GSE212299
Deletion of the Alzheimer's disease risk associated Abi3 gene locus in mice results in obesity and systemic metabolic disruption
A rare coding variant was identified within the human ABI3 gene that is associated with increased risk of Alzheimer's disease (AD). Following this discovery, we recently demonstrated that deletion of Abi3 gene locus notably   exacerbates AD neuropathology in the 5xFAD transgenic mouse model of amyloidosis. In the course of a related investigation into the functional impact of Abi3 deletion in mice, we made an unexpected discovery regarding the impact of Abi3 deletion on the non-transgenic littermates of those 5xFAD mice. In those mice, we found that deletion of Abi3 gene locus resulted in an obese phenotype. Therefore, we investigated this serendipitous discovery. In this report, we demonstrate that mice lacking Abi3   have dramatically increased body weight and body fat. Further, we determined that these mice without Abi3 have reduced energy expenditure. Additionally, we found that deletion of the Abi3 gene locus altered gene expression, particularly within immune pathways, within the hypothalamus. Subsequent immunohistological analysis of the central nervous system (CNS) revealed that microglia number and area were decreased specifically within the mediobasal hypothalamus of mice without Abi3. Altogether, this investigation establishes the functional importance of the Abi3 gene locus, particularly within the CNS, in the regulation of systemic metabolism and maintenance of healthy weight. Overall design: Quant-seq (3' mRNA-seq) analysis of hypothalami & brown adipose of male mice with Abi3 WT or Abi3 KO genotypes at 15 months of age