Neuropeptide Y (NPY) dual role in stress response and energy homeostasis

The control of CRH neuronal activity in the PVN is integral to the appropriate functioning of the HPA axis. Neuropeptide Y exerts potent actions within the PVN including the regulation of feeding, influence of cardiovascular and GI functioning as well as a myriad of neuroendocrine action. This work explores the mechanism by which neuropeptide Y (NPY) interacts with corticotropin-releasing hormone (CRH) neurons of the hypothalamic paraventricular nucleus (PVN) to activate the hypothalamic-pituitary-adrenal (HPA) axis. Identification of neuroendocrine neurons using intraperitoneal injection of the retrograde tracer, FluoroGold (FG) showed that 88.8% of the neuroendocrine CRH-ir neurons coexpressed Y1 receptor immunoreactivity (Y1r-ir) in the PVN. The highest coexpression of CRH/FG/Y1r-ir was found in the anterior and medial part of PVN, gradually declining posteriorly. The likely link between NPY and PVN projection neurons was addressed by a FG injection into locus coeruleus (LC) and nucleus tractus solitarii (NTS). The PVN projection neurons to both nuclei were found to have a high degree of Y1r-ir coexpression. Additionally, some of the neurons projecting from the PVN to the NTS were oxytocin (OT-ir) positive. The central amygdaloid nucleus (CeAm) also demonstrated FG positive neurons after a FG injection into LC. A high percent of these FG labeled neurons in the CeAm also coexpressed Y1r-ir and CRH-ir. Bilateral infusion of the Y1/Y5 receptor agonist [leu 31pro34]NPY into the PVN activated the HPA axis as indicated by elevated corticosterone secretion. Additionally, CRH neurons had increased expression of c-Fos and pCREB (markers of neuronal activation) 90 and 15 minutes post [leu31pro34]NPY injection.; Food deprivation is one stressor that is known to elevate NPY levels within the PVN. Fasting led to decreases in body weight, plasma glucose and increased ACTH and corticosterone blood levels and led to a transient hypertrophy of the adrenal gland. pCREB-ir, but not c-Fos, was induced in a percent of hypothalamic CRH/Y1r-ir positive cells after 24 and 48 hours food deprivation. Food deprivation increased NPY mRNA signal in the hypothalamus and C2/A2 groups of the brainstem, suggesting increased transmission of endocrine and visceral sensory information to PVN. The increased CRH mRNA signal intensity in the CeAm and the PVN points to their participation in the continuous HPA axis activation during food deprivation. This fasting-induced HPA axis activation was blocked by infusion of Y1 receptor antagonist BIBP3226 into the PVN. The results of these studies indicate possible regulation of the HPA axis activity by direct NPY signaling to endocrine and autonomic pathways via Y1 receptors expressed by a variety of hypothalamic and limbic neurons.