OR30-1 GHSRs expressed in AgRP neurons mediate ghrelin-induced acute feeding in mice

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: OR30-Central Regulation of Appetite & Feeding
Monday, June 17, 2013: 11:15 AM-12:45 PM
Presentation Start Time: 11:15 AM
Room 304 (Moscone Center)
Qian Wang*, Chen Liu, Aki Uchida, Angela Kay Walker, Tiemin Liu, Joel K Elmquist and Jeffrey Marc Zigman
UT Southwestern Medical Center, Dallas, TX
Hypothalamic AgRP neurons are essential for feeding regulation. Activity of these orexigenic neurons is modulated by hormones including ghrelin. Ghrelin is the endogenous ligand of the growth hormone secretagogue receptor (GHSR), which is highly expressed in AgRP neurons. Ghrelin administration strongly promotes food intake in wild-type but not GHSR-null mice. GHSR-null mice also display lower fasting blood glucoses. While previous studies support the hypothesis that GHSRs in AgRP neurons mediate ghrelin-induced feeding, the impact of AgRP neuronal expression of GHSRs remains unclear. Here, we set out to determine whether selective GHSR expression in AgRP neurons is sufficient to mediate the orexigenic and glucoregulatory effects of ghrelin. This involved first generating a novel tamoxifen-inducible AgRP-CreERT2 transgenic mouse that allows for spatial (AgRP neuron-selective) and temporal (upon tamoxifen delivery) gene targeting. These mice were then crossed to an existing GHSR-null mouse model, in which the Ghsr locus is modified by the addition of a loxP-flanked transcriptional blocking cassette, enabling Cre recombinase–mediated reexpression of GHSR selectively in AgRP neurons. Mice were then injected with ghrelin to measure effects on food intake and also were fasted overnight to monitor effects on blood glucose. The expected tamoxifen-dependent, AgRP neuron-selective expression of Cre activity was confirmed using reporter mice in which Tomato fluorescence is dependent on Cre-mediated removal of a loxP-flanked transcriptional blocking cassette. Ghrelin-induced acute feeding was partially restored in mice with selective GHSR-reexpression in AgRP neurons.  Also, the lower fasting blood glucose observed in GHSR-null mice returned to wild-type levels in mice with selective GHSR-reexpression in AgRP neurons. These data confirm a key role for AgRP neuronal GHSR expression in mediating the feeding and glucoregulatory actions of ghrelin, and add further insight to the complex central neural circuits that help control both body weight and glucose homeostasis.

Nothing to Disclose: QW, CL, AU, AKW, TL, JKE, JMZ

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