Peptidergic Control of Appetitive Ingestive Behaviors

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DESCRIPTION (provided by applicant): Current approaches focusing on curtailing food intake have largely been unsuccessful in treating obesity. Because food has to be acquired (foraging, even in humans) and often is stored for later consumption (hoarding in refrigerators, freezers), this could provide another point of attack for pharmacological/behavioral intervention, but the mechanisms underlying foraging/hoarding largely are unknown. Hungry and obese humans bring home more food and higher fat/calorie food than their sated and lean counterparts, respectively. We developed a novel model of human foraging/hoarding in Siberian hamsters, where they run a prescribed number of wheel revolutions to earn food pellets and found that hungry hamsters also bring home more food, but unlike most animals, do not overeat post-fast; thus feeding is separated from foraging/hoarding making them ideal subjects. The overall purpose here is to test for the neurochemical/neuroanatomical basis of these appetitive behaviors (foraging/hoarding) across three Specific Aims (SAs). Our overarching hypothesis is that foraging/hoarding largely are governed by several orexigenic and anorexigenic peptides shown previously in laboratory rats and mice to affect feeding. We will test peripheral and central peptides that change with fasting and thus may be mechanisms underlying deprivation-induced increases in foraging/hoarding. In SA 1, we will test whether ghrelin receptor (R) antagonism blocks fasting-and ghrelin-induced increases in foraging/hoarding. We will test whether cholecystokinin (CCK), a known satiety peptide, inhibits ad libitum foraging/hoarding by giving selective CCK-R antagonists and whether systemic CCK inhibits fasting-induced increased foraging/hoarding. We will test whether the adipokine feeding suppressant leptin, inhibits fasting-induced increased foraging/hoarding. In SA 2, we will test whether selective immunolesioning of neuropeptide Y (NPY)-R bearing paraventricular nucleus (PVN) neurons via NPY-saporin blocks fasting-induced increased foraging/hoarding and which NPY- R subtype is important for fasting-induced increases by icv injections of NPY-R subtype antagonists. We will test whether icv injections of orexin A or B, peptides implicated in activity and food intake, stimulate ad libitum foraging/hoarding and whether antagonism of each receptor subtype blocks fasting-induced increased foraging/hoarding. In SA 3, we will test whether co-injection of NPY and agouti-related protein that co-localize in arcuate neurons, increase with fasting and each stimulates foraging/hoarding, will do so when co-injected at subthreshold doses. Because arcuate NPY/AgRP ghrelin-R bearing neurons likely underlie ghrelin-induced increased food intake, we will test whether blockade of downstream NPY-Rs by icv injections of subtype antagonists block ghrelin-induced increased foraging/hoarding. We will test whether destruction of downstream NPY-Rs by PVN injection of NPY-saporin blocks ghrelin-induced increased foraging/hoarding.