Proteomics

Dataset Information

103

Mouse Liver LC-MS/MS LNA miR-676 treated dbdb mice


ABSTRACT: Over 40 % of microRNAs are located in introns of coding genes, and many intronic microRNAs are co-regulated with their host genes. In such cases of co-regulation, the products of host genes and their intronic microRNAs can cooperate to coordinately regulate biologically important pathways. Therefore, we screened intronic microRNAs dysregulated in liver of obese mouse models to identify previously uncharacterized coding host genes that may contribute to the pathogenesis of obesity-associated insulin resistance and type 2 diabetes mellitus. Our approach identified that expression of both Ectodysplasin A (Eda), the causal gene of X-linked hypohidrotic ectodermal dysplasia (XLHED; MIM 305100) and its intronic microRNA, miR-676, was strongly increased in liver of obese mouse models. Moreover, hepatic EDA expression is increased in obese human subjects, reduced upon weight loss, and its hepatic expression correlates with systemic insulin resistance. Eda expression in murine liver is controlled via PPARg activation, increases in circulation and promotes JNK activation and inhibitory serine phosphorylation of IRS1 in skeletal muscle. Consistently, bi-directional modulation of hepatic Eda expression in mouse models affects systemic glucose metabolism with alterations of muscle insulin signaling, revealing a novel role of EDA as an obesity-associated hepatokine, which impairs insulin sensitivity in skeletal muscle.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Mus musculus  

TISSUE(S): Liver

DISEASE(S): Not Available

SUBMITTER: Hendrik Nolte  

LAB HEAD: Marcus Krüger

PROVIDER: PXD006573 | Pride | 2017-11-14

REPOSITORIES: Pride

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Publications

A microRNA screen reveals that elevated hepatic ectodysplasin A expression contributes to obesity-induced insulin resistance in skeletal muscle.

Awazawa Motoharu M   Gabel Paula P   Tsaousidou Eva E   Nolte Hendrik H   Krüger Marcus M   Schmitz Joel J   Ackermann P Justus PJ   Brandt Claus C   Altmüller Janine J   Motameny Susanne S   Wunderlich F Thomas FT   Kornfeld Jan-Wilhelm JW   Blüher Matthias M   Brüning Jens C JC  

Nature medicine 20171106 12


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. In such cases of co-regulation, the products of host genes and their intronic miRNAs can cooperate to coordinately regulate biologically important pathways. 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 patho  ...[more]

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