Arcuate AgRP neurons mediate orexigenic and glucoregulatory actions of ghrelin

The hormone ghrelinstimulates eating and helps maintain blood glucose upon caloric restriction. While previous studies have demonstrated that hypothalamic arcuate AgRP neurons are targets of ghrelin, the overall relevance of ghrelinsignaling within intact AgRP neurons is unclear. Here, we tested the functional significance of ghrelinaction on AgRP neurons using a new, tamoxifen-inducible AgRP-CreERT2 transgenic mouse model that allows spatiotemporally-controlled re-expression of physiological levels of ghrelinreceptors (GHSRs) specifically in AgRP neurons of adult GHSR-null mice that otherwise lack GHSR expression. AgRP neuron-selective GHSR re-expression partially restored the orexigenicresponse to administered ghrelinand fully restored the lowered blood glucose levels observed upon caloric restriction. The normalizing glucoregulatory effect of AgRP neuron-selective GHSR expression was linked to glucagon rises and hepatic gluconeogenesisinduction. Thus, our data indicate that GHSR-containing AgRP neurons are not solely responsible for ghrelin's orexigeniceffects but are sufficient to mediate ghrelin's effects on glycemia.