Date of Award
Doctor of Philosophy (PhD)
Pituitary adenylate cyclase-activating polypeptide (PACAP) is a member of the secretin-glucagon superfamily of peptide hormones, with homology to vasoactive intestinal polypeptide (VIP) and activity at both the VIP receptors and the PACAP specific PAC1 receptor (PAC1R). Abundantly expressed in the hypothalamus, PACAP was recently discovered to regulate energy balance when central injections produced hypophagia and increased metabolic rate. However, the neurocircuitry mediating these effects in the hypothalamus are poorly understood.
To characterize how hypothalamic PACAP signaling affects energy homeostasis we microinjected PACAP site-specifically into the hypothalamic paraventricular (PVN) and ventromedial nuclei (VMN) and examined feeding behavior and metabolism. PACAP injected into both areas significantly decreased food intake, while only VMN injections increased core body temperature and spontaneous locomotor activity. In addition, all responses resulting from hypothalamic PACAP administration were blocked by pretreatment with a PAC1R antagonist. Retrograde-labeling from the PVN or VMN identified PACAP afferents originating from the brainstem, amygdala, and hypothalamus that co-expressed PACAP mRNA. These projections to the PVN and VMN represent the first description of PACAP circuits regulating energy balance.
PACAP signaling is also important for modulating glutamate neurotransmission, however whether glutamatergic signaling is necessary for PACAP-induced hypophagia is unknown. Though PACAP-PAC1R signaling potentiates postsynaptic NMDA receptor activity, PACAP treatment was found to also augment the activity of the astrocytic cystine-glutamate antiporter, system xc-, in primary cortical cultures suggesting another possible means of glutamatergic modulation by PACAP. PACAP increased VMN system xc- mRNA expression in vivo, however, inhibition of system xc- activity did not attenuate PACAP-induced hypophagia. Conversely, NMDA receptor antagonism prior to PACAP administration in the VMN did block PACAP-mediated decreases in feeding, suggesting that PACAP neurotransmission in the VMN augments glutamate signaling by potentiating postsynaptic NMDA receptors.
The current findings suggest that PACAP signaling, from both hypothalamic and extrahypothalamic sites, potently regulates energy balance by decreasing food intake and increasing metabolism. Furthermore, the results of our studies involving PACAP-mediated modulation of glutamate neurotransmission indicate that PACAP affects glutamatergic signaling in multiple ways, however, modulation of NMDA receptor activity in the hypothalamus may be the primary mechanism for the regulation of food intake.