Brown adipose tissue ankyrin-B cell-autonomously modulates lipid content and its deletion protects male mice against diet-induced obesity

Fatty acid (FA) availability for brown adipose tissue (BAT) thermogenesis depends in part on lipolysis of lipid droplet (LD) triglycerides. Here, we identify the membrane adaptor ankyrin-B (AnkB), encoded by the cardiometabolic disease-associated ANK2 gene, as a regulator of brown adipocyte lipid homeostasis and metabolic adaptation. BAT-specific AnkB deficiency caused excess lipid accumulation, enlarged LDs, and BAT whitening without altering mitochondrial oxidative capacity or thermogenesis in the fed state in male mice. Mechanistically, AnkB promoted basal lipolysis by recruiting hormone-sensitive lipase to LDs. However, AnkB loss compromised thermoregulation during cold exposure with fasting, linking AnkB-dependent FA release to thermogenesis under energetic stress. Unexpectedly, BAT AnkB deficiency protected male mice from high-fat diet-induced obesity (DIO), hepatic steatosis, glucose intolerance, and insulin resistance. This protection was associated with enhanced BAT mitochondrial oxidative capacity, oxidative remodeling of white adipose tissue, and increased circulating FGF21. Together, these findings establish AnkB as a previously unrecognized regulator of BAT lipid mobilization that coordinates thermogenic fuel availability with mitochondrial oxidative adaptation during metabolic stress. Ankyrin-B couples BAT lipid droplet lipolysis to thermogenic fuel availability. Its loss impairs thermoregulation during fasting but preserves fed-state thermogenesis and protects against diet-induced metabolic dysfunction.