Browsing by Subject "Abi3"

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    Deletion of the Alzheimer's disease risk gene Abi3 locus results in obesity and systemic metabolic disruption in mice
    (Frontiers Media, 2022-12-22) Smith, Daniel C.; Karahan, Hande; Sagara Wijeratne, H. R.; Al-Amin, Mamun; McCord, Brianne; Moon, Younghye; Kim, Jungsu; Medical and Molecular Genetics, School of Medicine
    Alzheimer’s disease (AD) genetics studies have identified a coding variant within ABI3 gene that increases the risk of developing AD. Recently, we demonstrated that deletion of the Abi3 gene locus dramatically exacerbates AD neuropathology in a transgenic mouse model of amyloidosis. In the course of this AD project, we unexpectedly found that deletion of the Abi3 gene locus resulted in a dramatic obese phenotype in non-transgenic mice. Here, we report our investigation into this serendipitous metabolic finding. Specifically, we demonstrate that mice with deletion of the Abi3 gene locus (Abi3–/–) have dramatically increased body weight and body fat. Further, we determined that Abi3–/– mice have impaired energy expenditure. Additionally, we found that deletion of the Abi3 gene locus altered gene expression within the hypothalamus, particularly within immune-related pathways. Subsequent immunohistological analysis of the central nervous system (CNS) revealed that microglia number and area were decreased specifically within the mediobasal hypothalamus of Abi3–/– mice. Altogether, this investigation establishes the functional importance of the Abi3 gene locus in the regulation of systemic metabolism and maintenance of healthy body weight. While our previous findings indicated the importance of Abi3 in neurodegeneration, this study indicates that Abi3 related functions are also essential for metabolic regulation.
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    The Role of ABI3 in Obesity and Metabolic Regulation
    (2024-04) Smith, Daniel Curtis; Oblak, Adrian; Kim, Jungsu; Flak, Jonathan; Lasagna-Reeves, Cristian; Evans-Molina, Carmella
    Abelson Interactor Protein 3 is an adaptor protein involved in cytoskeletal remodeling. ABI3 is predominantly expressed within mononuclear phagocytotic immune cells within the brain, such as macrophages, peripherally, and microglia. Until recently, little was known about the function of the ABI3 protein, and even less was known regarding its role in disease. Following the identification of a rare mutation within ABI3 that increases the risk of developing Alzheimer’s disease, our laboratory began to investigate the impact of deleting Abi3 in mouse models. While we initially set out to investigate ABI3 in the context of neurodegeneration, we unexpectedly discovered that loss of Abi3 led to obesity in mice. This discovery and the subsequent efforts to uncover the mechanisms by which loss of Abi3 induces obesity are the subject of this dissertation. First, we demonstrate that deletion of Abi3 leads to severe obesity in aged mice. We identified significant Abi3-dependent transcriptomic changes within the hypothalamus, but not adipose tissue, of these mice. These changes occurred within pathways related to immune function, and subsequent immunostaining revealed decreased microglia number and area within the mediobasal hypothalamus of Abi3-/- mice. Next, we performed a longitudinal high-fat diet study to explore the impact of loss of Abi3 on mouse body weight and metabolic regulation during chronic nutrient excess and control conditions. Intriguingly, we found that only female Abi3-/- mice exhibited increased body weight during high-fat diet feeding. Subsequent transcriptomics from the hypothalamus of female Abi3+/+ and Abi3-/- mice from both high-fat and control diet groups revealed cytoskeletal-related changes only in the obese, high-fat diet-fed female Abi3-/- mice. Follow-up immunostaining revealed decreased microglia coverage within the mediobasal hypothalamus of the obese, high-fat diet-fed female Abi3-/- mice. While much remains to be explored regarding the precise role of ABI3 in the setting of energy balance regulation and obesity, our investigations revealed that loss of ABI3 is sufficient to induce obesity and appears to occur through altered microglia function within the hypothalamus. This dissertation represents a critical first step in the investigation of a novel regulator of obesity pathology.