1684-P: Transgene Integration-Induced Genomic Rearrangement in a Noncoding Region of Chromosome 1 Leads to Spontaneous Obesity and Type 2 Diabetes in Mice

• Published in: Diabetes (New York, N.Y.) Vol. 72; no. Supplement_1; p. 1
• Main Authors: WHITE, DONNELL, WU, JIAN, KANG, SUNGWOOK, LAUTERBOECK, LOTHAR, MOBASHERAN, PARNIA, PALIARIN, FRANCIELY, NGUYEN, TINA, ELGAZZAZ, MONA, MAIYA, RAJANI, ALAHARI, SURESH, LAZARTIGUES, ERIC D., YANG, QINGLIN
• Format: Journal Article
• Language: English
• Published: New York American Diabetes Association 20.06.2023
• Subjects: Adipocytes; Adipose tissue; Body composition; Body fat; Body weight; Body weight gain; Chromosome 1; Diabetes; Diabetes mellitus (non-insulin dependent); Dyslipidemia; Glucose tolerance; Hyperglycemia; Inflammation; Obesity; Physical activity; Preadipocytes; Public health; Risk factors; Transgenes; Tumor necrosis factor-α
• ISSN: 0012-1797; 1939-327X
• DOI: 10.2337/db23-1684-P

Obesity is a critical risk factor for type 2 diabetes (T2D) and has become a global health issue. We found that a mouse line (C57/B6J) of Floxed-stop over expression of IF1 (ATPase Inhibitory Factor 1) (hereon called FEI) develops spontaneous obesity without induction of transgenic expression. Targeted-Locus-Amplification (TLA) analyses revealed a rearrangement in upstream sequences of the transgene integration site, and a duplication downstream in a non-coding region of chromosome 1. Male and female FEI mice show early dyslipidemia before weight gain at two months, reaching 50-60 grams at 6-8 months. Body composition revealed FEI mice have markedly increased fat mass and modestly increased lean mass, consistent with morphometric findings of substantially increased peripheral fat pads. FEI mice were hyperphagic. When subjected to pair-feeding, they reverted to comparable WT body weight levels, then gained weight again when fed ad libidum. Adult FEI mice maintain comparable physical activity levels to their WT counterparts, but indirect metabolic levels among FEI mice declined. These mice exhibited glucose and insulin tolerance at six weeks of age, as well as hyperglycemia, hyper-insulinemia, and hyper-leptinemia. Histology H&E staining revealed markedly enlarged adipocytes with crown-like structures on visceral white adipose tissue sections, and increased fat deposition in liver sections. RNAseq analyses from subcutaneous white adipose tissues of 5-month-old FEI mice demonstrate upregulation of adipogenic and inflammatory genes. Isolated FEI preadipocytes exhibited increased proliferation but impaired lipid deposition. RT-PCR revealed upregulation of inflammatory genes (IFI202b, TNF-α, and IL6). Together, we show FEI mice are a novel obese mouse model. Preclinical studies using this model may help yield insights into novel pathogenic mechanisms and effective treatments for obesity. Disclosure D.White: None. S.Alahari: None. E.D.Lazartigues: None. Q.Yang: None. J.Wu: None. S.Kang: None. L.Lauterboeck: None. P.Mobasheran: None. F.Paliarin: None. T.Nguyen: None. M.Elgazzaz: None. R.Maiya: None. Funding American Diabetes Association (1-17-IBS-184 to Q.Y.)