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.

A New Insight into the Roles of MiRNAs in Metabolic Syndrome

“…Furthermore, hepatic ectodysplasin A (EDA), together with its intronic miRNA, miR-676, was upregulated and released from hepatocytes under conditions of obesity and could act on SM as its main target tissue; its increased expression in liver occurs due to a systemic IR. The probable mechanism was that EDA-A2 could enhance c-Jun N-terminal kinase (JNK) phosphorylation and inhibit phosphorylation of Ser307 of IRS-1 in vivo to cause obesity-induced IR [32]. Overexpression of miR-16 has been reported to inhibit the synthesis of insulin-stimulated SM protein, while several other miRNAs involved in muscle metabolism may be responsive to IR, including miR-149, -182, and -696, deserving further investigation [33].…”

The Proposal of Molecular Mechanisms of Weak Organic Acids Intake-Induced Improvement of Insulin Resistance in Diabetes Mellitus via Elevation of Interstitial Fluid pH

“…At the present stage the purpose of drug developments is only or mainly to decrease the level of blood glucose or prevent elevation of blood glucose level. An increase in the blood glucose level is not the essential pathogenesis of type 2 diabetes mellitus, but only a result from occurrence of insulin resistance in type 2 diabetes mellitus [ 69 , 70 ]. For example, sulfonylurea stimulates insulin release from pancreatic β cells; biguanide blocks production of glucose from lactate mainly in the liver; glucosidase inhibitors diminish production of glucose by inhibiting glucosidases involved in breaking down of carbohydrates mainly in the intestine; thiazolidine stimulates glucose uptake via stimulation of adiponectin release from adipocytes by acting peroxisome proliferator-activated receptor (PPAR); dipeptidyl-peptidase IV (DPP-4) inhibitors maintain a high level of insulin by blocking brake-down of incretin in the intestine stimulating insulin release from pancreatic β cells; sodium-glucose cotransporter 2 (SGLT2) inhibitors diminish reuptake of glucose in the renal epithelia.…”

Neuronal activity regulates DROSHA via autophagy in spinal muscular atrophy

“…1 ug of total RNA per sample was used for library construction, and sequencing was performed in the Cologne Center for Genomics. Detailed methods were described previously 74 .…”