The melanocortin 4 receptor (MC4R) is essential for the central regulation of energy homeostasis. We have previously shown that the third intracellular loop of MC4R (MC4Ri3) is important in regulation of MC4R signaling. We identified that MC4Ri3 interacts with glucose-regulated protein 78 (GRP78), an ER stress-inducible molecular chaperone. We observed that GRP78 is expressed in paraventricular nucleus of hypothalamus, where MC4R is expressed also. Under ER stress condition, down-regulation of GRP78 by using siGRP78, significantly inhibited the internalization of MC4R and in brain, the MC4R-GRP78 interaction in hypothalamus was reduced. Pretreatment of the chemical chaperone 4-phenyl butyric acid (PBA) in mice blunted the food intake increase induced by intracerebroventricular injection of the MC4R antagonist, AgRP (agouti-related protein). These data suggest that GRP78 may play an important role in control of hypothalamic MC4R signaling in control of energy homeostasis. [supported by the NRF Korea (Grant No. 2009-0083608)]