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RESEARCH PRODUCT

Ink4/Arf locus restores glucose tolerance and insulin sensitivity by reducing hepatic steatosis and inflammation in mice with impaired IRS2-dependent signalling

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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-alpha 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/ART-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-alpha diminished insulin canonical IRS/AKT-signalling and enhanced the stress SAPMNK-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. Published by Elsevier B.V.