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Am J Physiol Regul Integr Comp Physiol 289: R353-R358, 2005. First published April 7, 2005; doi:10.1152/ajpregu.00756.2004
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Physiological Regulation of Appetite

Ghrelin is an orexigenic and metabolic signaling peptide in the arcuate and paraventricular nuclei

Paul J. Currie,1 Aaisha Mirza,1 Rebecca Fuld,1 Diana Park,1 and Joseph R. Vasselli2

1Department of Psychology, Barnard College, Columbia University, New York, New York; and 2New York Obesity Research Center, St. Luke's-Roosevelt Hospital Center, New York, New York

Submitted 5 November 2004 ; accepted in final form 5 April 2005


   ABSTRACT
TOP
 ABSTRACT
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
Ghrelin is a 28-amino acid acylated peptide and is the endogenous ligand for the growth hormone secretagogue receptor (GHS-R). The GHS-R is expressed in hypothalamic nuclei, including the arcuate nucleus (Arc) where it is colocalized with neuropeptide Y (NPY) neurons. In the present study, we examined the effects of ghrelin on feeding and energy substrate utilization (respiratory quotient; RQ) following direct injections into either the arcuate or the paraventricular nucleus (PVN) of the hypothalamus. Ghrelin was administered at the beginning of the dark cycle at doses of 15–60 pmol to male and female rats. In feeding studies, food intake was measured 2 and 4 h postinjection. Separate groups of rats were injected with ghrelin, and the RQ (CO2/O2) was measured using an open circuit calorimeter over a 4-h period. Both Arc and PVN injections of ghrelin increased food intake in male and female rats. Ghrelin also increased RQ, reflecting a shift in energy substrate utilization in favor of carbohydrate oxidation. Because these effects are similar to those observed after PVN injection of NPY, we then assessed the impact of coinjecting ghrelin with NPY into the PVN. When rats were pretreated with very low doses of ghrelin (2.5–10 pmol), NPY's (50 pmol) effects on eating and RQ were potentiated. Overall, these data are in agreement with evidence suggesting that ghrelin functions as a gut-brain endocrine hormone implicated in the regulation of food intake and energy metabolism. Our findings are also consistent with a possible interactive role of hypothalamic ghrelin and NPY systems.

energy substrate utilization; food intake; hypothalamus; respiratory quotient

GHRELIN IS THE ENDOGENOUS ligand for an orphan G-protein-coupled receptor, growth hormone secretagogue receptor (GHS-R) (34, 58). Both rat and human ghrelin peptides consist of 28 amino acids differing only in two residues, and both are modified at serine 3 by n-octanoic acid. (34, 58). The fatty acid (n-octanolyl) side chain at serine 3 is a unique biochemical characteristic associated with its bioactivity and identifies the peptide hormone as an endogenous factor unique in mammalian biology (29). In situ hybridization and immunohistochemical analyses indicate that ghrelin-containing cells are a distinct endocrine cell type localized in the mucosal epithelium of the stomach (18, 21, 48).

Recent evidence suggests that the gastric peptide plays a particularly important role in the regulation of energy homeostasis and that this role is exerted at the level of the central nervous system (CNS). Central injections of ghrelin elicit food intake (4, 8, 24, 68), and chronic ventricular administration to rodents induces body weight gain and enhanced body fat mass deposition (28, 64). Indeed, ghrelin appears to interact with other peptidergic systems within the hypothalamus, including neuropeptide Y/agouti-related peptide (NPY/AGRP) neurons of the arcuate nucleus (Arc) (25, 61, 67). This latter finding suggests that hypothalamic nuclei may be key sites of action for the peptide. In support of this hypothesis, a limited number of microinjections studies, including our own data, indicate that ghrelin administration into discrete hypothalamic nuclei stimulates appetite and/or energy metabolism (16, 37, 66, 68). Ghrelin's orexigenic action is comparable to that of NPY in magnitude (62, 68), and similar changes in nutrient partitioning have been reported with neuropeptide Y (NPY) (11–17). Paraventricular nucleus (PVN) injections of NPY evoke a marked increase in respiratory quotient (RQ), independent of its feeding stimulant effects (10–17, 38). Interestingly, compared with peripheral treatment, ghrelin alters food intake and body weight greater than 1,000-fold more potently after central administration (28), consistent with the hypothesis that the peptide influences energy homeostasis predominantly through the stimulation of central mechanisms. Moreover, these effects are observed using physiologically relevant doses (64).

On the basis of such findings, we propose that ghrelin alters appetite and energy metabolism, including the promotion of carbohydrate oxidation and the conservation of fat stores, by an action on hypothalamic circuits mediating positive energy balance. In the present study, we examined the effects of ghrelin administration in two key regions of the hypothalamus, the Arc and PVN, to examine the peptide's effects on food intake and energy substrate use as measured by indirect calorimetry. We also examined a possible interactive role for ghrelin and NPY on these measures.


   MATERIALS AND METHODS
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 ABSTRACT
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
Subjects. Adult male Sprague-Dawley rats weighing 275–325 g at the time of surgery were purchased from Charles River Laboratories (Wilmington, MA). Rats were housed individually in polypropylene cages with free access to standard rodent food (Purina) and water. The colony room was maintained at a temperature of 22 ± 2 °C and on a 12:12-h light-dark cycle.

Apparatus. Oxygen consumption (O2) and carbon dioxide (CO2) production were measured using an Oxyscan open-circuit indirect calorimeter (AccuScan Instruments, Columbus, OH). Detectors measured O2 and CO2 sequentially across each acrylic test chamber. A constant flow rate of 1,500 ml/min was established. Concentrations of the gases were recorded in milliliters per kilogram body weight per minute. RQ was calculated as the volume of CO2 produced (CO2) divided by the volume of O2 consumed (O2). Analyzers were calibrated before each use with primary gas standards of high purity (Matheson, New York, NY).

Surgery. Chronic indwelling guide cannulas (steel 22-gauge; Plastics One, Roanoke, VA) were implanted in all animals aimed at either the Arc or the PVN. Rats were anesthetized with ketamine (75 mg/kg ip) and xylazine (5 mg/kg ip) and placed in a Kopf stereotaxic apparatus with the incisor bar set at 3.5 mm below the interaural line. Cannulas were implanted 4 mm dorsal to target, as described previously (14, 15) according to the following coordinates (43) relative to bregma: Arc AP –2.3 mm, L –0.3 mm, V –5.8 mm; PVN AP –1.8 mm, L –0.4 mm, V –4.0 mm. Each implant was secured with acrylic cement, and three stainless screws penetrated the skull. Guide cannulas were fitted with 28-gauge stainless steel stylets to maintain patency. All rats were administered 0.4 mg/kg subcutaneously of the analgesic buprenorphine at the time of surgery and once again 12 h later. Testing began after a postoperative recovery period of 10 days. During this time, food intake and body weights were monitored, and animals were familiarized with the injection and testing procedures.

Design and procedure. Male and female rats were injected with ghrelin or vehicle just before the beginning of the nocturnal cycle. Ghrelin was administered at doses of 15, 30, and 60 pmol, in a 0.3-µl volume and dissolved in sterile saline. A repeated-measures design was used with all rats receiving each dose of peptide or vehicle, administered in a randomized order. A minimum of 4 days separated successive testing. In feeding studies (n = 9/group), rats were tested in their home cages and food intake, corrected for spillage, was measured 2 and 4 h postinjection. In metabolic testing (n = 8), identical injection procedures were followed. Immediately after treatment, rats were placed in individual chambers of the metabolic apparatus, where O2 consumption and CO2 production were measured over 4 h. Food and water were not available during this time.

In separate groups of male and female rats with cannulas aimed at the PVN, ghrelin (2.5, 5, or 10 pmol), or vehicle was administered 5 min before injection of NPY (50 pmol) or vehicle. NPY administration coincided with the start of the dark cycle. Feeding (n = 9) and metabolic (n = 8) protocols were identical to the above paradigms, except that food intake and RQ were measured over 2 h postinjection. Again, injections were separated by 4 days with treatments conducted in randomized order. In the control condition, rats received two injections of sterile saline. Ghrelin and NPY coinjections were examined in the PVN alone since only PVN injections of NPY are reported to alter RQ (10–17, 38).

Statistical and histological analyses. Data were analyzed using two- and three-way repeated-measures ANOVA followed by post hoc analysis of individual mean comparisons where appropriate. The criterion for statistical significance was P < 0.05. The accuracy of all cannula placements was confirmed via histological assessment as described previously (11, 15). Sections were examined by light microscopy and viewed relative to the stereotaxic atlas of Paxinos and Watson (43). All animals reported here were found to have injector tracts extending into the appropriate target nucleus.


   RESULTS
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 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
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Figures 1 and 2 depict the dose-response effects of ghrelin in male and female rats after injection into either the Arc or PVN of the hypothalamus. Ghrelin increased food intake when administered into the Arc of male and female rodents [F(1,14) = 56.6, P < 0.0001]. A similar effect on food intake was observed upon injection into the PVN [F(1,14) = 146.1, P < 0.0001]. Intake was significantly increased at both 2 and 4 h into the dark period. The effect of ghrelin on energy substrate use is illustrated in Fig. 3 and Fig. 4. RQ values are shown in 40 min intervals across 4 h. When injected into either the Arc [F(144,1,008) = 9.8, P < 0.0001] or PVN [F(144,1,008) = 50.5, P < 0.0001], ghrelin elicited an increase in RQ within the first 20–40 min of testing. The potentiation began to decline to near control values by the end of the 4-h test. Although all doses of ghrelin reliably increased RQ, for clarity, only the 30-pmol dose is depicted graphically. No sex differences were observed.



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  		Fig. 1. Food intake in male (A) and female (B) rats after ghrelin injection into the arcuate nucleus (Arc). Data represent mean intakes ± SE measured at 2 h and 4 h. *P < 0.05 compared with vehicle.

 


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  		Fig. 2. Food intake in male (A) and female (B) rats following microinjection of ghrelin into the paraventricular nucleaus (PVN). Values represent mean intakes ± SE measured at 2 h and 4 h. *P < 0.05 compared with vehicle (VEH).

 


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  		Fig. 3. Mean ± SE respiratory quotient (RQ) following Arc injection of ghrelin (30 pmol) in male and female rodents measured over 4 h.

 


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  		Fig. 4. Mean ± SE RQ after PVN administration of ghrelin (30 pmol) in male and female rats measured over 4 h.

 
The impact of ghrelin pretreatment on eating elicited by PVN NPY is illustrated in Fig. 5. Significance is represented compared with NPY paired with vehicle. Note that while the vehicle-vehicle condition is not shown, NPY (paired with vehicle) did significantly increase food intake. In both male and female rats, PVN injections of ghrelin potentiated or enhanced eating resulting from NPY treatment [F(4,64) = 78.1, P < 0.001]. In male rats, this occurred at all doses of ghrelin, including low doses of 2.5 and 5 pmol, which we have previously reported to be subthreshold (16). Pilot work in this study also confirmed their ineffectiveness in stimulating eating or altering RQ when injected alone (data not shown). In female rats, both the 5-pmol and 10-pmol doses were effective in potentiating NPY-elicited eating. Similarly, as shown in Fig. 6, PVN injections of ghrelin enhanced the effect of NPY on RQ in male [F(72,504) = 202.19, P < 0.0001] and female [F(72,504) = 96.4, P < 0.001] rodents, respectively. That is, NPY alone increased RQ, and this increase was enhanced by ghrelin pretreatment (all doses for both sexes). For clarity of illustration, only the 5-pmol dose of ghrelin is shown graphically, and values are given in 20-min intervals. The potentiation was evident within 40 min of injection and persisted throughout the remainder of the 2-h test session.



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  		Fig. 5. Food intake mean ± SE over the initial 2 h of the dark cycle following PVN injections of ghrelin and neuropeptide Y (NPY; 50 pmol). *P < 0.05 compared with NPY paired with vehicle.

 


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  		Fig. 6. Mean ± SE RQ after PVN administration of ghrelin (5 pmol) and NPY (50 pmol) in male (A) and female (B) rats measured over 2 h.

 

   DISCUSSION
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
GRANTS
 REFERENCES
 
In the present study, ghrelin stimulated eating when injected into the Arc and PVN. This effect was observed in both male and female rats. Additionally, ghrelin injections into these same anatomical sites within the hypothalamus altered energy substrate utilization as reflected in an increase in RQ. The elevation in RQ elicited by Arc and PVN injections of ghrelin, to values near or exceeding 1.0, indicates that the peptide acts locally to promote carbohydrate oxidation and fat storage (7, 33). The diversion of metabolism away from fat oxidation in favor of carbohydrate use and fat synthesis, and its orexigenic action, are in fact consistent with the effects of NPY administration into the PVN (10–12, 15). Indeed, our findings demonstrate that ghrelin enhances the feeding stimulant action of NPY and potentiates NPY's effects on RQ, and we did not observe any sex-related differences.

Ghrelin binds to a G-protein coupled receptor, the GHS-R, which has two subtypes, 1a and 1b, and their sequences do not show significant homology with other known receptors (58). The GHS-R 1a is believed to be highly conserved across species, and the human 1a subtype shares 96% identity with the rat 1a receptor (58). Although ghrelin and synthetic GHS bind with high affinity to the GHS1a receptor, this is not the case with the GHS1b, and the functional role of the 1b receptor remains poorly defined (30, 41). Expression for the GHS1a receptor is reported in the hypothalamus and anterior pituitary (30, 56). Recently, a transgenic rat model overexpressing antisense oligonucleotides against the GHS-R 1a was reported to exhibit decreased food intake and lower body fat (57), consistent with ghrelin's hypothesized positive action on energy balance.

The precise mechanism of action of ghrelin in energy homeostasis remains controversial. Circulating ghrelin is derived largely from the stomach and intestine (18, 21, 48). If ghrelin readily crosses the blood-brain barrier, then peripheral ghrelin might be expected to activate hypothalamic receptors. However, Banks et al. (5) suggest that the quantity of ghrelin transport in the blood to brain direction appears negligible (5). In a recent study, the expression patterns of ghrelin in the hypothalamus were measured (9). Expression of ghrelin was localized to a novel, previously uncharacterized cell group. These neurons are adjacent to the third ventricle and localized between the PVN, Arc, ventromedial hypothalamus, and dorsomedial hypothalamus. Their axonal projections target key hypothalamic circuits producing NPY, AGRP, proopiomelanocortin (POMC) and corticotropin releasing hormone (CRH) in both the Arc and PVN. The identification of this novel distribution of ghrelin provides strong support for a unique role of hypothalamic ghrelin in eating and energy metabolism in addition to its documented role as a peripheral orexigenic peptide. Therefore, at the level of the Arc and PVN, ghrelin may stimulate the release of orexigenic neurotransmitters controlling energy balance and metabolic function. Cowley et al. (9) have also reported that within the hypothalamus, ghrelin binds largely to presynaptic NPY terminals and stimulates the activity of ARC NPY neurons; its actions within the PVN parallel or resemble those of PVN NPY. It seems likely that this close relationship between Arc and PVN NPY underlies the potentiation of NPY's feeding and RQ effects observed in the present study.

Indeed, our current understanding of the involvement of hypothalamic systems in metabolic regulation indicates that a complex network of neuropeptide and transmitter systems are involved (51, 53, 54, 60). It is also clear that extrahypothalamic mechanisms participate in the process (53, 54). Within the hypothalamus, distinct effects on food intake and energy metabolism have been reported in discrete regions or nuclei. In addition to the effects of NPY described above, some of the other appetite-stimulating neuropeptides include melanin concentrating hormone, hypocretins/orexins, AGRP, CRH and urocortin (6, 19, 44, 49). AGRP is coproduced with NPY in the same Arc neurons (23, 36, 42). Appetite-suppressive neuropeptides include the POMC derivative, {alpha}-melanocyte-stimulating hormone ({alpha}MSH), and cocaine and amphetamine-related transcript, coproduced in a separate population of Arc neurons. (1, 26, 40, 59). Leptin receptors have been localized to the hypothalamus, particularly the Arc nucleus, where they exert primary feedback signaling by influencing the production of appetite-stimulating and inhibiting peptides (20, 22, 39, 69). Interestingly, ghrelin also appears to act on these same leptin-responsive neurons in the rat Arc, and it is now proposed that ghrelin-sensitive circuits are dynamically regulated by leptin (27).

During food deprivation, leptin levels rapidly decline (50), and the production of NPY and AGRP is enhanced, while POMC neuronal activity is suppressed (45–47, 50, 52). At the same time, circulating ghrelin levels increase (2, 64, 65), possibly augmenting the action of leptin by directly activating Arc NPY/AGRP neurons and inhibiting POMC neurons. Thus circulating ghrelin and leptin, although responding to food deprivation in an inverse manner, may regulate hypothalamic peptidergic systems, directed at preventing further energy deficit. Moreover, whereas plasma levels of ghrelin decrease in obesity, leptin levels increase (29, 31, 59, 64, 65), reflecting a physiological adaptation to a state of positive energy balance.

With respect to specific hypothalamic peptidergic circuits, as outlined above, recent attention has focused in large part on Arc neurons producing {alpha}-MSH, an anorectic peptide that enhances energy expenditure (42) and their interrelationship with Arc neurons producing both NPY and AGRP (36). AGRP is an endogenous antagonist of {alpha}-MSH (36). The interaction of these two distinct populations of neurons is considered significant in the regulation of energy homeostasis. It is proposed that these two major hypothalamic pathways mediate the action of ghrelin on energy balance (41, 55, 63). Ghrelin itself increases AGRP and NPY mRNA levels in the hypothalamus (32). Conversely, the orexigenic action of ghrelin is abolished or reduced by NPY Y1 receptor antagonism, melanocortin agonists, and antisera to both NPY and AGRP (3, 55, 63). Consistent with a direct action on hypothalamic structures, ICV ghrelin administration activates c-Fos expression in multiple hypothalamic areas, including the Arc, PVN, dorsomedial nucleus, and lateral hypothalamus (35).

Although relatively few studies have examined the effects of ghrelin on appetite after direct microinjection into CNS tissue (16, 24, 37, 66, 68), our findings extend current knowledge of the anatomical sites of action within the hypothalamus wherein ghrelin acts to alter feeding and energy metabolism, and where the peptide interacts with NPY mechanisms. Overall, our data are consistent with the hypothesis that ghrelin alters appetite and energy metabolism, including the promotion of carbohydrate oxidation and the conservation of fat stores, by an action on hypothalamic circuits mediating positive energy balance.


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 ABSTRACT
 MATERIALS AND METHODS
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This work is supported by National Institutes of Health Grants MH-070496–01A1 to P. J. Currie and the Undergraduate Biological Sciences Education Program of the Howard Hughes Medical Institute.


   FOOTNOTES
 

Address for reprint requests and other correspondence: P. J. Currie, Dept. of Psychology, Barnard College, Columbia Univ., New York, New York 10027 (E-mail: pjc37{at}columbia.edu)

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.


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  1. Ahima RS and Osei SY. Molecular regulation of eating behavior: new insights and prospects for therapeutic strategies. Trends Mol Med 7: 205–213, 2001.[CrossRef][Web of Science][Medline]
  2. Arvat E, Maccario M, Di Vito L, Broglio F, Benso A, Gottero C, Papotti M, Muccioli G, Dieguez C, Casanueva FF, Deghenghi R, Camanni F, and Ghigo E. Endocrine activities of ghrelin, a natural growth hormone secretagogue (GHS), in humans: comparison and interactions with hexarelin, a nonnatural peptidyl GHS, and GH-releasing hormone. J Clin Endocrinol Metab 86: 1169–1174, 2001.[Abstract/Free Full Text]
  3. Asakawa A, Inui A, Kaga T, Katsuura G, Fujimiya M, Fujino MA, and Kasuga M. Antagonism of ghrelin receptor reduces food intake and body weight gain in mice. Gut 52: 947–952, 2003.[Abstract/Free Full Text]
  4. Asakawa A, Inui A, Kaga T, Yuzuriha H, Nagata T, Ueno N, Makino S, Fujiyama M, Nijina A, Fujino MA, and Kasuga M. Ghrelin is an appetite-stimulatory signal from stomach with structural resemblance to motilin. Gastroenterology 120: 337–345, 2001.[CrossRef][Web of Science][Medline]
  5. Banks WA, Tschöp M, and Heiman ML. Extent and direction of ghrelin transport across the blood-brain barrier is determined by its unique primary structure. J Pharmacol Exp Ther 302: 822–827.
  6. Bittencourt JC, Presse F, Arias C, Peto C, Vaughan J, Nahon JL, Vale W, and Sawchenko PE. The melanin-concentrating hormone system of the rat brain: an immuno-and hybridization histochemical characterization. J Comp Neurol 319: 218–245, 1992.[CrossRef][Web of Science][Medline]
  7. Bray GA. Nutrient balance and obesity: an approach to control of food intake in humans. Med Clin North Am 73: 29–45, 1989.[Medline]
  8. Broglio F, Gottero C, Arvat E, and Ghigo E. Endocrine and nonendocrine actions of ghrelin. Horm Res 59: 109–117, 2003.[CrossRef][Web of Science][Medline]
  9. Cowley MA, Smith RG, Diano S, Tschöp M, Pronchuk N, Grove KL, Strasberger CJ, Bidlingmaier M, Esterman M, Heiman ML, Garcia-Segura LM, Nillni EA, Mendez P, Low MJ, Sotonyi P, Friedman JM, Liu H, Pinto S, Colmers WF, Cone RD, and Horvath TL. The distribution and mechanism of action of ghrelin in the CNS demonstrates a novel hypothalamic circuit regulating energy homeostasis. Neuron 37: 649–661, 2003.[CrossRef][Web of Science][Medline]
  10. Currie PJ. Integration of hypothalamic feeding and metabolic signals: focus on neuropeptide Y. Appetite 41: 335–337, 2003.[CrossRef][Medline]
  11. Currie PJ, Coiro CD, Niyomchai T, Lira A, and Farahmand F. Hypothalamic paraventricular 5-hydroxytryptamine: receptor specific inhibition of NPY stimulated eating and energy metabolism. Pharmacol Biochem Behav 72: 709–716, 2002.[CrossRef]
  12. Currie PJ, Coscina DV, Bishop C, Coiro CD, Koob GF, Rivier J, and Vale W. Hypothalamic paraventricular injections of urocortin alter food intake and respiratory quotient. Brain Res 916: 222–228, 2001.[CrossRef][Web of Science][Medline]
  13. Currie PJ and Coscina DV. 5-Hydroxytryptaminergic receptor agonists: Effects on neuropeptide Y potentiation of feeding and respiratory quotient. Brain Res 803: 212–217, 1998.[Medline]
  14. Currie PJ and Coscina DV. Stimulation of 5-HT2A/2C receptors within specific hypothalamic nuclei differentially antagonizes NPY-induced feeding. Neuroreport 8: 3759–3762, 1997.[Web of Science][Medline]
  15. Currie PJ and Coscina DV. Regional hypothalamic differences in neuropeptide Y-induced feeding and energy substrate utilization. Brain Res 737: 238–242, 1996.[CrossRef][Web of Science][Medline]
  16. Currie PJ, Mirza A, Fuld R, and Vasselli JR. Metabolic and orexigenic action of ghrelin following microinjection into the arcuate and paraventricular nuclei of the hypothalamus (CD-ROM). Program No. 283.16 Abstract Viewer/Itineray Planner. Washington, DC: Society for Neuroscience.
  17. Currie PJ, Saxena N, and Tu AY. 5-HT2A/2C antagonists in the paraventricular nucleus attenuate the action of DOI on NPY stimulated eating. Neuroreport 10: 3033–3036, 1999.[Medline]
  18. Date Y, Kojima M, Hosoda H, Sawaguchi A, Mondal MS, Suganama T, Matsukura S, Kanagawa K, and Nakazato M. Ghrelin, a novel growth hormone-releasing acylated peptide, is synthesized in a distinct endocrine cell type in the gastrointestinal tracts of rats and humans. Endocrinology 141: 4255–4261, 2000.[Abstract/Free Full Text]
  19. De Lecea L, Kilduff TS, Peyron C, Gao X, Foye PE, Danielson PE, Fukuhara C, Battenberg EL, Gautvik VT, Bartlett FS, Frankel WN, van den Pol AN, Bloom FE, Gautvik KM, and Sutcliffe JG. The hypocretins: two hypothalamic peptides with neuroexcitatory activity. Proc Natl Acad Sci USA 95: 322–327, 1998.[Abstract/Free Full Text]
  20. Diano S, Kalra SP, and Horvath TL. Leptin receptor immunoreactivity is associated with the golgi apparatus of hypothalamic cells. J Neuroendocrinol 9: 647–650, 1998.
  21. Dornoville de la Cour C, Bjorkqvist M, Sandvik AK, Bakke I, Zhao CM, Chen D, and Hakanson R. A-like cells in the rat stomach contain ghrelin and do not operate under gastrin control. Regul Pept 99: 141–150, 2001.[CrossRef][Web of Science][Medline]
  22. Elmquist JK, Bjorbaek C, Ahima RS, Flier JS, and Saper CB. Distributions of leptin receptor mRNA isoforms in the rat brain. J Comp Neurol 395: 535–547, 1998.[CrossRef][Web of Science][Medline]
  23. Fan W, Boston BA, Kesterson RA, Hruby VJ, and Cone RD. Role of melanocortinergic neurons in feeding and the agouti obesity syndrome. Nature 385:165–168, 1997.[CrossRef][Medline]
  24. Faulconbridge LF, Cummings DE, Kaplan JM, and Grill HJ. Hyperphagic effects of brainstem ghrelin administration. Diabetes 52: 2260–2265, 2003.[Abstract/Free Full Text]
  25. Guan XM, Yu H, Palyha OC, McKee KK, Feighner SD, Sirinathsinghi DJ, Smith RG, Van der Ploeg LH, and Howard AD. Distribution of mRNA encoding the growth hormone secretagogue receptor in brain and peripheral tissues. Brain Res Mol Brain Res 48: 23–29, 1997.[Medline]
  26. Hahn TM, Breininger JF, Baskin DG, and Schwartz MW. Coexpression of Agrp and NPY in fasting-activated hypothalamic neurons. Nature Neurosci 1: 271–272, 1998.[CrossRef][Web of Science][Medline]
  27. Hewson AK, Tung LYC, Connell DW, Tookman L, and Dickson SL. The rat arcuate nucleus integrates peripheral signals provided by leptin, insulin, and a ghrelin mimetic. Diabetes 51: 3412–3419, 2002.[Abstract/Free Full Text]
  28. Horvath TL, Castaneda T, Tang-Christensen M, Pagotto U, and Tschöp M. Ghrelin as a potential anti-obesity target. Curr Pharm Des 9: 1383–1395, 2003.[CrossRef][Web of Science][Medline]
  29. Hosoda H, Kojima Matsuo M, H, and Kanagawa K. Ghrelin and des-acyl ghrelin: two major forms of rat ghrelin peptide in gastrointestinal tissue. Biochem Biophys Res Commun 279: 909–913, 2000.[CrossRef][Web of Science][Medline]
  30. Howard HD, Feighner SD, Cully DF, Arena JP, Liberator PA, Rosenblum CI, Hamelin M, Hreniuk DL, Palyha OC, Anderson J, Paress PS, Diaz C, Chou M, Liu KK, McKee KK, Pong SS, Chaung LY, Elbrecht A, Dashkevicz M, Heavens R, Rigby M, Sirinathsinghji DJS, Dean DC, Melillo DG, Patchett AA, Nargund R, Griffith PR, DeMartino JA, Gupta SK, Shaeffer JM, Smith RG, and Van der Ploeg LHT. A receptor in pituitary and hypothalamus that functions in growth hormone release. Science 273: 974–976, 1996.[Abstract]
  31. Kalra SP, Dube MG, Pu S, Xu B, Horvath TL, and Kalra PS. Interacting appetite-regulating pathways in the hypothalamic regulation of body weight. Endocr Rev 20: 68–100, 1999.[Abstract/Free Full Text]
  32. Kamegai J, Tamura H, Shimizu T, Ishii S, Sugihara H, and Wakabayashi I. Chronic central infusion of ghrelin increases hypothalamic neuropeptide Y and Agouti-related protein mRNA levels and body weight in rats. Diabetes 50: 2438–2443, 2001.[Abstract/Free Full Text]
  33. Kleiber M. The Fire of Life: An Introduction to Animal Energetics. New York: Kreiger, 1975.
  34. Kojima M, Hosoda H, Date Y, Nakazato M, Matsuo H, and Kanagawa K. Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature 402: 656–660, 1999.[CrossRef][Medline]
  35. Lawrence CB, Snape AC, Baudoin FMH, and Luckman SM. Acute central ghrelin and GH secretagogues induce feeding and activate brain appetite centers. Endocrinology 143: 155–162, 2002.[Abstract/Free Full Text]
  36. Lu D, Willard D, Patel IR, Kadwell S, Overton L, Kost T, Luther M, Chen W, Woychik RP, and Wilkison WO. Agouti protein is an antagonist of the melanocyte-stimulating-hormone receptor. Nature 371: 799–802, 1994.[CrossRef][Medline]
  37. Melis MR, Mascia MS, Succu S, Torsello A, Muller EE, Deghenghi R, and Argiolas A. Ghrelin injection into the paraventricular nucleus of the hypothalamus of male rats induces feeding but not penile erection. Neurosci Lett 329: 339–343, 2002.[Medline]
  38. Menendez JA, McGregor IS, Healey PA, and Atrens DM. Metabolic effects of neuropeptide Y injections into the paraventricular nucleus of the hypothalamus. Brain Res 516: 8–14, 1990.[CrossRef][Web of Science][Medline]
  39. Mercer JG, Hoggard N, Williams LM, Lawrence CB, Hannah LT, and Trayhurn P. Localization of leptin receptor mRNA and the long splice variant (O-Rb) in mouse hypothalamus and adjacent brain regions by in situ hybridization. FEBS Lett 387:113–116, 1996.[CrossRef][Web of Science][Medline]
  40. Mezey E, Kiss JZ, Mueller GP, Eskay R, Odonohue TL, and Palkovits M. Distribution of pro-opiomelanocortin derived peptides, adrenocorticotrope hormone, {alpha}-melanocyte-stimulating hormone and {beta}-endorphin (ACTH, {alpha}-MSH, {beta}-END) in the rat hypothalamus. Brain Res 328: 341–347, 1985.[CrossRef][Web of Science][Medline]
  41. Muccioli G, Tschöp M, Papotti M, Deghenghi R, Heiman M, and Ghigo E. Neuroendocrine and peripheral activities of ghrelin: implications in metabolism and obesity. Eur J Endocrinol 440: 235–254, 2002.[CrossRef]
  42. Ollmann MM, Wilson BD, Yang YK, Kerns JA, Chen Y, Gantz I, and Barsh GS. Antagonism of central melanocortin receptors in vitro and in vivo by agouti-related protein. Science 278: 135–138, 1997.[Abstract/Free Full Text]
  43. Paxinos G and Watson C. The Rat Brain in Stereotaxic Coordinates. New York: Academic Press, 1998.
  44. Qu D, Ludwig DS, Gammeltoft S, Piper M, Pelleymounter MA, Cullen MJ, Mathes WF, Przypek R, Kanarek R, and Maratos-Flier, E. A role for melanin-concentrating hormone in the central regulation of feeding behavior. Nature 380: 243–247, 1996.[CrossRef][Medline]
  45. Sahu A, Kalra PS, and Kalra SP. Food deprivation and ingestion induced reciprocal changes in neuropeptide Y concentrations in the paraventricular nucleus. Peptides 9: 83–86, 1988.[CrossRef][Web of Science][Medline]
  46. Sahu A, White JD, Kalra PS, and Kalra SP. Hypothalamic neuropeptide Y gene expression in rats on scheduled feeding regimen. Mol Brain Res 15: 15–18, 1992.[Medline]
  47. Sahu A. Evidence suggesting that galanin (GAL), melanin-concentrating hormone (MCH), neurotensin (NT), proopiomelanocortin (POMC) and neuropeptide Y (NPY) are targets of leptin signaling in the hypothalamus. Endocrinology 139: 795–798, 1998.[Abstract/Free Full Text]
  48. Sakata I, Nakamura K, Yamazaki M, Matsubara M, Hayashi Y, Kanagawa K, and Sakai T. Ghrelin-producing cells exist in two types of cells, closed- and opened-type cells, in the rat gastrointestinal tract. Peptides 23: 531–536, 2002.[CrossRef][Web of Science][Medline]
  49. Sakurai T, Amemiya A, Ishii Matsuzaki M, I, Chemelli RM, Tanaka H, Williams SC, Richarson JA, Kozlowski GP, Wilson S, Arch JR, Buckingham RE, Haynes AC, Carr SA, Annan RS, McNulty DE, Liu WS, Terrett JA, Elshourbagy NA, Bergsma DJ, and Yanagisawa M. Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior. Cell 92: 573–585, 1998.[CrossRef][Web of Science][Medline]
  50. Saladin R, De Vos P, Geurre-Millo M, Leturque A, Girard J, Staels B, and Auwerx J. Transient increase in obese gene expression after food intake or insulin administration. Nature 377: 527–529, 1995.[CrossRef][Medline]
  51. Schwartz MW and Seeley RJ. Seminars in medicine of the Beth Israel Deaconess Medical Center. Neuroendocrine responses to starvation and weight loss. N Engl J Med 336: 1802–1811, 1997.[Free Full Text]
  52. Schwartz MW, Seeley Woods RJ, S, Weigle DS, Campfield LA, Burn P, and Baskin DG. Leptin increases hypothalamic pro-opiomelanocortin mRNA expression in the rostral arcuate nucleus. Diabetes 46: 2119–2123, 1997.[Abstract]
  53. Schwartz MW, Woods S, Porte D, Seeley RJ, and Baskin DG. Central nervous system controls food intake. Nature 404: 661–671, 2000.[Medline]
  54. Seeley RJ and Schwartz MW. The regulation of energy balance: peripheral hormonal signals and hypothalamic neuropeptides. Curr Dir Psych Sci 6: 39–44, 1997.
  55. Shintani M, Ogawa Y, Ebihara K, Aizwa-Abe M, Miyanaga F, Takaya K, Hayashi T, Inoue G, Hosoda K, Kojima M, Kangawa K, and Nakao K. Ghrelin, an endogenous growth hormone secretagogue, is a novel orexigenic peptide that antagonizes leptin action through the activation of hypothalamic neuropeptide Y/Y1 receptor pathway. Diabetes 50: 227–232, 2001.[Abstract/Free Full Text]
  56. Shuto Y, Shibasaki T, Wada K, Parhar I, Kamegai J, Sugihara H, Oikawa S, and Wakabayashi I. Generation of polyclonal antiserum against the growth hormone secretagogue receptor (GHS-R). Evidence the GHS-R exists in the hypothalamus, pituitary and stomach of rats. Life Sci 68: 991–996, 2001.[CrossRef][Web of Science][Medline]
  57. Shuto Y, Shibasaki T, Otagiri A, Kuriyama H, Ohata H, Tamara H, Kamegai J, Sugihara H, Oikawa S, and Wakabayashi I. Hypothalamic growth hormone secretagogue receptor regulates growth hormone secretion feeding and adiposity. J Clin Invest 109: 1429–1436, 2002.[CrossRef][Web of Science][Medline]
  58. Smith RG, Leonard R, Bailey AR, Palyha O, Feighner S, Tan C, McKee KK, Pong SS, Griffin P, and Howard A. Growth hormone secretagogue receptor family members and ligands. Endocrine 14: 9–14, 2001.[CrossRef][Medline]
  59. Spiegelman BM and Flier JS. Obesity and the regulation of the energy balance. Cell 104: 656–660, 2001.
  60. Stanley BG. Neuropeptide Y in multiple hypothalamic sites controls eating behavior, endocrine and autonomic systems for body energy balance. In: The Biology of Neuropeptide Y and Related Peptides, edited by Colmers WF and Wahlestedt C. Totowa, NJ: Humana Press, 1993.
  61. Tannenbaum GS, Lapointe Beaudet M, A, and Howard AD. Expression of growth hormone secretagogue-receptors by growth hormone-releasing hormone neurons in the mediobasal hypothalamus. Endocrinology 139: 4420–4423, 1998.[Abstract/Free Full Text]
  62. Torsello A, Locatelli V, Mellis MR, Succu S, Spano MS, Deghenghi R, Muller EE, and Argiolas A. Differential orexigenic effects of hexarelin and its analogs in the rat hypothalamus: indication for multiple growth hormone secretagogue receptor subtypes. Neuroendocrinology 72: 327–332, 2000.[CrossRef][Web of Science][Medline]
  63. Tschöp M, Statnick ML, Suter T, and Heiman ML. Adipogenic effect of a ghrelin receptor antagonist: lessons from mice lacking neuropeptide Y. Endocrinology 143: 558–568, 2002.[Abstract/Free Full Text]
  64. Tschöp M, Smiley DL, and Heiman ML. Ghrelin induces adiposity in rodents. Nature 407: 908–913, 2000.[CrossRef][Medline]
  65. Tschöp M, Weyer C, Tataranni PA, Devanarayan V, Ravussin E, and Heiman ML. Circulating ghrelin levels are decreased in human obesity. Diabetes 50: 707–709, 2001.[Abstract/Free Full Text]
  66. Tucci SA, Rogers EK, Korbonits M, and Kirkham TC. The cannabinoid CB1 receptor antagonist SR141716 blocks the orexigenic effects of intrahypothalamic ghrelin. Br J Pharmacol 143: 520–523, 2004.[CrossRef]
  67. Willesen MG, Kristensen P, and Romer J. Co-localization of growth hormone secretagogue receptor and NPY mRNA in the arcuate nucleus of the rat. Neuroendocrinology 70: 306–316, 1999.[CrossRef][Web of Science][Medline]
  68. Wren AM, Small CJ, Abbott CR, Dhillo WS, Seal LJ, Cohen MA, Batterham RL, Taheri S, Stanley SA, Ghatei MA, and Bloom SR. Ghrelin causes hyperphagia and obesity in rats. Diabetes 50: 2540–2547, 2001.[Abstract/Free Full Text]
  69. Yarnell DO, Knight DS, Hamilton K, Tulp O, and Tso P. Localization of leptin receptor immunoreactivity in the lean and obese zucker rat brain. Brain Res 785: 80–90, 1998.[CrossRef][Web of Science][Medline]



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