Transforming growth factor β-activated kinase 1 (TAK1) is a member of the mitogen-activated kinase kinase kinase (MAPKKK) family and is a key signalling intermediate of proinflammatory signalling pathways. Here (p. ), Jun Ninomiya-Tsuji and colleagues investigate the previously unrecognised role of TAK1 in ER stress tolerance. The authors find that Tak1-deficient cells are resistant to endoplasmic reticulum (ER) stress in vitro. They show that this resistance is due to increased activity of the lipogenic transcription factor sterol-regulator-element-binding protein (SREBP), a previously identified target of TAK1. Upregulated SREBP increases ER volume and functional capacity, resulting in the amelioration of ER stress tolerance. The authors next ask whether targeting TAK1 could be applicable to the treatment of ER stress-associated disorders such as obesity. They find that CNS-specific deletion of Tak1 increases ER volume in the hypothalamus and protects mice against high-fat-diet-induced leptin resistance and hyperphagic obesity. These findings demonstrate a new connection between TAK1 and the regulation of ER stress, suggesting that TAK1 could be a therapeutic target in obesity and other ER-stress-associated disorders.
