama insulina, može da inhibira termogeni odgovor tkiva, o čemu svedoči i povećana učestalost mitohondrijalnih oštećenja. Povećana ekspresija proinflamatornih citokina (TNF-α - tumor-necrosis factor – α, engl., interleukina 6), nukleusnog faktora – kB (NF-kB) i makrofagnog inflamatornog proteina - 3β (MIP-3β) u pojedinačnim zrelim, multilokulusnim adipocitima, preadipocitima i unilokulusnim adipocitima ukazuje na njihovu potencijalnu ulogu u lokalnom smanjenju insulinske senzitivnosti. U vezi sa hiperplazijom ćelija, primećeno je da su adipogeneza i angiogeneza u BAT vremenski i prostorno povezane, tj. da postoji udruženost navedenih procesa, koja ukazuje na potrebu udruženog nastanka adipocita i endotelskih ćelija, u svrhu efikasnog strukturno-funkcijskog remodeliranja tkiva. Sumarno, može se zaključiti da hiperinsulinemija ima značajan efekat na BAT – potvrđeno je anaboličko dejstvo insulina i važnost njegove uloge u stimulaciji BAT, ali je i pokazana toksičnost visoke doze i hroničnog izlaganja na ćelije BAT; što je sve doprinelo rasvetljavanju molekulskih mehanizama u osnovi strukturnog remodeliranja ovog tkiva. Takođe, pokazano je da se visoka plastičnost BAT ogleda u postojanju funkcionalnih klastera ćelija, u kojima se odvijaju svi važni tkivni procesi (adipo/angiogeneza, ćelijska smrt, eritrofagocitoza), što ukazuje na pravilnu uređenost tkivne organizacije i strukturnog remodeliranja, kao preduslova za pravilno funkcionisanje tkiva, kako u fiziološkim, tako i u uslovima izmenjene tkivne homeostaze, što je pokazano na modelu hiperinsulinemije.sr
dc.description.abstractThere is an increasing amount of evidence that indicates presence of brown adipose tissue (BAT) in adult humans, and its potential role in prevention of obesity, insulin resistance and metabolic syndrom, in general. That is why number of studies on elucidation of the metabolic importance of this tissue, along with its thermogenic stimulation in order to treat these disorders, increases. As an important anabolic hormone, insulin is considered as a major modulator of BAT structure and function. The aim of this study was to elucidate the molecular basis of insulin-induced structural remodeling of BAT through the identification of mechanisms that regulate insulin-stimulated proliferation and differentiation and through the identification of mechanisms involved in cell damage and death. Wistar strain rats were treated intraperitoneally with physiological (0.4 IU/kg BW) or supraphysiological (4 IU/kg BW ) dose of insulin for one (acute treatment) or three days (chronic treatment), respectively. Two groups of rats served as physiological controls, and were treated with saline (acute and chronic control). Three hours after the last injection the animals were sacrificed and the interscapular portion of BAT was removed, its weight was measured and it was processed for electron and light microscopic examinations. Methods of histochemical staining, immunohistochemical labeling, confocal and transmission electron microscopy, tissue electron-dispersive X-ray microanalysis (EDX) and stereological and morphometric analyses were performed. The results showed the existence of structural and functional remodeling of BAT, based on adipocyte hypertrophy and hyperplasia which are followed by increasing of thermogenic capacity (expression of uncoupling protein 1 (UCP1), cellular proportion of mitochondria, mitochondrial biogenesis). On the other hand, it is obvious that, especially after chronic and high-dose treatments, insulin cytotoxic and inhibitory effects on individual cells or cell clusters occur: incidence of cell death increases, as well as red blood cell extravasation and their removal by brown adipocytes and macrophages (which is evidently toxic for the adipocyte, since expression of antioxidative defense enzymes, lipid peroxidation, protein nitrosilation and lipofuscin formation were increased). Also, during chronically high hyperinsulinemia, expression of peroxisome proliferator-activated receptor - γ coactivator - 1α (PGC-1α), regulator of thermogenesis decreases, indicating that prolonged exposure to high doses of insulin can inhibit thermogenic response of BAT, as evidenced by the increased frequency of mitochondrial damage in brown adipocytes. Increased expression of proinflammatory cytokines (tumornecrosis factor - α (TNF-α), interleukin 6), nuclear factor – kB (NF-kB) and macrophage inflammatory protein - 3β (MIP-3β) in individual mature, multilocular adipocytes, preadipocytes and unilocular adipocytes, demonstrates their potential role in local decrease of insulin sensitivity. Regarding hyperplasia of cells, it was noticed spaciotemporal association between processes of adipogenesis and angiogenesis, which means that there is a connection between these processes, demonstrating the need for the coupled differentiation of adipocytes and endothelial cells, for the purpose of efficient structural and functional remodeling of the tissue. In summary, it can be concluded that hyperinsulinemia has a significant impact on BAT – we confirmed the anabolic effect of insulin, and the importance of its role in BAT stimulation, but also demonstrated the toxicity of high dose and chronic exposure to insulin on BAT cells, all of which contribute to understanding the molecular mechanisms underlying structural remodeling of the tissue. In addition, it was shown that the high plasticity of BAT is reflected in the existence of functional clusters of cells, which take place in all the important processes in the tissue (adipo/angiogenesis, cell death, erythrophagocytosis), indicating the proper arrangement of tissue organization and structural remodeling as a prerequisite for the proper functioning of the tissue under physiological conditions and during altered tissue homeostasis, as shown on the model of hyperinsulinemia.en
dc.formatapplication/pdf
dc.languagesr
dc.publisherУниверзитет у Београду, Биолошки факултетsr
dc.relationinfo:eu-repo/grantAgreement/MESTD/Basic Research (BR or ON)/173055/RS//
dc.rightsopenAccessen
dc.rights.urihttps://creativecommons.org/licenses/by-nc-nd/4.0/
dc.sourceУниверзитет у Београдуsr
dc.subjectMrko masno tkivosr
dc.subjectBrown adipose tissueen
dc.subjectinsulinsr
dc.subjecthiperinsulinemijasr
dc.subjectstrukturno remodeliranje tkivasr
dc.subjectadipogenezasr
dc.subjectangiogenezasr
dc.subjecttermogenezasr
dc.subjectmrki adipocitsr
dc.subjectinsulinen
dc.subjecthyperinsulinaemiaen
dc.subjectstructural tissue remodelingen
dc.subjectadipogenesisen
dc.subjectangiogenesisen
dc.subjectthermogenesisen
dc.subjectbrown adipocyteen
dc.titleMolekulski mehanizmi strukturnog remodeliranja mrkog masnog tkiva pacova indukovanog insulinomsr
dc.titleMolecular mechanisms of insulin-induced rat brown adipose tissue structural remodellingen
dc.typedoctoralThesisen
dc.rights.licenseBY-NC-ND
dcterms.abstractКораћ, Aлександра; Јанковић, Aлександра; Станчић, Aна; Кораћ, Бато; Бузаджић, Биљана; Маркелић, Милица Б.; Молекулски механизми структурног ремоделирања мрког масног ткива пацова индукованог инсулином; Молекулски механизми структурног ремоделирања мрког масног ткива пацова индукованог инсулином;
dc.identifier.fulltexthttps://nardus.mpn.gov.rs/bitstream/id/1890/Disertacija.pdf
dc.identifier.fulltexthttp://nardus.mpn.gov.rs/bitstream/id/1890/Disertacija.pdf
dc.identifier.doi10.2298/bg20120504markelic
dc.identifier.rcubhttps://hdl.handle.net/21.15107/rcub_nardus_2051


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