Conservation of Expression of Neuropeptide Y5 Receptor between Human and Rat Hypothalamus and Limbic Regions Suggests an Integral Role in Central Neuroendocrine Control

Abstract

Neuropeptide Y receptors belong to the G-protein-coupled receptor superfamily and mediate a wide variety of physiological functions, including blood pressure regulation, hormone release, appetite control, seizure propensity, cognition, and emotion. The recent description of a new neuropeptide Y receptor, Y5, expressed in hypothalamic nuclei in rat brain, raised the possibility that Y5 was the receptor mediating the feeding and appetite-related functions of neuropeptide Y. This was supported by subsequent data showing a downregulation of this "feeding" receptor in the brain of the obese Zucker rat (Widdowson, 1997). We have performed a detailed analysis of Y5 expression in rat brain using in situ hybridization histochemistry with digoxygenin-labeled riboprobes and compared this to expression of Y5 in human brain regions. mRNA for the human Y5 receptor was highly expressed in human hypothalamic and thalamic nuclei. In particular, the arcuate and paraventricular nuclei of the hypothalamus, midline thalamic nuclei, and amygdala showed very high levels of expression with high levels in hippocampus. The striking conservation of expression of the rat and human Y5 receptors in relevant hypothalamic and other nuclei implies sharing of a major neuroendocrine functional role by this receptor. Key words: NPY; Y5; in situ hybridization; appetite; hypothalamus; paraventricular; arcuate; thalamusNeuropeptide Y (N PY) is the most abundant neuropeptide in the mammalian C NS (Heilig and Widerlöv, 1990) and mediates diverse physiological responses, including alterations in blood pressure, hormone release, induction of anxiolysis, enhancement of memory retention, and alterations in circadian rhythms (Wahlestedt and Reis, 1993;Heilig and Widerlöv, 1995;Wettstein et al., 1995). NPY also has a well established role in the regulation of appetite and feeding (Zimanyi et al., 1998), and evidence from the NPY-deficient mouse has implicated NPY with a major protective role in kainic acid-induced seizures (Baraban et al., 1997).The richest source of N PYergic neurons is found in the arcuate nucleus of hypothalamus, which sends dense projections to the paraventricular nucleus (PV N) (Stanley et al., 1993). This pathway appears to be the crucial N PY system acting on feeding as intracerebral injection of N PY into PV N results in increased food intake (Levine and Morley, 1984;Stanley and Leibowitz, 1984) and, in rats, chronic administration of N PY produces a prolonged effect on food intake with resultant obesity (Zarjevski et al., 1993). Leptin administration reduces N PY mRNA in the arcuate and PV N (Schwartz et al., 1996;Wang et al., 1997), and fasting increases N PY secretion from PV N (Kalra et al., 1991). Thus, N PYergic arcuate-PV N neurons form part of a homeostatic loop regulating body fat mass in which leptin acts as a signal of energy excess or deficiency (Flier, 1998).The NPY family of peptides mediates the specificity of the actions of NPY through a family of G-protein-coupled receptors (Dumont et al., 1993;Balasubramaniam, 1997...

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

“…4, 5, 6, 7). The pattern and high level of Y5 receptor protein expression are consistent with the reported distribution and level of expression of Y5 mRNA [20, 21]. Although there is an abundance of Y5 mRNA in the hypothalamus, reports on the distribution of Y5-like receptor binding, by in vitro receptor autoradiography, have demonstrated only low levels of Y5 receptors in the hypothalamus [18, 34].…”

“…Previous studies have demonstrated that the Y5 receptor mRNA and binding has a wide distribution throughout the hypothalamus [18, 19, 20, 21]. However, there is little information available on the cellular localization (i.e.…”

Melanocortin 4 receptor distribution in the human hypothalamus

“…However, NPY innervation directly onto the PVN in humans (43), as well as low levels of Y1-and higher levels of Y2-receptor binding sites, have been described in the PVN (44). In addition, Y5 receptor mRNA is expressed in magnocellular neurons of the PVN and SON (45), as well as in other nuclei in which we found MC4R to be expressed. In this study, we found NPY terminals in close proximity to MC4R-expressing neurons in the PVN (Fig.…”

Selective Antagonism of the NPY Y5 Receptor Does Not Have a Major Effect on Feeding in Rats

“…Notably, the majority of these data have been generated in rodents. Supportive data in humans has been restricted to a neuroanatomical distribution similar to rodents (39,40) and to preliminary human genetic evidence in a very specific cohort (41). Indeed, other human genetic studies have resulted in negative findings (42,43).…”