Izraženost i učinci urogvanilina u mozgu miša [Expression and effects of uroguanylin in the mouse brain]

Habek, Nikola (2018) Izraženost i učinci urogvanilina u mozgu miša [Expression and effects of uroguanylin in the mouse brain]. PhD thesis, Sveučilište u Zagrebu.

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Abstract

Uroguanylin (UGN) belongs to the family of guanylin peptides. They regulate electrolyte and water transport in intestine via guanylate cyclase C, the only known receptor for guanylin peptides. In this thesis we are showing expression of UGN in different brain regions which is regulated by feeding, although it was believed that brain is not expressing UGN. Guanylate cyclase C (GC-C) is expressed in midbrain and hypothalamus, while we discovered additional brain regions expressing GC-C in neurons (cerebral cortex, Purkinje cells and deep nuclei of the cerebellum) but not in astrocytes. UGN hyperpolarized Purkinje cells and decreased firing rate while in astrocytes lead to increase in intracellular Ca2+ concentration via GC-C/cGMP independent signalling pathway. Effects of UGN in hypothalamus on diet-induced thermogenesis and brown adipose tissue (BAT) activation after a meal exist in male but not female WT animals and GC-C KO animals of both genders. Similar research was performed on healthy volunteers which showed that activation of BAT after a meal is gender, age, and body mass index dependent. Role of UGN in BAT regulations is of immeasurable importance for development of the new therapeutic approaches in treatment of obesity, metabolic syndrome, and diabetes mellitus.

Abstract in Croatian

Urogvanilin (UGN) pripada porodici gvanilinskih peptida (GP) koji u probavnom sustavu reguliraju transport elektrolita i vode aktivacijom gvanilat-ciklaze C, do danas jedinog poznatog receptora za GP-e. Ovim radom pokazujemo izražaj UGN-a na mRNA i proteinskoj razini u pojedinim regijama mozga koji je ovisan o hranjenju iako se do sada smatralo da se UGN ne stvara u mozgu. Uz do sada poznati izražaj gvanilat-ciklaze C (GC-C) u srednjem mozgu i hipotalamusu, otkrili smo nova mjesta izražaja GC-C u neuronima (korteks velikog mozga, Purkinjeove stanice i duboke jezgre malog mozga), ali ne i u astrocitima. UGN hiperpolarizira staničnu membranu Purkinjeovih stanica i smanjuje frekvenciju izbijanja dok u astrocitima dovodi do povećanja unutarstanične koncentracije Ca2+ putem signalnog puta neovisnog o GC-C/cGMP-u. Učinak UGN-a u hipotalamusu na termogenezu uzrokovanu hranom te aktivaciju smeđeg masnog tkiva (BAT) nakon obroka postoji kod mužjaka, ali ne i ženki divljeg tipa životinja ni kod oba spola životinja kojima nedostaje GC-C. Istraživanje je provedeno i na zdravim dobrovoljcima i pokazuje kako je aktivacija BAT-a nakon obroka ovisna o spolu, dobi i indeksu tjelesne mase. Rad ukazuje na ulogu UGN-a u regulaciji BAT-a koja je od neizmjerne važnosti za razvoj novih terapijskih pristupa u terapiji pretilosti, metaboličkog sindroma i šećerne bolesti.

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