Targeting the GCC endocrine signaling axis to reduce appetite in obesity

Abstract

In light of our discovery that the transmembrane receptor guanylyl cyclase C (GCC) regulates appetite through a novel gut‐brain endocrine axis, we aimed to further define hypothalamic GCC expression and, moreover, determine the consequence of obesity to this GCC signaling axis. Nuclei were microdissected from mouse hypothalamus and GCC expression was quantified by RT‐PCR. Mouse brains were also cryosectioned and hypothalamic slices were immunostained for GCC. Further, hypothalamus and intestine were harvested from lean and obese mice, and GCC and GCC ligand expression was quantified by RT‐PCR, immunoblot, and immunofluorescence. Our studies revealed the suppression of intestinal ligand expression with the concomitant overexpression of hypothalamic GCC in obese mice. Further, our studies suggested that GCC was enriched in the arcuate nucleus, a key regulator of appetite. Our results suggest a corruption of the GCC axis in obesity, which in part reflects an endocrine deficiency of GCC ligands that could be therapeutically targeted to supersensitized receptors by hormone replacement. Thus, GCC represents a new target to develop anti‐obesity pharmacotherapies against this accelerating pandemic. This research was supported by the Thomas Jefferson University Doctoral Student Research Fellowship.