Abstract 243: Decreased Adiponectin Levels in Obese Mice with Polygenetic Susceptibility to Type 2 Diabetes Is Linked to Altered miRNA Levels of the ATF3 Gene In Visceral Adipose Tissue

Abstract

INTRODUCTION: Adiponectin encoded by the APMI gene is an adipocyte-expressed protein with insulin sensitizing, antiatherogenic and antiinflammatory properties. Activating transcription factor 3 (ATF3) is a member of the ATF/cAMP responsive element binding family that acts as a stress-inducible transcriptional repressor. ATF3 was recently shown to repress adiponectin gene expression. HYPOTHESIS: High fat diet with genetic susceptibility for T2D alters the miRNA profile for the adiponectin gene in visceral adipose (VA). METHODS: NONcNZO10 (NZ10) mice with polygenic susceptibility to T2D or NONLt controls (60 per group) were subjected to normal chow (NC; 6% fat), Western diet (WD; high fat/carb) or Mediterranean diet (MD; high protein/unsaturated fat) for 25 weeks. After a 16h fast, VA was isolated from all groups (5 mice per group) and subjected to gene-microarray, micro-RNA and protein analyses. RESULTS: NONLt (control) mice retained normal glycemic control and blood chemistry over 25 weeks with all diets. WD-fed NZ10 mice had increased plasma triglycerides (3-fold, p<0.001), insulin (1.8-fold. P<0.01) and severely impaired glucose tolerance relative to the MD or control groups (p<0.01). NZ10 mice on all diets accumulated 2.5-fold more VA than NONLt controls. Body weights of WD-fed NZ10 mice were 18% greater and fat depots were 22±3.1% larger than SB mice at 25 weeks (p<0.01). Serum adiponectin levels decreased >50% at 25–30 weeks in NZ10 mice fed WD compared with NONLt (p<0.01). The ATF3 gene was upregulated (5-fold, p<0.0001) in the NZ10 mice fed WD compared with MD and 2-fold (p<0.001) compared with NC. NONLt mice did not show any diet-related difference of ATF3 expression. Expression of ATF3 was increased 20-fold in NZ10 mice relative to NONLt mice independently of diet (p<0.001). MiR profiling of the ATF3 gene in VA revealed that miR-203, 685, 191 and 29a were markedly downregulated in NZ10-WD mice (all 2.5-fold, p<0.001). MiR expression in NONLt controls was unchanged and similar to that of NZ10 mice fed MD. CONCLUSIONS: Combined T2D susceptibility and a permissive diet cause selective repression of miR-203, 685, 191 and 29a and up-regulation of ATF3 gene expression. The consequences include defective adiponectin production and predisposition to T2D.