title: Ink4/Arf locus restores glucose tolerance and insulin sensitivity by reducing hepatic steatosis and inflammation in mice with impaired IRS2-dependent signalling.
abstract: Single nucleotide polymorphisms near the Ink4/Arf locus have been associated with type-2 diabetes mellitus. Previous studies indicate a protective role of the locus in the carbohydrate metabolism derangement associated with ageing in wild-type mice. The present study demonstrates that the increased Ink4/Arf locus expression in 1-year-old mice, partially-deficient for the insulin receptor substrate (IRS)2 (Irs2+/-SuperInk4/Arf mice) ameliorates hepatic steatosis, inflammation and insulin resistance. Irs2+/-SuperInk4/Arf mice displayed improved glucose tolerance and insulin sensitivity compared with Irs2+/- mice which were glucose intolerant and insulin resistant compared with age-matched wild-type mice. These changes in Irs2+/- mice were accompanied by enhanced hepatic steatosis, proinflammatory macrophage phenotype, increased Ly6C(hi)-monocyte percentage, T-lymphocyte activation and MCP1 and TNF-α cytokine levels. In Irs2+/-SuperInk4/Arf mice, steatosis and inflammatory parameters were markedly reduced and similar to those of wild-type counterparts. In vivo insulin signalling also revealed reduced activation of the IRS/AKT-dependent signalling in Irs2+/- mice. This was restored upon increased locus expression in Irs2+/-SuperInk4/Arf mice which display similar activation levels as those for wild-type mice. In vivo treatment of Irs2+/-SuperInk4/Arf mice with TNF-α diminished insulin canonical IRS/AKT-signalling and enhanced the stress SAPK/JNK-phosphoSer307IRS1-pathway suggesting that cytokine levels might potentially affect glucose homeostasis through changes in these insulin-signalling pathways. Altogether, these results indicate that enhanced Ink4/Arf locus expression restores glucose homeostasis and that this is associated with diminished hepatic steatosis and inflammation in mice with insulin resistance. Therefore, pharmacological interventions targeted to modulate the Ink4/Arf locus expression could be a tentative therapeutic approach to alleviate the inflammation associated with insulin resistance.
authors.affiliation: Institute of Health Research-INCLIVA, 46010 Valencia, Spain.
authors.forename: Ángela
authors.initials: Á
authors.lastname: Vinué
authors.affiliation: Institute of Health Research-INCLIVA, 46010 Valencia, Spain.
authors.forename: Irene
authors.initials: I
authors.lastname: Andrés-Blasco
authors.affiliation: Institute of Health Research-INCLIVA, 46010 Valencia, Spain.
authors.forename: Andrea
authors.initials: A
authors.lastname: Herrero-Cervera
authors.affiliation: Institute of Health Research-INCLIVA, 46010 Valencia, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: Piqueras
authors.affiliation: Department of Atherothrombosis, Imaging and Epidemiology, Centro Nacional de Investigaciones Cardiovasculares (CNIC), 28029 Madrid, Spain.
authors.forename: Vicente
authors.initials: V
authors.lastname: Andrés
authors.affiliation: Centro de Investigación Príncipe Felipe (CIPF), 46012 Valencia, Spain; CIBER de Diabetes y Enfermedades Metabólicas (CIBERDEM), Spain.
authors.forename: Deborah J
authors.initials: DJ
authors.lastname: Burks
authors.affiliation: Institute of Health Research-INCLIVA, 46010 Valencia, Spain; Departamento de Farmacología, Universidad de Valencia, 46010 Valencia, Spain.
authors.forename: María Jesús
authors.initials: MJ
authors.lastname: Sanz
authors.affiliation: Institute of Health Research-INCLIVA, 46010 Valencia, Spain; CIBER de Diabetes y Enfermedades Metabólicas (CIBERDEM), Spain. Electronic address: gonzaleh@uv.es.
authors.forename: Herminia
authors.initials: H
authors.lastname: González-Navarro
keywords: CDKN2A/2B; Diabetes; Inflammation; Insulin resistance; Macrophage; Steatosis