Hypothalamic Circuitry of Neuropeptide Y Regulation of Neuroendocrine Function and Food Intake via the Y5 Receptor Subtype

Abstract

Neuropeptide Y (NPY) displays diverse modes of action in the CNS including the modulation of feeding behavior, gonadotropin releasing hormone release, and stress responses. Many of the above physiological actions have been at least partially attributed to actions of NPY on the NPY Y5 receptor subtype. We utilized an antibody directed against the NPY Y5 receptor to characterize the distribution of this receptor in the rat brain. Using Western blot analysis, this antibody recognized a single major band at approximately 57 kD. To further verify the specificity of the antibody, animals were treated for 5 days with antisense oligonucleotides for the Y5 receptor. The antisense treatment significantly reduced food intake and body weight. Furthermore, the Y5 antibody detected a significant decrease in Y5 receptor protein. Y5-like immunoreactivity (-ir) was observed throughout the hypothalamus, thalamus, hippocampus and cortex. Double-label immunofluorescence demonstrated that Y5-ir was colocalized with the following neuronal phenotypes in the hypothalamus, gonadotropin-releasing hormone, neurophysins, corticotropin-releasing hormone, and γ-amino butyric acid. In addition, functional interactions were demonstrated by the presence of close appositions of NPY fibers with Y5-ir expressing cells. The wide distribution of the Y5 receptor-ir, as well as the colocalization within specific neuronal populations, agrees with the distribution of the Y5 receptor mRNA and the known physiological roles of the NPY/Y5 system. The role of the NPY/Y5 receptor system as a mediator between signals of peripheral energy availability and reproductive neuroendocrine function is discussed.

The Novel Neuropeptide Y Y5 Receptor Antagonist Lu AA33810 [N-[[trans-4-[(4,5-Dihydro[1]benzothiepino[5,4-d]thiazol-2-yl)amino]cyclohexyl]methyl]-methanesulfonamide] Exerts Anxiolytic- and Antidepressant-Like Effects in Rat Models of Stress Sensitivity

“…The ability of Lu AA33810 to inhibit cPP-evoked increases in plasma ACTH and corticosterone in F344 rats was consistent with results previously reported for the structurally diverse Y 5 receptor antagonist FMS586 (Kakui and Kitamura, 2007). A mechanistic rationale may be derived from immunohistochemical studies revealing extensive coexpression of Y 5 receptor immunoreactivity with CRFor vasopressin-positive neurons in the paraventricular nucleus and supraoptic nucleus of the hypothalamus (Campbell et al, 2001 (Kakui and Kitamura, 2007). Taken together, these data implicate central Y 5 receptors in activation of the HPA axis, a key component of the core stress system (Gold and Chrousos, 2002).…”

“…The tissue distributions of Y 5 and Y 1 overlap significantly, possibly reflecting their opposite and coordinate transcriptional regulation at the gene level (Wolak et al, 2003). Immunohistochemical studies in the rat show coexpression of the Y 5 receptor in hypothalamic nuclei with stress-associated transmitters such as CRF, GABA, vasopressin, and oxytocin (Campbell et al, 2001). A similar coexpression pattern of Y 5 with CRF and GABA is evident in higher brain regions too, including cortex and hippocampus (Grove et al, 2000).…”

Gonadotropin-Releasing Hormone Neurons Express KATPChannels That Are Regulated by Estrogen and Responsive to Glucose and Metabolic Inhibition

“…However, it is believed that metabolic signals are transmitted to GnRH neurons via the area postrema and the mediobasal hypothalamus (Wade and Jones, 2004;The ESHRE Capri Workshop Group, 2006). Mediobasal hypothalamic POMC and NPY neurons project directly onto GnRH to modulate GnRH neuronal activity through -opioid and NPY5 receptors, respectively (Lagrange et al, 1995;Campbell et al, 2001;Zheng et al, 2005). However, until now, there has been little evidence that GnRH neurons respond directly to metabolic factors such as glucose.…”

Pharmacological Characterization and Feeding-Suppressive Property of FMS586 [3-(5,6,7,8-Tetrahydro-9-isopropyl-carbazol-3-yl)-1-methyl-1-(2-pyridin-4-yl-ethyl)-urea Hydrochloride], a Novel, Selective, and Orally Active Antagonist for Neuropeptide Y Y5 Receptor

“…The involvement of Y5 receptor in the regulation of natural feeding also does not appear to reach a general consensus. The repeated treatment of normal rats with antisense oligonucleotides for Y5 reduced cumulative spontaneous food intake by 32% and resultant hypothalamic Y5 protein expression by 50% without any modification of water intake levels or Y2 receptor expression (Campbell et al, 2001). According to Dube et al (1994), central infusion of NPY antibodies to normal rats suppressed cumulative food intake by 40 to 60% relative to the control group.…”