To be or not to be fat : a novel role of Jak/Stat pathway in brown fat development and preventing obesity

To be or not to be fat : a novel role of Jak/Stat pathway in brown fat development and preventing obesity

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To be or not to be fat : a novel role of Jak/Stat pathway in brown fat development and preventing obesity

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dc.contributor.advisor	Cichy, Joanna [SAP11013475]	pl
dc.contributor.advisor	Larner, Andrew	pl
dc.contributor.author	Derecka, Marta [USOS12973]	pl
dc.date.accessioned	2021-06-25T08:24:31Z
dc.date.available	2021-06-25T08:24:31Z
dc.date.submitted	2011-05-27	pl
dc.identifier.uri	https://ruj.uj.edu.pl/xmlui/handle/item/274841
dc.language	eng	pl
dc.rights	Copyright	*
dc.rights.uri	http://ruj.uj.edu.pl/4dspace/License/copyright/licencja_copyright.pdf	*
dc.title	To be or not to be fat : a novel role of Jak/Stat pathway in brown fat development and preventing obesity	pl
dc.title.alternative	Być czy nie być otyłym : nowa rola ścieżki przekazu sygnału Jak/Stat w rozwoju brunatnej tkanki tłuszczowej i zapobieganiu otyłości	pl
dc.type	Thesis	pl
dc.place	Kraków	pl
dc.description.physical	133	pl
dc.description.additional	Bibliogr. s. 113-133	pl
dc.abstract.en	Obesity is defined as abnormal or excessive fat accumulation that presents a significant risk to health and is a major risk factor for a number of chronic diseases such as diabetes, cardiovascular disorders and cancer. Janus kinases (Jaks) and signal transducers and activators of transcription (Stats) have emerged as critical regulators of numerous fundamental biological processes and are important in the etiology of various disease conditions. The Jak/Stat pathway is a primary mediator of leptin signaling, which has been implicated in obesity. We found that mice lacking Tyk2, one of the Jak’s, become spontaneously obese. We discovered that expression of a variety of mRNAs that regulate fatty acid and glucose homeostasis are altered in liver, skeletal muscle and adipose tissue of Tyk2- null mice, which is consistent with metabolic syndrome. Proper energy balance prevents the development of obesity and is dependent on energy expenditure. Brown adipose tissue (BAT) dissipates chemical energy in the form of heat in response to excess of calories and constitutes a natural defense mechanism against hypothermia and obesity. Our data suggest that differentiation and function of BAT is defective in mice that do not express Tyk2, which might explain the obese phenotype in these animals. Using an in vitro differentiation model of brown preadipocytes isolated from mice with a Tyk2 deletion, we were able to restore the differentiation by expression of either wild type or kinase inactive Tyk2 (Tyk2KD), as well as constitutively active form of Stat3 (Stat3CA). Recent data provided evidence that PRDM16 is the master regulator controlling the brown fat/skeletal muscle switch from a common progenitors. Consistent with severe decrease in PRDM16 expression, we observed up-regulation of muscle-specific mRNAs in Tyk2- null cells. Remarkably, differentiation of Tyk2 -/- preadipocytes cannot be rescued by PRDM16. These data suggest that Tyk2 is key player in brown preadipocytes differentiation acting upstream of PRDM16 or in parallel with it. Interestingly, we also found that the absence of Tyk2 results in epigenetic changes in the promoters of BAT- specific genes such as UCP1 (uncoupling protein 1) and Cidea (cell death-inducing DFFA-like effector a), abrogating their expression. Consistent with our in vitro data, BAT- specific expression of the Stat3CA transgene restores BAT differentiation in mice. Animals expressing Stat3CA in BAT exhibit significantly reduced body weight and improved insulin sensitivity in comparison to control mice, which demonstrate that the obese phenotype of Tyk2 -/- mice is most likely a result of defects in BAT differentiation occurring in these animals. The above observations present a novel role of Jak/Stat pathway in development of BAT and the control of obesity. The fact that kinase inactive Tyk2 also restores brown adipocytes differentiation reinforces the innovative concept that the actions of this kinase are not mediated by its well described activation in cytokine activation of the Jak/Stat cascade.	pl
dc.subject.pl	otyłość	pl
dc.subject.pl	brunatna tkanka tłuszczowa	pl
dc.subject.pl	Tyk2	pl
dc.subject.pl	Stat3	pl
dc.subject.en	obesity	pl
dc.subject.en	brown adipose tissue	pl
dc.subject.en	Tyk2	pl
dc.subject.en	Stat3	pl
dc.identifier.callnumber	Dokt. 2011/099	pl
dc.contributor.institution	Jagiellonian University	pl
dc.contributor.institution	Virginia Commonwealth University. Department of Biochemistry and Molecular Biology	pl
dc.contributor.reviewer	Bryła, Jadwiga	pl
dc.contributor.reviewer	Józkowicz, Alicja [SAP11114690]	pl
dc.affiliation	Wydział Biochemii, Biofizyki i Biotechnologii : Zakład Immunologii	pl
dc.rights.original	OTHER; otwarte repozytorium; ostateczna wersja autorska (postprint); w momencie opublikowania; 0	pl
dc.identifier.project	ROD UJ / OP	pl