Genetic variants of the scaffolding protein ankyrin-B (AnkB), encoded by ANK2, have been implicated in obesity and type 2 diabetes. Previous research has shown that AnkB plays a crucial role in facilitating GLUT4 endocytosis in white adipocytes, and its combined deficiency in white (WAT) and brown adipose tissues (BAT) leads to insulin resistance and obesity. To investigate the BAT-specific role of AnkB, we established a mouse model lacking AnkB in (BAT-AnkB KO). In previous work, combined AnkB deficiency in both WAT and BAT was associated with susceptibility to diet-induced obesity. This prompted us to evaluate metabolic health in BAT-AnkB KO and littermate control mice subjected to high-fat diet (HFD) feeding for 18 weeks.

In this study, we explored the consequences of HFD feeding on BAT-AnkB KO mice. Surprisingly, BAT-AnkB KO mice on HFD gained less weight and had lower fat mass compared to control mice on the same diet. Histological analysis also revealed smaller lipid droplet in BAT and WAT of the BAT-AnkB KO mice after HFD. Additionally, BAT-AnkB KO mice maintained a higher percentage of lean mass while on the HFD compared to control mice. These findings suggest that losing AnkB in BAT may protect against diet-induced obesity. Western blot analysis revealed that BAT-AnkB KO mice under HFD conditions exhibited altered lipid metabolism, with decreases in key lipogenesis and lipolysis regulators. Additionally, there was a trending increase in markers of fatty acid oxidation and thermogenesis, including upregulation of Cpt1b and Ucp1, suggesting that loss of AnkB in BAT may cause enhanced fatty acid oxidation. Future studies will directly investigate fatty acid oxidation and other potential compensatory mechanisms causing protection from diet-induced obesity