Co-Localization of Growth Hormone Secretagogue Receptor and NPY mRNA in the Arcuate Nucleus of the Rat

Willesen, Mette Georgi; Kristensen, Peter; Rømer, John

doi:10.1159/000054491

Cited by 549 publications

(364 citation statements)

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“…The rats were weighed every 3 days from the beginning of the experiment until they were killed. The rat groups (each group consisted of at least five rats) were killed at days 8,12,16,19, and 21 of gestation under anesthesia.…”

Section: Animals and Study Designmentioning

confidence: 99%

Effect of Food Restriction on Ghrelin in Normal‐Cycling Female Rats and in Pregnancy

et al. 2002

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GUALILLO, ORESTE, JORGE E. CAMINOS, RUBÉ N NOGUEIRAS, LUISA M. SEOANE, EVA ARVAT, EZIO GHIGO, FELIPE F. CASANUEVA, AND CARLOS DIÉ GUEZ. Effect of food restriction on ghrelin in normalcycling female rats and in pregnancy. Obes Res. 2002;10: 682-687. Objective: Ghrelin is a 28-amino-acid acylated peptide that was recently identified as the endogenous ligand for the growth hormone secretagogue receptor. Previous studies have shown that ghrelin potently increases growth hormone release and food intake. The aim of this study was to clarify the physiological implications of ghrelin in the regulation of energy balance, by assessing the effect of undernutrition throughout 21 days in normal-cycling and pregnant rats on ghrelin. Research Methods and Procedures:We have determined ghrelin levels by radioimmunoassay and gastric ghrelin mRNA expression by Northern blot analysis during 21 days of chronic food restriction (30% of ad libitum available diet) in normal-cycling female rats and in pregnancy. Results: Our results show that chronic food restriction led to an increase in plasmatic ghrelin levels in normal-cycling female rats. In pregnancy, ghrelin plasmatic levels were enhanced particularly during the latter part of gestation (19 and 21 days) compared with pregnant rats with free access to food. Gastric ghrelin mRNA expression showed a similar expression pattern, being higher in the food-restricted group than in the group fed ad libitum, in normal-cycling as well as in pregnant rats.Discussion: These observations indicate that ghrelin plasmatic levels and ghrelin gastric mRNA are up-modulated during undernutrition in normal-cycling rats and in pregnancy. These findings suggest that increased ghrelin levels may have a role in mediating the physiological responses to undernutrition and could represent an adaptative response to prevent long-lasting alterations in energy balance and body weight homeostasis.

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Section: Animals and Study Designmentioning

confidence: 99%

Effect of Food Restriction on Ghrelin in Normal‐Cycling Female Rats and in Pregnancy

et al. 2002

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“…Supporting the possibility that ghrelin acts as a key regulator of appetite and food intake by actions on the hypothalamus, GHS-R is colocalized with neuropeptide Y (NPY)͞agouti-related protein (AgRP) neurons (12) in the arcuate nucleus, a region that is responsive to circulating peripheral nutrients and hormones and critically involved in the regulation of food intake (13). Indeed, ghrelin stimulates the spontaneous activity of these neurons (14), and central ghrelin administration increases NPY and AgRP gene expression (15).…”

mentioning

confidence: 99%

Genetic deletion of ghrelin does not decrease food intake but influences metabolic fuel preference

Wortley

Anderson²,

García³

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

415

325

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Ghrelin is a recently identified growth hormone (GH) secretogogue whose administration not only induces GH release but also stimulates food intake, increases adiposity, and reduces fat utilization in mice. The effect on food intake appears to be independent of GH release and instead due to direct activation of orexigenic neurons in the arcuate nucleus of the hypothalamus. The effects of ghrelin administration on food intake have led to the suggestion that inhibitors of endogenous ghrelin could be useful in curbing appetite and combating obesity. To further study the role of endogenous ghrelin in appetite and body weight regulation, we generated ghrelin-deficient (ghrl ؊/؊ ) mice, in which the ghrelin gene was precisely replaced with a lacZ reporter gene. ghrl ؊/؊ mice were viable and exhibited normal growth rates as well as normal spontaneous food intake patterns, normal basal levels of hypothalamic orexigenic and anorexigenic neuropeptides, and no impairment of reflexive hyperphagia after fasting. These results indicate that endogenous ghrelin is not an essential regulator of food intake and has, at most, a redundant role in the regulation of appetite. However, analyses of ghrl ؊/؊ mice demonstrate that endogenous ghrelin plays a prominent role in determining the type of metabolic substrate (i.e., fat vs. carbohydrate) that is used for maintenance of energy balance, particularly under conditions of high fat intake.G hrelin is a 28-aa peptide produced predominantly in the stomach (1, 2) that has recently been identified as a ligand of the growth hormone (GH) secretogogue (GHS) receptor (GHS-R). Like other GHSs, activation of the receptor stimulates GH secretion from the pituitary gland (1). In addition to inducing GH release, administration of exogenous ghrelin also stimulates food intake and body weight gain (3-7), increases gastric motility and acid secretion (8, 9), and decreases lipid metabolism in mice and rats (3, 4). The effects of centrally administered ghrelin on food intake are independent of its ability to induce GH release and thought to result from its direct actions on the arcuate nucleus of the hypothalamus. Furthermore, recent studies have demonstrated that plasma ghrelin levels increase preceding meals and during fasting (10, 11). Thus, it has been suggested that ghrelin stimulates appetite and that inhibitors of endogenous ghrelin, therefore, could prove useful in reducing food intake and combating obesity (11).Supporting the possibility that ghrelin acts as a key regulator of appetite and food intake by actions on the hypothalamus, GHS-R is colocalized with neuropeptide Y (NPY)͞agouti-related protein (AgRP) neurons (12) in the arcuate nucleus, a region that is responsive to circulating peripheral nutrients and hormones and critically involved in the regulation of food intake (13). Indeed, ghrelin stimulates the spontaneous activity of these neurons (14), and central ghrelin administration increases NPY and AgRP gene expression (15). Moreover, ghrelin-immunoreactivity has been reported in the h...

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“…11 The arcuate is a dense site of insulin receptor expression, and a site of glucose-responsive neurons as well. More recently, arcuate NPY neurons have been demonstrated to express growth hormone secretagogue receptor (GHS-R) or ghrelin receptor, 12 the receptor for the appetite stimulatory factor, ghrelin, produced by the stomach. 13,14 Additionally, the arcuate is a unique hypothalamic site expressing fatty acid synthase, and has been proposed as a site sensitive to intermediates of fatty acid metabolism.…”

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confidence: 99%

The arcuate nucleus as a conduit for diverse signals relevant to energy homeostasis

et al. 2001

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Arcuate nucleus neurons are known to be responsive to a wide array of hormones and nutrients, including leptin, insulin, gonadal steroids and glucose. In addition to potential transport mechanisms, peripheral substances may access these neurons via arcuate cell bodies in and projections to the median eminence, a region considered to be a circumventricular organ. The arcuate is a potent site of leptin action, probably mediating a component of leptin's effects via arcuate neuropeptide Y=agouti-related peptide (NPY=AgRP) and pro-opiomelanocortin (POMC) neurons, and implicating this structure in the long-term control of energy stores. However, ghrelin, the endogenous ligand of the growth hormone secretagogue receptor, may also stimulate feeding and weight gain, in part through action on receptors in arcuate NPY neurons. Since ghrelin is secreted by the stomach upon content depletion, with a half-life of no more than an hour, the arcuate nucleus may also be important in sensing and responding to acute changes in nutrients. We have developed a system for recording from arcuate POMC neurons using a mouse containing a transgene in which the POMC promoter is driving expression of the green fluorescent protein (GFP). In these mice, 99% of the b-endorphin positive neurons express GFP, making whole cell patch clamp recordings from the sparsely distributed POMC neurons facile. All of the POMC neurons appear to be activated by leptin, via two different mechanisms, while approximately 30 -50% of the neurons appear to be inhibited by a gamma-melanocyte stimulating hormone (MSH) specific agonist. The latter result suggests that the melanocortin-3 receptor (MC3-R) may act as an autoinhibitory receptor on some POMC neurons. This hypothalamic slice preparation also confirms the responsiveness of arcuate POMC neurons to a wide variety of nutrients and hormones. Thus the arcuate melanocortin system is best described as a conduit of many diverse signals involved in energy homeostasis, with leptin acting tonically to regulate the responsiveness of the circuit to a wide variety of hormones and nutrients.

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Co-Localization of Growth Hormone Secretagogue Receptor and NPY mRNA in the Arcuate Nucleus of the Rat

Cited by 549 publications

References 33 publications

Effect of Food Restriction on Ghrelin in Normal‐Cycling Female Rats and in Pregnancy

Effect of Food Restriction on Ghrelin in Normal‐Cycling Female Rats and in Pregnancy

Genetic deletion of ghrelin does not decrease food intake but influences metabolic fuel preference

The arcuate nucleus as a conduit for diverse signals relevant to energy homeostasis

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