Universität zu Köln

Hansmeier, Nils Rouven (2018). Decoding the Impact of Obesity Long Noncoding RNAs on Murine Liver Energy Homeostasis. PhD thesis, Universität zu Köln.

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Abstract

Long noncoding RNAs (lncRNAs) have recently been recognised as multifaceted regulators of gene expression across multiple cellular and developmental contexts, yet their contribution to liver energy homeostasis remains poorly understood. Using global transcriptome profiling we demonstrate that both chronic and acute nutrient challenges elicit global anticorrelative transcriptional responses of protein-coding mRNAs and lncRNAs in liver. To address if lncRNAs functionally contribute to the control of liver metabolism, we performed in vitro characterisation of regulated hepatic lncRNAs and selected metabolically-responsive lncRNAs Gm15441 and lincIRS2 for further characterisations in vivo. Through CRISPR/Cas9-mediated genome engineering we generated deletion alleles of both selected lncRNAs and verified that expression of the respective transcripts were successfully abrogated in in vivo mouse models. Finally, we show that lincIRS2 deficiency causes hyperglycemia and impaired insulin tolerance in in vivo mouse models and provide evidence that lncIRS2 is essential for proper glucose homeostasis and insulin-evoked suppression of hepatic glucose production by impacting on AKT phosphorylation and gluconeogenic and lipogenic gene expression. Collectively, we propose the concept that nutrient-sensitive lncRNA lincIRS2 is transcriptionally coupled to alterations of systemic nutrient states and functions as molecular relay controlling liver energy homeostasis.

Item Type:	Thesis (PhD thesis)
Translated title:	Title Language Die Entschlüsselung des Einflusses von Übergewichts-assozierten, langen, nicht-kodierenden RNAs auf die hepatische Energiehomeostase German
Creators:	Creators Email ORCID ORCID Put Code Hansmeier, Nils Rouven Nils.Hansmeier@sf.mpg.de UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-94007
Date:	1 October 2018
Language:	English
Faculty:	Faculty of Mathematics and Natural Sciences
Divisions:	Außeruniversitäre Forschungseinrichtungen > MPI for Metabolism Research
Subjects:	Life sciences
Uncontrolled Keywords:	Keywords Language Long Noncoding RNA, Liver Metabolism English
Date of oral exam:	26 November 2018
Referee:	Name Academic Title Kornfeld, Jan-Wilhelm Prof. Dr. Trifunovic, Aleksandra Prof. Dr.
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/9400