izvor podataka: poirot

Serotonergična modulacija pretilosti: međuovisnost regulatornih molekula i puteva

Serotonergic modulation of obesity: cross-talk between regulatory molecules and pathways


Održavanje energetske ravnoteže organizma kompleksan je proces koji uključuje interakciju različitih centralnih i perifernih regulatornih molekula. Uloga neurotransmitera serotonina (5HT) u modulaciji unosa hrane odavno je poznata, no rezultati novijih istraživanja na životinjama sa genetički promijenjenim 5HT sustavom, u suprotnosti su sa pretpostavkom da veća bioraspoloživost 5HT dovodi do redukcije tjelesne težine, te traže bolje poznavanje integrativnih mehanizama regulacije energetske homeostaze.Ovim projektom se istražuje uloga individualne razine aktivnosti 5HT sustava u regulaciji unosa i potrošnje energije, korištenjem originalnog životinjskog modela (Wistar-Zagreb 5HT štakor), razvijenog u vlastitom laboratoriju selektivnim parenjem životinja prema aktivnosti perifernog 5HT transportera, ključnog proteina u regulaciji bioraspoloživosti 5HT. Dvije sublinije životinja, 5HT-visoka i 5HT-niska, dobivene genetičkom selekcijom, konstitucijski se razlikuju u homestazi centralnog i perifernog 5HT, što je pokazano neurokemijskim, farmakološkim i bihevioralnim studijama. Jedna od posljedica genetičke selekcije je i značajno povećana tjelesna težina životinja iz 5HT-visoke sublinije. Cilj projekta je otkriti biološku podlogu povezanosti povećane 5HT aktivnosti i pretilosti kod hiperserotonergičnih životinja, te njezine funkcionalne posljedice. Istraživanja na molekularnoj razini fokusirana su na ekspresiju regulatornih peptida u hipotalamusu i adipocitima, njihove receptore i nizvodne signalne molekule, te transkripcijske faktore uključene u regulaciju adipogeneze i energetske homeostaze općenito. Istraživanja na razini organizma uključuju funkcionalni odgovor životinja na specifične fiziološke izazove - sklonost debljanju pri visoko kaloričnoj prehrani i sposobnost termogeneze pri izlaganju hladnoći. Pored doprinosa temeljnom znanju u području neuroadipologije, ovaj projekt omogućiti će uspostavu novog životinjskog modela za istraživanje pretilosti.

The rise in obesity has driven a major interest in the mechanisms maintaining energy homeostasis, a complex physiological process which includes interactions of various central and peripheral regulatory molecules. It is known that serotonin (5HT) - mediated mechanisms play a role in the pathophysiology of obesity, but results from recent studies utilizing genetic perturbations of the serotonin system are often at odds with the historical notion that increased 5HT bioavailability leads to body weight reduction, and highlight the need to better understand integrative mechanisms at work during lifelong alterations in 5HT signaling. This project is aimed to study the impact of constitutionally altered activity of 5HT system on the regulation of hypothalamic-adipose tissue axis that regulates energy balance. For this purpose we plan to use an original animal model, Wistar-Zagreb 5HT rats, developed in our laboratory by the use of selective breding toward extreme activities of peripheral 5HT transporter, a key regulator of 5HT bioavailability. As a result of genetic selection two sublines of the model, high-5HT and low-5HT subline, show constitutional differences in central and peripheral 5HT homeostasis. One of the consequences of genetic selection is also a markedly overweight phenotype of high-5HT animals. We will investigate biological basis of interplay between increased 5HT tone and adiposity in the hyperserotonergic subline, and their functional consequences. Studies at the molecular level will be focused on the expression of adipocyte- and hypothalamic-derived peptides, their receptors and downstream signaling as well as transcriptional factors and cofactors involved in the regulation of adipogenesis and energy homeostasis in general. Studies on the whole body level will include investigations of the functional responses of 5HT sublines to specific physiological challenges - susceptibility to diet-induced obesity and capability for cold-induced thermogenesis.


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Znanstveno-istraživački projekti

SERT-OB

IP-2014-09-7827

01.09.2015

09.01.2019

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HRK 936.100,00