In the current study, we aimed to establish the RGS expression profile of native human intestinal EECs, describe alterations to their transcriptional landscape in obesity, and further explore the physiological role of RGS in GPCR-mediated secretion of GLP-1 from EECs and the functional consequence of its dysregulation. Here, GPBAR1 is linked to obesity due to melanocortin 4 receptor deficiency.