title: Arcuate AgRP neurons mediate orexigenic and glucoregulatory actions of ghrelin.
abstract: 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.
authors.affiliation: Division of Hypothalamic Research, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX, USA ; Division of Endocrinology and Metabolism, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Qian
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Division of Hypothalamic Research, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX, USA ; Division of Endocrinology and Metabolism, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Chen
authors.initials: C
authors.lastname: Liu
authors.affiliation: Division of Hypothalamic Research, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX, USA ; Division of Endocrinology and Metabolism, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Aki
authors.initials: A
authors.lastname: Uchida
authors.affiliation: Division of Hypothalamic Research, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX, USA ; Division of Endocrinology and Metabolism, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Jen-Chieh
authors.initials: JC
authors.lastname: Chuang
authors.affiliation: Division of Hypothalamic Research, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX, USA ; Division of Endocrinology and Metabolism, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX, USA ; Department of Psychiatry, The University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Angela
authors.initials: A
authors.lastname: Walker
authors.affiliation: Division of Hypothalamic Research, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX, USA ; Division of Endocrinology and Metabolism, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Tiemin
authors.initials: T
authors.lastname: Liu
authors.affiliation: Division of Hypothalamic Research, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX, USA ; Division of Endocrinology and Metabolism, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Sherri
authors.initials: S
authors.lastname: Osborne-Lawrence
authors.affiliation: Division of Hypothalamic Research, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX, USA ; Division of Endocrinology and Metabolism, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Brittany L
authors.initials: BL
authors.lastname: Mason
authors.affiliation: Division of Hypothalamic Research, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX, USA ; Division of Endocrinology and Metabolism, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Christina
authors.initials: C
authors.lastname: Mosher
authors.affiliation: Division of Hypothalamic Research, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX, USA ; Division of Endocrinology and Metabolism, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Eric D
authors.initials: ED
authors.lastname: Berglund
authors.affiliation: Division of Hypothalamic Research, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX, USA ; Division of Endocrinology and Metabolism, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Joel K
authors.initials: JK
authors.lastname: Elmquist
authors.affiliation: Division of Hypothalamic Research, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX, USA ; Division of Endocrinology and Metabolism, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX, USA ; Department of Psychiatry, The University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Zigman
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