Silencing the Uroguanylin-GUCY2C Gut-Brain Axis Mediates Leptin Resistance in Obesity
Leptin is a potent anorexigenic hormone and compelling candidate to treat diet-induced obesity (DIO). However, DIO induces leptin resistance by downregulating leptin receptors (LepRs) on hypothalamic neurons, rendering leptin therapy ineffective. Overcoming leptin resistance has become a promising goal for obesity therapy. This project discovered that the guanylyl cyclase C (GUCY2C) receptor is specifically expressed in hypothalamic LepR(+) neurons. Hypothalamic GUCY2C induces satiety, but is silenced in DIO by loss of its hormone, uroguanylin, produced in the intestine. Importantly, reconstitution of GUCY2C signaling induces weight loss and leptin sensitivity in DIO mice. These data suggest that loss of uroguanylin in obesity silences hypothalamic GUCY2C, downregulating LepRs on neurons, while reconstituting GUCY2C signaling by ligand replacement should reverse downregulation of LepRs, overcoming leptin resistance. Here, the pathophysiologic aim will demonstrate that the uroguanylin-GUCY2C axis regulates leptin sensitivity. The mechanistic aim will establish that GUCY2C signaling regulates neuronal surface LepRs. Finally, the therapeutic aim will define the ability of GUCY2C ligands to overcome leptin resistance in DIO mice. These studies will reveal new mechanisms in obesity and novel solutions to overcome leptin resistance. The potential to translate these results into patients is underscored by approval of GUCY2C ligands to treat constipation.
It is a privilege to be a recipient of the Predoctoral Fellowship in Pharmacology/Toxicology from the PhRMA Foundation. This funding provided the opportunity for me to test novel therapies for metabolic diseases and has been integral in helping me establish a track-record of funding. I’m extremely grateful for this award!