Awazawa, Motoharu, Gabel, Paula, Tsaousidou, Eva ORCID: 0000-0003-2751-1911, Nolte, Hendrik, Krueger, Marcus, Schmitz, Joel, Ackermann, P. Justus, Brandt, Claus ORCID: 0000-0002-7871-7437, Altmueller, Janine, Motameny, Susanne, Wunderlich, F. Thomas, Kornfeld, Jan-Wilhelm ORCID: 0000-0002-6802-4442, Blueher, Matthias and Bruning, Jens C. (2017). A microRNA screen reveals that elevated hepatic ectodysplasin A expression contributes to obesity-induced insulin resistance in skeletal muscle. Nat. Med., 23 (12). S. 1466 - 1478. NEW YORK: NATURE PUBLISHING GROUP. ISSN 1546-170X

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Abstract

Over 40% of microRNAs (miRNAs) are located in introns of protein-coding genes, and many of these intronic miRNAs are co-regulated with their host genes(1,2). In such cases of co-regulation, the products of host genes and their intronic miRNAs can cooperate to coordinately regulate biologically important pathways(3,4). Therefore, we screened intronic miRNAs dysregulated in the livers of mouse models of obesity to identify previously uncharacterized protein-coding host genes that may contribute to the pathogenesis of obesity-associated insulin resistance and type 2 diabetes mellitus. Our approach revealed that expression of both the gene encoding ectodysplasin A (Eda), the causal gene in X-linked hypohidrotic ectodermal dysplasia (XLHED)(5), and its intronic miRNA, miR-676, was increased in the livers of obese mice. Moreover, hepatic EDA expression is increased in obese human subjects and reduced upon weight loss, and its hepatic expression correlates with systemic insulin resistance. We also found that reducing miR-676 expression in db/db mice increases the expression of proteins involved in fatty acid oxidation and reduces the expression of inflammatory signaling components in the liver. Further, we found that Eda expression in mouse liver is controlled via PPAR gamma and RXR-alpha, increases in circulation under conditions of obesity, and promotes JNK activation and inhibitory serine phosphorylation of IRS1 in skeletal muscle. In accordance with these findings, gain-and loss-of-function approaches reveal that liver-derived EDA regulates systemic glucose metabolism, suggesting that EDA is a hepatokine that can contribute to impaired skeletal muscle insulin sensitivity in obesity.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Awazawa, MotoharuUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gabel, PaulaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tsaousidou, EvaUNSPECIFIEDorcid.org/0000-0003-2751-1911UNSPECIFIED
Nolte, HendrikUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Krueger, MarcusUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schmitz, JoelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ackermann, P. JustusUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Brandt, ClausUNSPECIFIEDorcid.org/0000-0002-7871-7437UNSPECIFIED
Altmueller, JanineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Motameny, SusanneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wunderlich, F. ThomasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kornfeld, Jan-WilhelmUNSPECIFIEDorcid.org/0000-0002-6802-4442UNSPECIFIED
Blueher, MatthiasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bruning, Jens C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-210332
DOI: 10.1038/nm.4420
Journal or Publication Title: Nat. Med.
Volume: 23
Number: 12
Page Range: S. 1466 - 1478
Date: 2017
Publisher: NATURE PUBLISHING GROUP
Place of Publication: NEW YORK
ISSN: 1546-170X
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
HYPOHIDROTIC ECTODERMAL DYSPLASIA; LARGE GENE LISTS; GLUCOSE-PRODUCTION; ADIPOSE-TISSUE; MOUSE; MICE; IDENTIFICATION; DEFICIENCY; HOMOLOG; DOMAINSMultiple languages
Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & ExperimentalMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/21033

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