GYY4137 Promotes Mice Feeding Behavior via Arcuate Nucleus Sulfur-Sulfhydrylation and AMPK Activation

Hydrogen sulfide (H₂S) is an endogenous gaseous molecule and plays important biological and neurochemical roles in many processes such as the neural activity and immunity. The arcuate nucleus (ARC) of hypothalamus is a control center for appetite and energy metabolism. AMPK is a gage kinase in the monitoring of energy status and regulation of energy metabolism, and it can be activated by H₂S via CaMKKβ/AMPK pathway. But the role of H₂S in ARC and appetite has not been reported. Here we studied the orexigenic effect of H₂S and the mechanisms by means of GYY4137, a water soluble and slow-releasing donor of H₂S, and protein sulfur-sulfhydrylation analysis. We demonstrated that GYY4137-derived H₂S increased food intake of mice, augmented the production of neuropeptide Y (NPY), and elevated the protein sulfur-sulfhydrylation level and the activation of AMPK and CaMKKβ in ARC. Blocking sulfur-sulfhydrylation with DTT eliminated GYY4137-induced activation of AMPK and CaMKKβ. DTT and preventing AMPK activation in ARC with Compound C and Ara-A could both attenuate the orexigenic effect of GYY4137. These findings suggest that H₂S enhances appetite through protein sulfur-sulfhydrylation and the activation of AMPK and NPY function in ARC.