title: The diabetes gene Zfp69 modulates hepatic insulin sensitivity in mice.
abstract: OBJECTIVE
  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
  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.
authors.affiliation: Department of Experimental Diabetology, German Institute of Human Nutrition Potsdam-Rebruecke, Arthur-Scheunert-Allee 114-116, D-14558, Nuthetal, Germany.|German Center for Diabetes Research (DZD), Neuherberg, Germany.
authors.forename: Bomee
authors.initials: B
authors.lastname: Chung
authors.affiliation: Department of Experimental Diabetology, German Institute of Human Nutrition Potsdam-Rebruecke, Arthur-Scheunert-Allee 114-116, D-14558, Nuthetal, Germany.|German Center for Diabetes Research (DZD), Neuherberg, Germany.
authors.forename: Mandy
authors.initials: M
authors.lastname: Stadion
authors.affiliation: Department of Experimental Diabetology, German Institute of Human Nutrition Potsdam-Rebruecke, Arthur-Scheunert-Allee 114-116, D-14558, Nuthetal, Germany.|German Center for Diabetes Research (DZD), Neuherberg, Germany.
authors.forename: Nadja
authors.initials: N
authors.lastname: Schulz
authors.affiliation: German Center for Diabetes Research (DZD), Neuherberg, Germany.|Institute of Metabolic Physiology, Heinrich Heine University of Düsseldorf, Universitätsstrasse, 1, D-40225, Duesseldorf, Germany.
authors.forename: Deepak
authors.initials: D
authors.lastname: Jain
authors.affiliation: Department of Experimental Diabetology, German Institute of Human Nutrition Potsdam-Rebruecke, Arthur-Scheunert-Allee 114-116, D-14558, Nuthetal, Germany.|German Center for Diabetes Research (DZD), Neuherberg, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Scherneck
authors.affiliation: Department of Experimental Diabetology, German Institute of Human Nutrition Potsdam-Rebruecke, Arthur-Scheunert-Allee 114-116, D-14558, Nuthetal, Germany.|German Center for Diabetes Research (DZD), Neuherberg, Germany.
authors.forename: Hans-Georg
authors.initials: HG
authors.lastname: Joost
authors.affiliation: Department of Experimental Diabetology, German Institute of Human Nutrition Potsdam-Rebruecke, Arthur-Scheunert-Allee 114-116, D-14558, Nuthetal, Germany. schuermann@dife.de.|German Center for Diabetes Research (DZD), Neuherberg, Germany. schuermann@dife.de.
authors.forename: Annette
authors.initials: A
authors.lastname: Schürmann
mesh_terms: D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000378:metabolism; D059305:Diet, High-Fat; D005234:Fatty Liver / Q000235:genetics* / Q000378:metabolism; D006949:Hyperlipidemias / Q000235:genetics* / Q000378:metabolism; D007333:Insulin Resistance / Q000235:genetics*; D050417:Insulin-Secreting Cells / Q000378:metabolism; D008099:Liver / Q000378:metabolism*; D051379:Mice; D008820:Mice, Obese; D008822:Mice, Transgenic; D009765:Obesity / Q000235:genetics* / Q000378:metabolism; D040641:Quantitative Trait Loci; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism
chemical_list: D014157:Transcription Factors; C544163:Zfp69 protein, mouse
keywords: Diabetes; Hepatosteatosis; Insulin resistance; Lipid metabolism; Zfp69