1272-P: Genomic Rearrangement in Noncoding Region of Chromosome 1 Leads to Spontaneous Obesity and Type 2 Diabetes

Abstract

Obesity is a major health risk for type 2 diabetes, along with many other disease conditions. We discovered spontaneous obese mice among a conditional transgenic mouse line (Floxed-stop Overexpression of IF1, or FEI) , which was originally generated and maintained for Cre-mediated conditional transgenic IF1 expression. Severe obesity became a fixed phenotype in FEI mice after inbreeding for 5-6 generations. Targeted-Locus-Amplification (TLA) analyses revealed that a rearrangement occurred in upstream sequences (48,224,9 to 48,248,586) of the transgenic integrated site, and are duplicated downstream at a non-coding region of chromosome 1. Early-onset obesity was consistent in both male and female FEI mice with progressive weight gain from 2 months and reached 50-60 grams at 6-8 months. Body composition analyses revealed that FEI mice have markedly increased fat mass and modestly increased lean mass compared to wild-type (WT) mice. Consistently, the FEI mice exhibited increased peripheral fat pads and dyslipidemia. The FEI mice exhibited increased food intake but reduced systemic metabolic rates. Moreover, we detected increased fed and fasting blood glucose, insulin, and leptin with impaired glucose and insulin tolerance in FEI mice as early as 6 weeks of age. Histology analyses with H&E staining revealed markedly enlarged adipocytes with crown-like structures on visceral white adipose tissue sections and increased fat deposition in liver sections from FEI mice. RNAseq analyses on RNA samples from subcutaneous white adipose tissues demonstrate the upregulation of adipogenesis and inflammation genes. These results indicate that the FEI mouse line is a novel obese mouse model with genomic rearrangement in a non-coding region, which may serve as cis-regulatory elements for obese genes. Further studies on these mice should yield novel and translational insight into the molecular and metabolic mechanisms underlying obesity development with complex genetic traits. Disclosure D.White: None. J.Wu: None. L.Lauterboeck: None. S.Kang: None. M.Elgazzaz: None. S.Alahari: None. E.D.Lazartigues: None. Q.Yang: None.