313-OR: A Cytoskeleton-Based Mechanism Regulates Lipid Metabolism and Energy Homeostasis in Brown Adipose Tissue

Abstract

Genetic variants in ANK2, encoding ankyrin-B (AnkB) , increase risk of obesity and type 2 diabetes in humans. We previously concluded that AnkB deficiency in white (WAT) and brown (BAT) adipose tissue (AT) of mice (AT-AnkB KO) led to lipotoxicity, WAT hypertrophy, and insulin resistance associated with age and consumption of a high-fat diet. These metabolic deficits were caused by impairments in glucose transporter GLUT4 endocytosis in WAT due to AnkB deficiency. Additionally, we found that AT-AnkB KO mice had decreased energy expenditure and lipid accumulation in BAT prior to the onset of obesity suggesting a potential role of AnkB in BAT. However, the role of AnkB in BAT and its contribution to metabolic homeostasis through BAT has not been elucidated. We investigated the role of AnkB in mice conditionally lacking AnkB in BAT (BAT-AnkB KO) . Based on histological and transmission electron microscopy analysis, we found that young (4-month-old) BAT-AnkB KO mice have enlarged lipid droplets, lipid accumulation, and decreased mitochondrial content in BAT with no changes in BAT size, body weight, or body composition. Consistent with these findings, primary brown adipocytes from BAT-AnkB KO mice exhibited lipid accumulation suggesting that AnkB may regulate lipid homeostasis in BAT in a cell-autonomous manner. Similar to our previous findings, young BAT-AnkB KO mice also had decreases in oxygen consumption and energy expenditure. These mice also exhibit minimal changes in glucose handling and insulin tolerance at 4-months of age. Proteomic-MS analysis was performed on AnkB associated proteins from BAT which revealed that GLUT4 as well as a number of critical regulators of lipid metabolism form complexes with AnkB in BAT. In combination with this data, we will present our latest findings in gene expression of genes regulating lipid metabolism and mitochondrial function as well as cellular assays in brown adipocytes that may highlight metabolic pathways regulated by AnkB in BAT. Disclosure A.Aguillard: None. J.Arricastres: None. J.Tzeng: None. D.Lorenzo: None. Funding American Diabetes Association (1-19-JDF-081)