Role of pituitary adenylate cyclase-activating polypeptide (PACAP) in energy balance

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Energy balance is achieved by regulating the amount of energy consumed through food intake and energy expended by metabolic processes. Our understanding of energy homeostasis has developed substantially in the past decade driven by a desire to understand the physiological consequences of disregulated energy balance. Predominantly, research has focused on the characterization of neuronal pathways involved in appetite regulation. The other side of the energy balance equation, hormonal regulation of energy expenditure, is poorly understood. The neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP) is expressed throughout the brain with a high level of expression in the hypothalamus, a region of the brain known to be involved in regulating energy balance. PACAP is made by all vertebrates and its protein structure has been highly conserved throughout evolution, suggesting it plays a role in fundamental physiological processes. Previously we generated mice that are unable to produce PACAP. These knockout mice are unable to regulate body temperature appropriately and if raised at an ambient temperature of 21oC die early in postnatal life. If however the mice are raised at an ambient temperature of only 3oC higher, survival is increased to 80%. These studies demonstrated that the hormone PACAP plays a role in thermoregulation. The mechanism by which PACAP regulates energy balance is still unknown. Our newly generated data suggests appetite is not affected in PACAP knockout mice, yet are leaner than wildtype control mice. Using transgenic animals that lack PACAP and wildtype animals subjected to different environmental temperatures I aim to elucidate the physiological role of the highly conserved neuropeptide PACAP in thermoregulation and energy balance. Additionally we aim to establish if neuronally derived PACAP is responsible for the thermoregulatory problems observed in PACAP knockout mice and to further characterize which PACAP expressing neurons are responsible for these effects. Importantly, studies put forth in this proposal will advance our understanding of the endocrine regulation of energy balance.