Characterization of the neuropeptide Y5 receptor in the human hypothalamus: a lack of correlation between Y5 mRNA levels and binding sites

Statnick, Michael A.; Schober, Douglas A.; Gackenheimer, Susan L.; Johnson, Dwayne; Beavers, Lisa S.; Mayne, N.G.; Burnett, J. Paul; Gadski, Robert A.; Gehlert, Donald R.

doi:10.1016/s0006-8993(98)00855-5

Cited by 41 publications

(25 citation statements)

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“…Using competitive RT-PCR techniques, high levels of Y5 were found in human hypothalamic nuclei, however, radioligand binding studies could not detect Y5-like binding sites in homogenates of human hypothalamus (Statnick et al, 1998). This latter finding is consistent with the finding of low Y5-like binding in rat hypothalamic nuclei (Dumont et al, 1998).…”

Section: Discussionsupporting

confidence: 77%

“…Our results should be viewed in light of two recent studies showing a lack of correlation between hypothalamic Y5 mRNA levels and receptor binding (Dumont et al, 1998;Statnick et al, 1998). Using competitive RT-PCR techniques, high levels of Y5 were found in human hypothalamic nuclei, however, radioligand binding studies could not detect Y5-like binding sites in homogenates of human hypothalamus (Statnick et al, 1998).…”

Section: Discussioncontrasting

confidence: 41%

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

et al. 1999

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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...

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Section: Discussionsupporting

confidence: 77%

Section: Discussioncontrasting

confidence: 41%

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

et al. 1999

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“…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]. Likewise, Statnick et al [35]reported high levels of Y5 mRNA in the hypothalamus of humans; however, receptor binding studies failed to detect Y5-like binding in homogenates from the human hypothalamus. The reason for the discrepancy between the high levels of Y5 mRNA and Y5-ir in the hypothalamus and the relatively low levels of Y5-like receptor binding is unknown.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2001

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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.

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“…In addition, the Y 1 -receptor gene is known to contain a putative glucocorticoid response element (38), and it has been reported that supplemental corticosterone treatment to ADX rats increases NPY receptor-binding sites and Y 1 -receptor mRNA levels within discrete hypothalamic nuclei (24,25). It should be noted that other response elements may also be involved in tissue-specific Y-receptor regulation (38) and that changes in mRNA levels do not necessarily equate to changes in the amount of receptor protein (39). However, these findings do link ADX-induced effects on Y-receptor expression in the VMH with alterations in the insulinemic response to exogenous NPY, indicating that these mRNA changes may indeed be of physiological significance.…”

Section: Discussionmentioning

confidence: 99%

Adrenalectomy reduces neuropeptide Y–induced insulin release and NPY receptor expression in the rat ventromedial hypothalamus

Wisialowski¹,

Parker²,

Preston³

et al. 2000

J. Clin. Invest.

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IntroductionObesity, which is an important risk factor for serious chronic illnesses such as insulin resistance, type 2 diabetes, and heart disease is caused by an imbalance between energy intake and energy expenditure. There are numerous factors influencing whole-body energy balance, including neural and hormonal signals, which, when altered could result in obesity. It is becoming increasingly evident that the central nervous system, particularly the hypothalamus, plays a critical role in integrating these signals to regulate energy balance and that neuropeptide Y (NPY) is an important neuromodulator in this system (1, 2).NPY is widely distributed throughout the brain (3). However, most of the metabolic actions of NPY appear to be mediated through defined hypothalamic nuclei, including the arcuate nucleus (Arc) where numerous NPY-containing neurons originate, the paraventricular nucleus (PVN), where many NPYcontaining arcuate neuron terminals and NPY-binding sites are located, and the ventromedial hypothalamic (VMH) nucleus, which has been referred to as "the satiety center" (3, 4). NPY is the most potent orexigenic agent known (5, 6) and can also cause changes in circulating hormone levels (7). Chronic intracerebroventricular (icv) administration of NPY results in hyperphagia, hyperinsulinemia, insulin resistance, and obesity (8-10). Lesions of the VMH in rodents also cause multiple changes in metabolic status, including hyperphagia, hyperglycemia, and hyperinsulinemia (11). Interestingly, injection of NPY directly into the VMH significantly increases food intake (12), and NPY-induced feeding is enhanced in VMH-lesioned rats (13). These data suggest the VMH may also be a site of action for NPY in the development of obesity; however, the mechanisms by which NPY is involved in each aspect of central energy regulation remain to be defined.Much research has focused on which of the 5 NPYreceptor subtypes cloned so far (Y 1 , Y 2 , Y 4 , Y 5 , and the y6) (14) might mediate the potent NPY-induced feeding response. Several lines of evidence point to the Y 1 -and/or Y 5 -receptor subtypes being the most likely candidates for such an action (15-19). In addition, our previous studies investigating the mRNA expression of all known Y receptors in the rat brain also show clearly that both Y 1 -and Y 5 -receptor subtype mRNAs are expressed in areas pivotal in regulating energy balance (20).Glucocorticoid hormones play a critical role in energy balance and also appear to mediate at least some of their actions through the central NPY axis Chronic central administration of neuropeptide Y (NPY) causes hyperphagia, hyperinsulinemia, and obesity, a response that is prevented by prior adrenalectomy (ADX) in rats. The basis of NPY's effect and how the acute responses to this peptide are affected by ADX remain unknown. This study investigates the role of glucocorticoids in acute NPY-stimulated food intake, acute NPY-induced insulin release, and hypothalamic NPY-receptor mRNA expression levels. NPYinduced food intake was similar in A...

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Characterization of the neuropeptide Y5 receptor in the human hypothalamus: a lack of correlation between Y5 mRNA levels and binding sites

Cited by 41 publications

References 38 publications

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

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

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

Adrenalectomy reduces neuropeptide Y–induced insulin release and NPY receptor expression in the rat ventromedial hypothalamus

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