The diabetes gene Zfp69 modulates hepatic insulin sensitivity in mice

• Published in: Diabetologia Vol. 58; no. 10; pp. 2403 - 2413
• Main Authors: Chung, Bomee, Stadion, Mandy, Schulz, Nadja, Jain, Deepak, Scherneck, Stephan, Joost, Hans-Georg, Schürmann, Annette
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.10.2015; Springer Nature B.V
• Subjects: Animals; Diabetes; Diabetes Mellitus, Type 2 - genetics; Diabetes Mellitus, Type 2 - metabolism; Diet; Diet, High-Fat; Fatty Liver - genetics; Fatty Liver - metabolism; Genes; Genomes; Glucose; Human Physiology; Hyperglycemia; Hyperlipidemias - genetics; Hyperlipidemias - metabolism; Insulin resistance; Insulin Resistance - genetics; Insulin-Secreting Cells - metabolism; Internal Medicine; Kinases; Liver; Liver - metabolism; Medicine; Medicine & Public Health; Metabolic Diseases; Metabolism; Mice; Mice, Obese; Mice, Transgenic; Nutrition research; Obesity; Obesity - genetics; Obesity - metabolism; Quantitative Trait Loci; Transcription Factors - genetics; Transcription Factors - metabolism; New Zealand; Germany; Insulin resistance; Diabetes; Lipid metabolism; Hepatosteatosis; Zfp69
• ISSN: 0012-186X; 1432-0428
• DOI: 10.1007/s00125-015-3703-8

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.