On the Pleiotropic Actions of Glucagon-like Peptide-1 in Its Regulation of Homeostatic and Hedonic Feeding

We examined the neuroanatomical substrates and signaling mechanisms underlying the suppressive effect of GLP1 on homeostatic and hedonic feeding. Electrophysiological and behavioral studies were conducted in agouti-related peptide (AgRP)-cre and tyrosine hydroxylase (TH)-cre mice, and AgRP-cre/pituitary adenylyl cyclase-activating polypeptide (PACAP) type I receptor (PAC1R)^fl/fl animals. GLP1 (30 pmol) delivered directly into the arcuate nucleus (ARC) decreased homeostatic feeding and diminished the rate of consumption. This anorexigenic effect was associated with an inhibitory outward current in orexigenic neuropeptide Y (NPY)/AgRP neurons. GLP1 injected into the ventral tegmental area reduced binge feeding, coupled with decrements in the rate of consumption and the percent daily caloric consumption during the binge interval. These reductions were associated with a GLP1-induced outward current in mesolimbic (A₁₀) dopamine neurons. GLP1 administered into the ventromedial nucleus (VMN) reduced homeostatic feeding that again was associated with a diminished rate of consumption and abrogated by the GLP1 receptor antagonist exendin 9-39 and in AgRP-cre/PAC1R^fl/fl mice. This suppressive effect was linked with a GLP-induced inward current in VMN PACAP neurons, and further supported by the fact that GLP1 neurons in the nucleus tractus solitarius project to the VMN. Conversely, intra-VMN GLP1 had modest effects on binge feeding behavior. Finally, apoptotic ablation of VMN PACAP neurons obliterated the anorexigenic effect of intra-VMN GLP1 on homeostatic feeding in PACAP-cre mice but not their wildtype counterparts. Collectively, these data demonstrate that GLP1 acts within the homeostatic and hedonic circuits to curb appetitive behavior by exciting PACAP neurons, and inhibiting NPY/AgRP and A₁₀ dopamine neurons.