The diabetes gene Zfp69 modulates hepatic insulin sensitivity in mice

AIMS/HYPOTHESIS: Zfp69 was previously identified by positional cloning as a candidate gene for obesity-associated diabetes. C57BL/6J and New Zealand obese (NZO) mice carry a loss-of-function mutation due to the integration of a retrotransposon. On the NZO background, the Zfp69 locus caused severe hyperglycaemia and loss of beta cells. To provide direct evidence for a causal role of Zfp69, we investigated the effects of its overexpression on both a lean [B6-Tg(Zfp69)] and an obese [NZO/B6-Tg(Zfp69)] background. METHODS: Zfp69 transgenic mice were generated by integrating the cDNA into the ROSA locus of the C57BL/6 genome and characterised. RESULTS: B6-Tg(Zfp69) mice were normoglycaemic, developed hyperinsulinaemia, and exhibited increased expression of G6pc and Pck1 and slightly reduced phospho-Akt levels in the liver. During OGTTs, glucose clearance was normal but insulin levels were significantly higher in the B6-Tg(Zfp69) than in control mice. The liver fat content and plasma triacylglycerol levels were significantly increased in B6-Tg(Zfp69) and NZO/B6-Tg(Zfp69) mice on a high-fat diet compared with controls. Liver transcriptome analysis of B6-Tg(Zfp69) mice revealed a downregulation of genes involved in glucose and lipid metabolism. Specifically, expression of Nampt, Lpin2, Map2k6, Gys2, Bnip3, Fitm2, Slc2a2, Ppargc1α and Insr was significantly decreased in the liver of B6-Tg(Zfp69) mice compared with wild-type animals. However, overexpression of Zfp69 did not induce overt diabetes with hyperglycaemia and beta cell loss. CONCLUSIONS/INTERPRETATION: Zfp69 mediates hyperlipidaemia, liver fat accumulation and mild insulin resistance. However, it does not induce type 2 diabetes, suggesting that the diabetogenic effect of the Zfp69 locus requires synergy with other as yet unidentified genes. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00125-015-3703-8) contains peer-reviewed but unedited supplementary material, which is available to authorised users.