Layne, Matthew D.McClendon, Phillip Seth2024-03-052023https://hdl.handle.net/2144/48313Adipose tissue serves as a caloric storage reservoir and a central regulator of whole-body energy homeostasis. Adipose tissue dysfunction can occur in type II diabetes resulting in cardiovascular disease. Hypertrophic adipocytes also secrete profibrotic factors including transforming growth factor β which represses adipogenesis and further contributes to metabolic dysfunction. In fibrosis, the capacity of the adipose tissue to store excess nutrients is impaired leading to consequences such as ectopic lipid deposition and hyperglycemia. These factors increase the risk of atherogenesis and other vascular diseases. Aortic carboxypeptidase-like protein (ACLP) is a secreted extracellular matrix protein that is essential for proper collagen formation and is upregulated in vascular smooth muscle cells in response to vascular injury. ACLP participates in liver and lung fibrotic remodeling however its role in adipose tissue is unknown. The central goal of this research was to develop an ACLP loss of function mouse model and test the hypothesis that eliminating ACLP would blunt adipose tissue fibrosis leading to improved metabolic function. In optimization experiments with an in vitro ACLP loss of function model we observed that tamoxifen-mediated Cre recombination was not successful. We also developed an in vitro tamoxifen controlled loss of function model in mice who were fed either a high fat or low-fat diet to study the role ACLP serves in the setting of diet-induced obesity. Though genotyping showed successful recombination in these mice, current studies are still determining the efficacy of Cre-mediated recombination in these mice. Currently, we believe that Cre-mediated recombination may not have been successful, and these mice do not serve as a complete ACLP loss of function model. In o other studies examining ACLP-dependent signaling in vascular cells, angiotensin II activated the MAP/Erk pathway in mouse aortic smooth muscle cells and this pathway has been implicated in vascular disease. Future work will study whether ACLP can potentiate Erk signaling in these cells. These studies have established the groundwork to examine ACLP function in adipose tissue fibrosis and current studies are testing the hypothesis that an ACLP loss of function will improve metabolic function by blunting adipose tissue fibrosis.en-USMedicineThesis/Dissertation2024-03-01