scholarly journals Functional requirement of AgRP and NPY neurons in ovarian cycle-dependent regulation of food intake

2009 ◽  
Vol 106 (37) ◽  
pp. 15932-15937 ◽  
Author(s):  
Louise E. Olofsson ◽  
Andrew A. Pierce ◽  
Allison W. Xu
Keyword(s):  
Food Intake ◽  
Estrous Cycle ◽  
Estrogen Receptor Alpha ◽  
Ovarian Cycle ◽  
Central Administration ◽  
Related Protein ◽  
17Β Estradiol ◽  
Cycle Dependent ◽  
Cyclic Changes ◽  
Agouti Related Protein

In female mammals including rodents and humans, feeding decreases during the periovulatory period of the ovarian cycle, which coincides with a surge in circulating estrogen levels. Ovariectomy increases food intake, which can be normalized by estrogen treatment at a dose and frequency mimicking those during the estrous cycle. Furthermore, administration of estrogen to rodents potently inhibits food intake. Despite these well-known effects of estrogen, neuronal subtypes that mediate estrogen's anorexigenic effects have not been identified. In this study, we show that changes in hypothalamic expression of agouti-related protein (Agrp) and neuropeptide Y (Npy) coincide with the cyclic changes in feeding across the estrous cycle. These cyclic changes in feeding are abolished in mice with degenerated AgRP neurons even though these mice cycle normally. Central administration of 17β-estradiol (E2) decreases food intake in controls but not in mice lacking the AgRP neurons. Furthermore, E2 treatment suppresses fasting-induced c-Fos activation in AgRP and NPY neurons and blunts the refeeding response. Surprisingly, although estrogen receptor alpha (ERα) is the key mediator of estrogen's anorexigenic effects, we find that expression of ERα is completely excluded from AgRP and NPY neurons in the mouse hypothalamus, suggesting that estrogen may regulate these neurons indirectly via presynaptic neurons that express ERα. This study indicates that neurons coexpressing AgRP and NPY are functionally required for the cyclic changes in feeding across estrous cycle and that AgRP and NPY neurons are essential mediators of estrogen's anorexigenic function.

scholarly journals Endogenous Melanocortin Antagonist in Fish: Structure, Brain Mapping, and Regulation by Fasting of the Goldfish Agouti-Related Protein Gene

Endocrinology ◽  
2003 ◽  
Vol 144 (10) ◽  
pp. 4552-4561 ◽  
Author(s):  
José Miguel Cerdá-Reverter ◽  
Richard Ector Peter
Keyword(s):  
Energy Balance ◽  
Food Intake ◽  
Brain Mapping ◽  
Arcuate Nucleus ◽  
Mrna Levels ◽  
Central Administration ◽  
Related Protein ◽  
Melanocortin Peptides ◽  
Agouti Related Protein ◽  
Tuberal Nucleus

Agouti-related protein (AGRP) is a naturally occurring antagonist of melanocortin. In mammals, central AGRP expression is restricted to the arcuate nucleus in which it plays a key role in the control of energy balance by antagonizing melanocortin effects at melanocortin 4 receptors. In goldfish, melanocortin 4 receptor is profusely expressed within the main brain areas for the control of energy balance, and central administration of agonist or antagonist analogs inhibits or stimulates food intake, respectively. Here we demonstrate that the goldfish genome has a homologous gene to mammalian AGRP. Detailed brain mapping by in situ hybridization shows that AGRP is exclusively expressed in the ventrobasal hypothalamic lateral tuberal nucleus, the teleostean homolog of the arcuate nucleus. Fasting up-regulates its mRNA levels in the lateral tuberal nucleus. In the periphery, AGRP is expressed in several tissues including ovary, muscle, and ventral skin, suggesting that AGRP might regulate peripheral actions of melanocortin peptides. The results provide the first evidence for an endogenous melanocortin antagonist in nontetrapod species and suggest that hypothalamic overexpression during fasting might regulate the inhibitory effects of melanocortin peptides on food intake in goldfish.

scholarly journals Central Administration of Ghrelin and Agouti-Related Protein (83–132) Increases Food Intake and Decreases Spontaneous Locomotor Activity in Rats

Endocrinology ◽  
2004 ◽  
Vol 145 (10) ◽  
pp. 4645-4652 ◽  
Author(s):  
Mads Tang-Christensen ◽  
Niels Vrang ◽  
Sylvia Ortmann ◽  
Martin Bidlingmaier ◽  
Tamas L. Horvath ◽  
...  
Keyword(s):  
Physical Activity ◽  
Locomotor Activity ◽  
Food Intake ◽  
Current Model ◽  
Peptide Hormone ◽  
Dependent Manner ◽  
Central Administration ◽  
Related Protein ◽  
Agouti Related Protein

Abstract Ghrelin was recently identified as an endogenous ligand of the GH secretagogue receptor. The novel peptide hormone is produced by gastric A-like cells, and circulating levels rise before feeding, suggestive of ghrelin as an endogenous hunger factor. ghrelin stimulates food intake and promotes adiposity after peripheral or central administration, likely by activating hypothalamic neurons expressing the orexigenic neuropeptides neuropeptide Y (NPY) and agouti-related protein (AGRP). To examine whether ghrelin-induced feeding resembles NPY and AGRP [AGRP fragment (83–132)] induced orexia, we compared the short- and long-term orexigenic capacity of the three peptides. A single intracerebroventricular injection of ghrelin (0.2, 1.0, and 5.0 μg) increased food intake in a dose-dependent manner. A prolonged and uncompensated increase in feeding was seen after the highest dose of ghrelin. The prolonged effects on feeding (+72 h) closely resembled those of AGRP (83–132) but not NPY. Surprisingly, ghrelin injections reduced overall locomotor activity by 20% during the first 24-h observation period. AGRP (83–132) had similar effects on locomotor behavior, whereas NPY had no effect. In summary, ghrelin causes long-term increases of food intake and, like AGRP, plays a previously unknown role as a suppressor of spontaneous physical activity. Expanding the current model of food intake control to include mechanisms regulating physical activity may promote our understanding of two major etiological factors causing obesity.

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.

Intraventricular melanin-concentrating hormone stimulates water intake independent of food intake

2003 ◽  
Vol 284 (2) ◽  
pp. R494-R499 ◽  
Author(s):  
Deborah J. Clegg ◽  
Ellen L. Air ◽  
Stephen C. Benoit ◽  
Randall S. Sakai ◽  
Randy J. Seeley ◽  
...  
Keyword(s):  
Food Intake ◽  
Water Intake ◽  
Historical Data ◽  
Critical Role ◽  
The Other ◽  
Related Protein ◽  
Melanin Concentrating Hormone ◽  
Access To Water ◽  
Agouti Related Protein ◽  
Dark Portion

The lateral hypothalamus (LH) has a critical role in the control of feeding and drinking. Melanin-concentrating hormone (MCH) is an orexigenic peptidergic neurotransmitter produced primarily in the LH, and agouti-related protein (AgRP) is an orexigenic peptidergic neurotransmitter produced exclusively in the arcuate (ARC), an area that innervates the LH. We assessed drinking and eating after third ventricular (i3vt) administration of MCH and AgRP. MCH (2.5, 5, and 10 μg i3vt) significantly increased food as well as water intake over 4 h when administered during either the light or the dark portion of the day-night cycle. When MCH (5 μg) was administered to rats with access to water but no food, they drank significantly more water than when given the vehicle. AgRP (7 μg i3vt), on the other hand, increased water intake but only in proportion to food intake during the dark and the light, and water intake was not increased after i3vt AgRP in the absence of food. Hence, in contrast to AgRP, MCH elicits increased water intake independent of food intake. These results are consistent with historical data linking activity of the LH with water as well as food intake.

scholarly journals Paraventricular Nucleus Administration of Calcitonin Gene-Related Peptide Inhibits Food Intake and Stimulates the Hypothalamo-Pituitary-Adrenal Axis

Endocrinology ◽  
2003 ◽  
Vol 144 (4) ◽  
pp. 1420-1425 ◽  
Author(s):  
Waljit S. Dhillo ◽  
Caroline J. Small ◽  
Preeti H. Jethwa ◽  
Sabina H. Russell ◽  
James V. Gardiner ◽  
...  
Keyword(s):  
Food Intake ◽  
Hpa Axis ◽  
Male Rats ◽  
Mrna Levels ◽  
Related Protein ◽  
Melanocyte Stimulating Hormone ◽  
Calcitonin Gene ◽  
Agouti Related Protein ◽  
Prior Administration

Abstract Calcitonin gene-related protein (CGRP) inhibits food intake and stimulates the hypothalamo-pituitary-adrenal (HPA) axis after intracerebroventricular injection in rats. However, the hypothalamic site and mechanism of action are unknown. We investigated the effects of intraparaventricular nucleus administration (iPVN) of CGRP on food intake and the HPA axis in rats and the effect of CGRP on the release of hypothalamic neuropeptides in vitro. In addition, we investigated the effects of food deprivation on hypothalamic CGRP expression. CGRP dose-dependently reduced food intake in the first hour after iPVN injection in fasted male rats (saline, 5.1 ± 0.8 g; 0.3 nmol CGRP, 1.1 ± 0.5 g; P < 0.001 vs. saline). iPVN injection of CGRP8–37 (a CGRP1 receptor antagonist) alone had no effect on food intake. However, the reduction in food intake by iPVN CGRP was attenuated by prior administration of CGRP8–37 [CGRP8–37 (10 nmol)/CGRP (0.3 nmol), 3.0 ± 0.8 g; P < 0.05 vs. 0.3 nmol CGRP]. CGRP (100 nm) stimulated the release of α-melanocyte stimulating hormone, cocaine- and amphetamine-related transcript, corticotropin-releasing hormone, and arginine vasopressin from hypothalamic explants to 127 ± 19%, 148 ± 10%, 158 ± 17%, and 198 ± 21% of basal levels, respectively (P < 0.05 vs. basal), but did not alter the release of either neuropeptide Y or agouti-related protein. Hypothalamic CGRP mRNA levels in 24-h fasted rats were increased to 130 ± 8% of control levels [CGRP mRNA (arbitrary units), 4.75 ± 0.4; controls, 3.65 ± 0.34; P < 0.05]. Our data suggest that CGRP administered to the PVN inhibits food intake and stimulates the HPA axis.

scholarly journals Agouti-Related Protein Is Posttranslationally Cleaved by Proprotein Convertase 1 to Generate Agouti-Related Protein (AGRP)83–132: Interaction between AGRP83–132 and Melanocortin Receptors Cannot Be Influenced by Syndecan-3

Endocrinology ◽  
2006 ◽  
Vol 147 (4) ◽  
pp. 1621-1631 ◽  
Author(s):  
John W. M. Creemers ◽  
Lynn E. Pritchard ◽  
Amy Gyte ◽  
Philippe Le Rouzic ◽  
Sandra Meulemans ◽  
...  
Keyword(s):  
Food Intake ◽  
Core Body Temperature ◽  
Full Length ◽  
Related Protein ◽  
Amino Terminal ◽  
Terminal Domain ◽  
Carboxyl Terminal ◽  
Agouti Related Protein

Agouti-related protein (AGRP) plays a key role in energy homeostasis. The carboxyl-terminal domain of AGRP acts as an endogenous antagonist of the melanocortin-4 receptor (MC4-R). It has been suggested that the amino-terminal domain of AGRP binds to syndecan-3, thereby modulating the effects of carboxyl-terminal AGRP at the MC4-R. This model assumes that AGRP is secreted as a full-length peptide. In this study we found that AGRP is processed intracellularly after Arg79-Glu80-Pro81-Arg82. The processing site suggests cleavage by proprotein convertases (PCs). RNA interference and overexpression experiments showed that PC1/3 is primarily responsible for cleavage in vitro, although both PC2 and PC5/6A can also process AGRP. Dual in situ hybridization demonstrated that PC1/3 is expressed in AGRP neurons in the rat hypothalamus. Moreover, hypothalamic extracts from PC1-null mice contained 3.3-fold more unprocessed full-length AGRP, compared with wild-type mice, based on combined HPLC and RIA analysis, demonstrating that PC1/3 plays a role in AGRP cleavage in vivo. We also found that AGRP83–132 is more potent an antagonist than full-length AGRP, based on cAMP reporter assays, suggesting that posttranslational cleavage is required to potentiate the effect of AGRP at the MC4-R. Because AGRP is cleaved into distinct amino-terminal and carboxyl-terminal peptides, we tested whether amino-terminal peptides modulate food intake. However, intracerebroventricular injection of rat AGRP25–47 and AGRP50–80 had no effect on body weight, food intake, or core body temperature. Because AGRP is cleaved before secretion, syndecan-3 must influence food intake independently of the MC4-R.

The role of photoperiod on the expression of hypothalamic genes regulating appetite in Chevrier’s field mouse (Apodemus chevrieri)

2015 ◽  
Vol 65 (1) ◽  
pp. 45-56 ◽  
Author(s):  
Lin Zhang ◽  
Fang Yang ◽  
Jinhong Cai ◽  
Chunmei Huang ◽  
Zhengkun Wang ◽  
...  
Keyword(s):  
Food Intake ◽  
Neuropeptide Y ◽  
Mrna Expression ◽  
Physiological Role ◽  
Field Mouse ◽  
Related Protein ◽  
Serum Leptin ◽  
Significant Difference ◽  
Agouti Related Protein

The hypothalamus and leptin play a key role in the regulation of food intake. The present study investigated the effects of 4 weeks of short- or long-photoperiod on serum leptin levels and food intake in relation to mRNA expression levels of neuropeptide Y, agouti-related protein, pro-opiomelanocortin, and cocaine- and amphetamine-regulated transcript in the hypothalamus of Chevrier’s field mouse (Apodemus chevrieri). There was a significant difference in body fat mass, food intake and neuropeptide Y mRNA expression between the two groups, but serum leptin level, agouti-related protein, pro-opiomelanocortin, and cocaine- and amphetamine-regulated transcript mRNA expression in the hypothalamus were not difference between the two groups. The elevation of neuropeptide Y mRNA regulated neuropeptides in the hypothalamus suggests a physiological role of neuroendocrine factors in food intake during the different photoperiod. We conclude that leptin may be involved in energy balance and body mass regulation.

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.

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