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

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. 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 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), 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 PPARγ and RXR-α, 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.

• Authors: Motoharu Awazawa, Paula Gabel, Eva Tsaousidou, Hendrik Nolte, Marcus Krüger, Joel Schmitz, P Justus Ackermann, Claus Brandt, Janine Altmüller, Susanne Motameny, F Thomas Wunderlich, Jan-Wilhelm Kornfeld, Matthias Blüher, Jens C Brüning
• Journal: Nature medicine (Nat Med) Vol. 23 Issue 12 Pg. 1466-1473 (Dec 2017) ISSN: 1546-170X [Electronic] United States
• PMID: 29106399 (Publication Type: Journal Article)

Chemical References

• Ectodysplasins
• Eda protein, mouse
• MicroRNAs

Topics

• Animals
• Cells, Cultured
• Ectodermal Dysplasia 1, Anhidrotic (genetics)
• Ectodysplasins (genetics, metabolism)
• Gene Expression Profiling
• Insulin Resistance (genetics)
• Liver (metabolism)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Inbred CBA
• Mice, Obese
• Mice, Transgenic
• MicroRNAs (genetics)
• Muscle, Skeletal (metabolism)
• Obesity (genetics, metabolism)