Human variants in the membrane adaptor ankyrin-B (AnkB) present at frequencies from 0.05 to 7% across different ethnicities have been linked to obesity and type 2 diabetes (T2D). We reported that knock-in mice bearing T2D-linked human AnkB variants develop age- or diet-dependent obesity and insulin resistance (IR). We also found that conditional loss of AnkB in both white (WAT) and brown (BAT) adipose tissue (AT) in mice (AT-AnkB KO) results in age-dependent obesity with WAT hypertrophy, lipotoxicity, systemic inflammation, and IR. We delineated that defects in the internalization of the glucose transporter GLUT4 in WAT, which resulted from deficits in AnkB, caused cell-autonomous WAT hyperplasia and ectopic lipid deposition in peripheral tissues. AT-AnkB KO mice also exhibit lower energy expenditure (EE) before the onset of obesity, which is concomitant with reduced BAT mitochondrial content and brown adipocyte whitening. However, whether primary BAT dysfunction caused by AnkB deficits contribute to metabolic syndrome in these mice and the roles of AnkB in BAT is unknown. Here, we present evidence of a cell-autonomous role of AnkB in lipid metabolism in brown adipocytes. Histological and electron microscopy analyses suggest that conditional AnkB loss in BAT of non-obese mice (BAT-AnkB KO) causes lipid accumulation in BAT characterized by an increase in surface area covered by lipid droplets, a shift towards larger lipid droplets, and a corresponding decrease in mitochondrial content. Differentiated brown adipocytes from mice with total AnkB deficiency (AnkB KO) or from BAT-AnkB KO mice phenocopy the in vivo changes in lipid and mitochondria content, which corresponds with changes in associated gene expression. We will discuss our latest results combining physiology, transcriptomic, proteomic, and cellular analysis that shed light into the pathways modulated by AnkB in BAT and their contribution to systemic metabolic regulation.
A. Aguillard: None. J. Tzeng: None. D. Lorenzo: None.
National Institutes of Health (3P30DK072476-13S1)