Central Ghrelin Increases Food Foraging/hoarding That Is Blocked by Ghsr Antagonism and Attenuates Hypothalamic Paraventricular Nucleus Neuronal Activation Running Head: Ghsr Blockade Blocks Fasting-/ghrelin-induced Hoarding Increases Center for Obesity Reversal

244 words out of 250) 31 The stomach-derived “hunger hormone” ghrelin increases in circulation in direct response to 32 time since the last meal, increasing preprandially and falling immediately following food 33 consumption. We found previously that peripheral injection of ghrelin potently stimulates food 34 foraging (FF), food hoarding (FH) and food intake (FI) in Siberian hamsters. It remains, 35 however, largely unknown if central ghrelin stimulation is necessary/sufficient to increase these 36 behaviors regardless of peripheral stimulation of the ghrelin receptor [growth hormone 37 secretagogue receptor (GHSR)]. We injected three doses (0.01 μg, 0.1 μg, and 1.0 μg) of ghrelin 38 into the third ventricle (3V) of Siberian hamsters and measured changes in FF, FH, and FI. To 39 test the effects of 3V ghrelin receptor blockade, we used the potent GHSR antagonist JMV2959 40 to block these behaviors in response to food deprivation or a peripheral ghrelin challenge. 41 Finally, we examined neuronal activation in the arcuate nucleus (Arc) and paraventricular 42 hypothalamic nucleus (PVH) in response to peripheral ghrelin administration and 3V GHSR 43 antagonism. Third ventricular ghrelin injection significantly increased FI through 24 h and FH 44 through Day 4. Pretreatment with 3V JMV2959 successfully blocked peripheral ghrelin-induced 45 increases in FF, FH and FI at all time points and food deprivation-induced increases in FF, FH 46 and FI up to 4h. c-Fos-immunoreactivity was significantly reduced in the PVH, but not the Arc 47 following pretreatment with i.p. JMV2959 and ghrelin. Collectively, these data suggest central 48 GHSR activation is both necessary and sufficient to increase appetitive and consummatory 49 behaviors in Siberian hamsters. 50