Research paperUnfolded protein response in hypothalamic cultures of wild-type and ATF6α-knockout mice

•Thapsigargin (TG) activated all the UPR arms similarly in mouse hypothalamic cultures.•TG-induced upregulation of BiP and CHOP was attenuated in ATF6α−/− mouse hypothalamus.•TG-induced upregulation of ERAD components was also attenuated in ATF6α−/− mouse hypothalamus.

Recent studies suggest that endoplasmic reticulum (ER) stress in the hypothalamus could affect systemic homeostatic regulation in areas such as energy and water balance. Activating transcription factor 6α (ATF6α) is an ER stress transducer which increases the expression of ER chaperones and ER-associated degradation (ERAD) components under ER stress. In the present study, we examined the regulation of the unfolding protein response (UPR) in mouse hypothalamic cultures of wild-type (WT) and ATF6α−/− mice. Thapsigargin (TG), an ER stressor, significantly increased the mRNA expression of immunoglobulin heavy chain binding protein (BiP), spliced X-box binding protein 1 (XBP1), activating transcription factor 4 (ATF4), C/EBP homologous protein (CHOP), and ERAD components, in hypothalamic cultures of WT mice with the same threshold (0.1 μM) and similar time courses. On the other hand, TG-induced upregulation of BiP and CHOP as well as most ERAD-related genes, but not spliced XBP1 or ATF4, was attenuated in ATF6α−/− mice compared with WT mice. Our data suggest that all the UPR arms are activated similarly in the mouse hypothalamus under ER stress conditions, where ATF6α regulates the expression of ER chaperones, CHOP, and ERAD components.