Inhibition of TAK1 (MAP3K7) upregulates unfolded protein response and prevents high‐fat diet‐induced obesity (765.4)

Abstract

High‐fat diet (HFD) ingestion induces endoplasmic reticulum (ER) stress in hypothalamic neurons leading to dysregulation of food intake and eventually obesity. Therefore, alleviating ER stress in the hypothalamus would be beneficial for treating obesity. Unfolded protein response (UPR) signaling pathways are activated to protect cells from ER stress. Several different pathways initiate induction of chaperones, attenuation of translation and protein degradation in UPR. However, it’s still elusive how each UPR pathway is regulated upon ER stress. TGF‐β‐activated kinase 1 (TAK1) is a member of MAP3K and known to be involved in various stress response signaling. In the present study, we investigated the role of TAK1 in ER stress response. We found that deletion of Tak1 protected cells from ER stress‐induced cell death. Intriguingly, induction of a molecular chaperon, BiP/GRP78, which is one of the major targets of UPR, was highly upregulated in Tak1‐deficient cells. These data suggest that TAK1 negatively regulates UPR and deletion of Tak1 alleviates ER stress and cell damage by upregulating BiP/GRP78. To examine the physiological relevance for the TAK1 regulation of ER stress, we generated mice harboring neuron‐specific deletion of Tak1 and tested the effect of Tak1 deletion in HFD‐induced obesity. We found that neuron‐specific deletion of Tak1 significantly reduced food intake and weight gain upon HFD feeding compared to wild type mice, suggesting that TAK1 may promote hypothalamic neuronal damage through ER stress. Our results revealed a new regulatory mechanism of ER stress which is involved in neuronal homeostasis.