The overall goal of this proposal is to identify novel actions of mammalian bombesin (BN)-like peptides in the controls of food intake and energy balance. The mammalian BN-like peptides, gastrin-releasing peptide (GRP) and neuromedin B (NMB) have been demonstrated to reduce food intake following both peripheral and central administration, but little is known about their underlying mechanisms of action. The proposed experiments examine aspects of three different hypotheses. The experiments under Specific Aim 1 will assess the idea that a GRP-ergic pathway from the hypothalamus to the caudal hindbrain plays a pivotal role in the ability of metabolic signals such as leptin to affect food intake through alterations in meal size. The experiments under Specific Aim 2 will focus on how metabolic signals indicating positive or negative energy balance alter the ability of peripheral and central GRP and NMB to inhibit food intake. Based on the demonstration that bombesin receptor subtype 3 (BRS-3) knockout mice are hyperphagic and obese, experiments under Specific Aim 3 will identify the role of this novel receptor signaling system in the control of food intake and energy balance. The experiments addressing these hypotheses will employ multiple measures of food intake and specific receptor agonists and antagonists to characterize intake and identify roles of specific receptor subpopulations, c-Fos expression as a measure of cellular activation to identify candidate brain sites where interactions occur and double-labeling techniques to characterize the phenotype of these cellular populations. Together, these studies will greatly enhance our understanding of the role of mammalian BN-like peptides in the interactions between short-term satiety signals and signals that regulate overall energy balance. Such an understanding will significantly enhance our understanding of the mechanisms underlying overall energy regulation and may lead to novel treatments for obesity or eating disorders
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