Expression of neuropeptide Y and agouti-related protein mRNA stimulated by glucocorticoids is attenuated via NF-κB p65 under ER stress in mouse hypothalamic cultures

There are several lines of evidence suggesting that glucocorticoid signaling in the hypothalamus plays an important role in energy balance, and recent studies suggest that endoplasmic reticulum (ER) stress in the hypothalamus could affect signaling related to energy balance. In the present study, we examined the regulation of glucocorticoid signaling under ER stress in mouse hypothalamic organotypic cultures. Incubation of the hypothalamic explants with dexamethasone (DEX) significantly increased expression levels of neuropeptide Y (NPY) and agouti-related protein (AgRP) mRNA, and treatment with thapsigargin (TG), an ER stressor, significantly attenuated DEX-induced NPY and AgRP mRNA expression. TG treatment increased the levels of phospho-NF-κB p65 in hypothalamic cultures, and inhibitors of NF-κB p65 reversed the inhibitory effects of TG on NPY and AgRP expression. Our data thus demonstrated that glucocorticoid-stimulated NPY and AgRP expression was attenuated via NF-κB p65 pathways under ER stress, and suggest crosstalk between ER stress and inflammation in the hypothalamus.