The hormone ghrelin stimulates 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 ghrelin signaling within intact AgRP neurons is unclear. Here, we tested the functional significance of ghrelin action on AgRP neurons using a new, tamoxifen-inducible AgRP-CreER(T2) transgenic mouse model that allows spatiotemporally-controlled re-expression of physiological levels of ghrelin receptors (GHSRs) specifically in AgRP neurons of adult GHSR-null mice that otherwise lack GHSR expression. AgRP neuron-selective GHSR re-expression partially restored the orexigenic response to administered ghrelin and 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 gluconeogenesis induction. Thus, our data indicate that GHSR-containing AgRP neurons are not solely responsible for ghrelin's orexigenic effects but are sufficient to mediate ghrelin's effects on glycemia.
Keywords: ARC, arcuate nucleus; AgRP; AgRP, Agouti-related peptide; BAC, bacterial artificial chromosome; Blood glucose homeostasis; CNS, central nervous system; DG, dentate gyrus; DVC, dorsal vagal complex; Food intake; Foxo1, Forkhead box protein O1; G6p, glucose-6 phosphatase; GABA, gamma-aminobutyric acid; GHRH, Growth-hormone-releasing hormone; GHSR, growth hormone secretagogue receptor, ghrelin receptor; GOAT, ghrelin O-acyltransferase; Ghrelin; Ghrelin receptor; Hnf4α, hepatocyte nuclear factor 4α; NAc, nucleus accumbens; NPY, neuropeptide Y; POMC, pro-opiomelanocortin; Pcx, pyruvate carboxylase; Pepck, phosphoenolpyruvate carboxykinase; Phox2b, paired-like homeobox 2b; VGAT, vesicular GABA transporter; VTA, ventral tegmental area.