scholarly journals LGR4 and Its Ligands, R-Spondin 1 and R-Spondin 3, Regulate Food Intake in the Hypothalamus of Male Rats

Endocrinology ◽  
2014 ◽  
Vol 155 (2) ◽  
pp. 429-440 ◽  
Author(s):  
Ji-Yao Li ◽  
Biaoxin Chai ◽  
Weizhen Zhang ◽  
Danielle M. Fritze ◽  
Chao Zhang ◽  
...  
Keyword(s):  
In Situ Hybridization ◽  
Food Intake ◽  
Neuropeptide Y ◽  
Paraventricular Nucleus ◽  
Median Eminence ◽  
Energy Homeostasis ◽  
Male Rats ◽  
The Third ◽  
The Brain

The hypothalamus plays a key role in the regulation of feeding behavior. Several hypothalamic nuclei, including the arcuate nucleus (ARC), paraventricular nucleus, and ventromedial nucleus of the hypothalamus (VMH), are involved in energy homeostasis. Analysis of microarray data derived from ARC revealed that leucine-rich repeat-containing G protein-coupled receptor 4 (LGR4) is highly expressed. LGR4, LGR5, and LGR6 form a subfamily of closely related receptors. Recently, R-spondin (Rspo) family proteins were identified as ligands of the LGR4 subfamily. In the present study, we investigated the distribution and function of LGR4–LGR6 and Rspos (1–4) in the brain of male rat. In situ hybridization showed that LGR4 is expressed in the ARC, VMH, and median eminence of the hypothalamus. LGR4 colocalizes with neuropeptide Y, proopiomelanocortin, and brain-derived neurotrophic factor neurons. LGR5 is not detectable with in situ hybridization; LGR6 is only expressed in the epithelial lining of the lower portion of the third ventricle and median eminence. Rspo1 is expressed in the VMH and down-regulated with fasting. Rspo3 is expressed in the paraventricular nucleus and also down-regulated with fasting. Rspos 1 and 3 colocalize with the neuronal marker HuD, indicating that they are expressed by neurons. Injection of Rspo1 or Rspo3 into the third brain ventricle inhibited food intake. Rspo1 decreased neuropeptide Y and increased proopiomelanocortin expression in the ARC. Rspo1 and Rspo3 mRNA is up-regulated by insulin. These data indicate that Rspo1 and Rspo3 and their receptor LGR4 form novel circuits in the brain to regulate energy homeostasis.

Expression of a Novel Neuropeptide Y Receptor Subtype Involved in Food Intake: An in Situ Hybridization Study of Y5 mRNA Distribution in Rat Brain

2000 ◽  
Vol 165 (1) ◽  
pp. 90-100 ◽  
Author(s):  
Margaret M. Durkin ◽  
Mary W. Walker ◽  
Kelli E. Smith ◽  
Eric L. Gustafson ◽  
Christophe Gerald ◽  
...  
Keyword(s):  
In Situ Hybridization ◽  
Food Intake ◽  
Neuropeptide Y ◽  
Rat Brain ◽  
Receptor Subtype ◽  
Hybridization Study ◽  
Neuropeptide Y Receptor

scholarly journals Altered Expression of Agouti-Related Protein and Its Colocalization with Neuropeptide Y in the Arcuate Nucleus of the Hypothalamus during Lactation*

Endocrinology ◽  
1999 ◽  
Vol 140 (6) ◽  
pp. 2645-2650 ◽  
Author(s):  
Peilin Chen ◽  
Chien Li ◽  
Carrie Haskell-Luevano ◽  
Roger D. Cone ◽  
M. Susan Smith
Keyword(s):  
In Situ Hybridization ◽  
Food Intake ◽  
Neuropeptide Y ◽  
Arcuate Nucleus ◽  
Mrna Levels ◽  
Related Protein ◽  
Altered Expression ◽  
Caudal Portion ◽  
Agouti Related Protein

Abstract During lactation, the levels of neuropeptide Y (NPY), which plays an important role in mediating food intake, are significantly elevated in a number of hypothalamic areas, including the arcuate nucleus (ARH). To identify additional hypothalamic systems that might be important in mediating the increase in food intake and alterations in energy homeostasis during lactation, the present studies examined the expression of agouti-related protein (AGRP), a recently described homologue of the skin agouti protein. AGRP is found in the hypothalamus and has been suggested to play an important role in the regulation of food intake. In the first experiment, animals were studied during diestrus of the estrous cycle, a stage of the cycle when estrogen levels are basal and similar to lactation, or during days 12–13 postpartum. Lactating animals had their litters adjusted to eight pups on day 2 postpartum. Brain tissue sections were used to measure AGRP messenger RNA (mRNA) levels by in situ hybridization. AGRP mRNA signal was found mostly in the ventromedial portion of the ARH, which has been shown to contain a high density of NPY neurons. A significant increase in AGRP mRNA content was observed in the mid- to caudal portion of the ARH of lactating animals compared with diestrous females. No difference was found in the rostral portion of the ARH. In the second experiment, double-label in situ hybridization for AGRP and NPY was performed in lactating animals to determine the extent of colocalization of the two peptides in the ARH, using 35S-labeled and digoxigenin-labeled antisense complementary RNA probes. It was found that almost all of the NPY-positive neurons throughout the ARH also expressed AGRP mRNA signal. Furthermore, AGRP expression was confined almost exclusively to NPY-positive neurons. Thus, the present study showed that during lactation, AGRP gene expression was significantly elevated in a subset of the AGRP neurons in the ARH. The high degree of colocalization of AGRP and NPY, coupled with previous reports from our laboratory demonstrating increased NPY expression in the ARH in response to suckling, suggests that AGRP and NPY are coordinately regulated and may be involved in the increase in food intake during lactation.

scholarly journals Evidence That the Caudal Brainstem Is a Target for the Inhibitory Effect of Leptin on Food Intake

Endocrinology ◽  
2002 ◽  
Vol 143 (1) ◽  
pp. 239-246 ◽  
Author(s):  
Harvey J. Grill ◽  
Michael W. Schwartz ◽  
Joel M. Kaplan ◽  
James S. Foxhall ◽  
John Breininger ◽  
...  
Keyword(s):  
In Situ Hybridization ◽  
Food Intake ◽  
Fluorescence In Situ Hybridization ◽  
Energy Homeostasis ◽  
Leptin Receptor ◽  
Neuronal Cell ◽  
Locus Ceruleus ◽  
Hybridization Signal ◽  
Dorsal Vagal Complex

Abstract Three experiments were performed to investigate the hypothesis that leptin action within the caudal brain stem (CBS) contributes to its intake inhibitory effects. The first experiment evaluated the anatomical distribution of leptin receptor mRNA in rat CBS using a sensitive fluorescence in situ hybridization method with a riboprobe specific for the long form of the leptin receptor (Ob-Rb). An Ob-Rb mRNA hybridization signal was detected in neurons of several CBS nuclei involved in the control of food intake, including the dorsal vagal complex and parabrachial nucleus. A strong hybridization signal was also obtained from neuronal cell bodies of a number of other structures including the hypoglossal, trigeminal, lateral reticular, and cochlear nuclei; locus ceruleus; and inferior olive. The anatomical profile revealed by fluorescence in situ hybridization was in good agreement with immunocytochemical analysis with an antibody specific to Ob-Rb. In a second experiment, exploring the relevance of CBS Ob-Rb to feeding behavior, rats were given a fourth intracerebroventricular (i.c.v.) injection of leptin (0.1, 0.83, or 5.0μ g; n = 9–11/group) or vehicle 30 min before lights-out on three consecutive days The two higher doses reduced food intake significantly at 2, 4, and 24 h after injection and caused significant reductions of body weight. The dose-response profiles for fourth i.c.v. administration were indistinguishable from those obtained from separate groups of rats that received leptin via a lateral i.c.v. cannula. In the last experiment, a ventricle-subthreshold dose of leptin (0.1 μg) microinjected unilaterally into the dorsal vagal complex suppressed food intake at 2, 4, and 24 h. The results indicate that the CBS contains neurons that are potentially direct targets for the action of leptin in the control of energy homeostasis.

scholarly journals Hypothalamic Cocaine- and Amphetamine-Regulated Transcript (CART) and Agouti-Related Protein (AgRP) Neurons Coexpress the NOP1 Receptor and Nociceptin Alters CART and AgRP Release

Endocrinology ◽  
2005 ◽  
Vol 146 (8) ◽  
pp. 3526-3534 ◽  
Author(s):  
Gavin A. Bewick ◽  
Waljit S. Dhillo ◽  
Sarah J. Darch ◽  
Kevin G. Murphy ◽  
James V. Gardiner ◽  
...  
Keyword(s):  
In Situ Hybridization ◽  
Food Intake ◽  
Energy Homeostasis ◽  
Ex Vivo ◽  
Zona Incerta ◽  
Related Protein ◽  
Orphanin Fq ◽  
Anatomical Basis ◽  
Agouti Related Protein

Abstract Nociceptin or orphanin FQ (N/OFQ) and its receptor NOP1 are expressed in hypothalamic nuclei involved in energy homeostasis. N/OFQ administered by intracerebroventricular or arcuate nucleus (ARC) injection increases food intake in satiated rats. The mechanisms by which N/OFQ increases food intake are unknown. We hypothesized that N/OFQ may regulate hypothalamic neurons containing peptides involved in the control of food intake such as cocaine- and amphetamine-regulated transcript (CART), αMSH, neuropeptide Y (NPY), and agouti-related protein (AgRP). We investigated the ability of N/OFQ to alter the release of CART, αMSH, NPY, and AgRP using ex vivo medial basal hypothalamic explants. Incubation of hypothalamic explants with N/OFQ (1, 10, 100 nm) resulted in significant changes in CART and AgRP release. One hundred nanomoles N/OFQ caused a 33% decrease in release of CART (55–102) immunoreactivity (IR) and increased release of AgRP-IR to 163% but produced no change in either αMSH-IR or NPY-IR. Double immunocytochemistry/in situ hybridization demonstrated that CART-IR and NOP1 mRNA are colocalized throughout the hypothalamus, in particular in the paraventricular nucleus, lateral hypothalamus, zona incerta, and ARC, providing an anatomical basis for N/OFQ action on CART release. Dual in situ hybridization demonstrated that AgRP neurons in the ARC also express the NOP1 receptor. Our data suggest that nociceptin via the NOP1 receptor may increase food intake by decreasing the release of the anorectic peptide CART and increasing the release of the orexigenic peptide AgRP.

Apolipoprotein A-IV interacts synergistically with melanocortins to reduce food intake

2006 ◽  
Vol 290 (1) ◽  
pp. R202-R207 ◽  
Author(s):  
Koro Gotoh ◽  
Min Liu ◽  
Stephen C. Benoit ◽  
Deborah J. Clegg ◽  
W. Sean Davidson ◽  
...  
Keyword(s):  
Food Intake ◽  
Paraventricular Nucleus ◽  
Median Eminence ◽  
Arcuate Nucleus ◽  
Reduce Food Intake ◽  
The Third ◽  
Apolipoprotein A ◽  
Anorectic Effect ◽  
Fos Expression ◽  
Long Evans

Apolipoprotein (apo) A-IV is an anorexigenic gastrointestinal peptide that is also synthesized in the hypothalamus. The goal of these experiments was to determine whether apo A-IV interacts with the central melanocortin (MC) system in the control of feeding. The third ventricular (i3vt) administration of a subthreshold dose of apo A-IV (0.5 μg) potentiated i3vt MC-induced (metallothionein-II, 0.03 nmol) suppression of 30-min feeding in Long-Evans rats. A subthreshold dose of the MC antagonist (SHU9119, 0.1 nmol, i3vt) completely attenuated the anorectic effect of i3vt apo A-IV (1.5 μg). The i3vt apo A-IV significantly elevated the expression of c-Fos in neurons of the paraventricular nucleus of the hypothalamus, but not in the arcuate nucleus or median eminence. In addition, c-Fos expression was not colocalized with proopiomelanocortin-positive neurons. These data support a synergistic interaction between apo A-IV and melanocortins that reduces food intake by acting downstream of the arcuate.

Prefeeding release of paraventricular neuropeptide Y is mediated by ascending noradrenergic neurons in rats

1996 ◽  
Vol 270 (4) ◽  
pp. E596-E600 ◽  
Author(s):  
T. Yoshihara ◽  
S. Honma ◽  
K. Honma
Keyword(s):  
Food Intake ◽  
Neuropeptide Y ◽  
Paraventricular Nucleus ◽  
The Other ◽  
Neuronal System ◽  
Noradrenergic Neurons ◽  
Norepinephrine Level ◽  
Control Value ◽  
6 Hydroxydopamine ◽  
The Brain

The neuronal system responsible for the release of neuropeptide Y (NPY) in the paraventricular nucleus (PVN) was examined in rats under food deprivation and restricted daily feeding (RF). The ascending noradrenergic bundle (NAB) of neurons from the brain stem were destructed by microinjection of 6-hydroxydopamine (6-OHDA), and the extracellular NPY level in the PVN was measured by push-pull perfusion. 6-OHDA significantly reduced the extracellular norepinephrine level in the PVN to 15% of the control value when injected into the PVN and to 40% when injected into the midbrain ventral NAB. 6-OHDA administration into the NAB affected neither the deprivation-induced increase nor the feeding-induced decrease in the extracellular NPY. The amount of food intake after refeeding was not changed by the 6-OHDA treatment. On the other hand, 6-OHDA injection into the PVN or NAB not only decreased the extracellular NPY level, the amount of food intake was not change by the 6-OHDA treatment. It is concluded that the NAB is involved in the prefeeding NPY release in rats under RF but not in the deprivation-induced NPY release.

scholarly journals Immunolesion of Norepinephrine and Epinephrine Afferents to Medial Hypothalamus Alters Basal and 2-Deoxy-d-Glucose-Induced Neuropeptide Y and Agouti Gene-Related Protein Messenger Ribonucleic Acid Expression in the Arcuate Nucleus

Endocrinology ◽  
2003 ◽  
Vol 144 (1) ◽  
pp. 75-83 ◽  
Author(s):  
G. S. Fraley ◽  
S. Ritter
Keyword(s):  
Gene Expression ◽  
In Situ Hybridization ◽  
Food Intake ◽  
Neuropeptide Y ◽  
Arcuate Nucleus ◽  
Special Importance ◽  
Related Protein ◽  
Medial Hypothalamus ◽  
Agouti Gene

Abstract Neuropeptide Y (NPY) and agouti gene-related protein (AGRP) are orexigenic peptides of special importance for control of food intake. In situ hybridization studies have shown that NPY and AGRP mRNAs are increased in the arcuate nucleus of the hypothalamus (ARC) by glucoprivation. Other work has shown that glucoprivation stimulates food intake by activation of hindbrain glucoreceptor cells and requires the participation of rostrally projecting norepinephrine (NE) or epinephrine (E) neurons. Here we determine the role of hindbrain catecholamine afferents in glucoprivation-induced increase in ARC NPY and AGRP gene expression. The selective NE/E immunotoxin saporin-conjugated antidopamineβ-hydroxylase (anti-dβh) was microinjected into the medial hypothalamus and expression of AGRP and NPY mRNA was analyzed subsequently in the ARC under basal and glucoprivic conditions using 33P-labeled in situ hybridization. Saporin-conjugated anti-dβh virtually eliminated dβh-immunoreactive terminals in the ARC without causing nonspecific damage. These lesions significantly increased basal but eliminated 2-deoxy-d-glucose-induced increases in AGRP and NPY mRNA expression. Results indicate that hindbrain catecholaminergic neurons contribute to basal NPY and AGRP gene expression and mediate the responsiveness of NPY and AGRP neurons to glucose deficit. Our results also suggest that catecholamine neurons couple potent orexigenic neural circuitry within the hypothalamus with hindbrain glucose sensors that monitor brain glucose supply.

scholarly journals The Orexigenic Activity of the Hypothalamic Neuropeptide 26RFa Is Mediated by the Neuropeptide Y and Proopiomelanocortin Neurons of the Arcuate Nucleus

Endocrinology ◽  
2009 ◽  
Vol 150 (5) ◽  
pp. 2342-2350 ◽  
Author(s):  
Benoît Lectez ◽  
Lydie Jeandel ◽  
Fatima-Zohra El-Yamani ◽  
Sébastien Arthaud ◽  
David Alexandre ◽  
...  
Keyword(s):  
Food Intake ◽  
Neuropeptide Y ◽  
Energy Homeostasis ◽  
Arcuate Nucleus ◽  
Central Administration ◽  
Inhibitory Effects ◽  
Hybridization Procedure ◽  
First Time ◽  
G Protein Coupled

26RFa is a hypothalamic RFamide neuropeptide that was identified as the endogenous ligand of the orphan G protein-coupled receptor, GPR103, and that stimulates appetite in mice. Up until now, the mechanism of action of 26RFa in the hypothalamic control of food intake remains unknown. The high density of GPR103 in the arcuate nucleus (Arc) prompted us to investigate, in the present study, the effects of 26RFa on the rat neuropeptide Y (NPY)/proopiomelanocortin (POMC) system. Intracerebroventricular injection of 26RFa stimulated NPY expression and release in the basal hypothalamus, whereas it decreased POMC expression and α-MSH release, and these effects were associated with an increase in food intake. A double in situ hybridization procedure indicated that the 26RFa receptor is present in NPY neurons of the Arc, but not in POMC neurons. Central administration of NPY Y1 and Y5 receptor antagonists abolished the inhibitory effects of 26RFa on POMC expression and α-MSH release, and reversed 26RFa-induced food consumption. Finally, 26RFa antagonized the effects of leptin on NPY expression and release, POMC expression and α-MSH release, and food intake. Altogether, the present data demonstrate for the first time that 26RFa exerts its orexigenic activity by stimulating the release of NPY in the Arc, which in turn inhibits POMC neurons by activating the Y1 and Y5 receptors. It is also suggested that the balance 26RFa/leptin is an important parameter in the maintenance of energy homeostasis.

scholarly journals Neuropeptide Y1 and Y5 Receptors Mediate the Effects of Neuropeptide Y on the Hypothalamic-Pituitary-Thyroid Axis

Endocrinology ◽  
2002 ◽  
Vol 143 (12) ◽  
pp. 4513-4519 ◽  
Author(s):  
Csaba Fekete ◽  
Sumit Sarkar ◽  
William M. Rand ◽  
John W. Harney ◽  
Charles H. Emerson ◽  
...  
Keyword(s):  
Thyroid Hormone ◽  
Food Intake ◽  
Neuropeptide Y ◽  
Paraventricular Nucleus ◽  
Receptor Agonist ◽  
Pituitary Thyroid Axis ◽  
Thyroid Axis ◽  
Ad Libitum ◽  
Thyroid Hormone Levels ◽  
Hpt Axis

Abstract Neuropeptide Y (NPY) is one of the most important hypothalamic-derived neuropeptides mediating the effects of leptin on energy homeostasis. Central administration of NPY not only markedly stimulates food intake, but simultaneously inhibits the hypothalamic-pituitary-thyroid axis (HPT axis), replicating the central hypothyroid state associated with fasting. To identify the specific NPY receptor subtypes involved in the action of NPY on the HPT axis, we studied the effects of the highly selective Y1 ([Phe7,Pro34]pNPY) and Y5 ([chicken pancreatic polypeptide1–7, NPY19–23, Ala31, Aib32 (aminoisobutyric acid), Q34]human pancreatic polypeptide) receptor agonists on circulating thyroid hormone levels and proTRH mRNA in hypophysiotropic neurons of the hypothalamic paraventricular nucleus. The peptides were administered continuously by osmotic minipump into the cerebrospinal fluid (CSF) over 3 d in ad libitum-fed animals and animals pair-fed to artificial CSF (aCSF)-infused controls. Both Y1 and Y5 receptor agonists nearly doubled food intake compared with that of control animals receiving aCSF, similar to the effect observed for NPY. NPY, Y1, and Y5 receptor agonist administration suppressed circulating levels of thyroid hormones (T3 and T4) and resulted in inappropriately normal or low TSH levels. These alterations were also associated with significant suppression of proTRH mRNA in the paraventricular nucleus, particularly in the Y1 receptor agonist-infused group [aCSF, NPY, Y1, and Y5 (density units ± sem), 97.2 ± 8.6, 39.6 ± 8.4, 19.9 ± 1.9, and 44.6 ± 8.4]. No significant differences in thyroid hormone levels, TSH, or proTRH mRNA were observed between the agonist-infused FSanimals eating ad libitum and the agonist-infused animals pair-fed with vehicle-treated controls. These data confirm the importance of both Y1 and Y5 receptors in the NPY-mediated increase in food consumption and demonstrate that both Y1 and Y5 receptors can mediate the inhibitory effects of NPY on the HPT axis.

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