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© 2005 The American Society for Nutritional Sciences J. Nutr. 135:1331-1335, May 2005

Symposium: Ghrelin: Its Role in Energy Balance

Stimulation of Appetite by Ghrelin Is Regulated by Leptin Restraint: Peripheral and Central Sites of Action1,2

Satya P. Kalra*,3, Naohiko Ueno{dagger} and Pushpa S. Kalra**

* Department of Neuroscience, University of Florida McKnight Brain Institute, Gainesville, FL 32610-0244; {dagger} Division of Diabetes, Digestive & Kidney Disease, Department of Clinical Molecular Medicine, Kobe University Graduate School of Medicine, 7–5-1 Kusunoki, Cho, Chuo-Ky, Kobe, Japan; and ** Department of Physiology & Functional Genomics, University of Florida, Gainesville, FL 32610-0274

3To whom correspondence should be addressed. E-mail: skalra{at}mbi.ufl.edu.


   ABSTRACT
TOP
 ABSTRACT
CONCLUSIONS
 LITERATURE CITED
 
A reciprocal rhythmic pattern of 2 afferent hormonal signals, anorexigenic leptin and orexigenic ghrelin, imparts rhythmicity to the neuropeptide Y (NPY) system, the final common pathway for appetite expression in the hypothalamus. We now show that leptin inhibits both the secretion of gastric ghrelin and the stimulation of feeding by ghrelin. We propose that this dual leptin restraint is the major regulatory arm of the feedback communication between the periphery and the hypothalamus for weight homeostasis, and disruption in the rhythmic communication at any locus in the leptin-ghrelin-NPY feedback loop impels loss of hypothalamic control, leading to abnormal weight gain and obesity.

KEY WORDS: • ghrelin • leptin • rhythms • restraint • obesity

Daily meal patterning is a highly regulated phenomenon. In vertebrates, the intermittent feeding pattern is integrated in the hypothalamus wherein the effector pathways transduce information from metabolic, neural, and hormonal signals and the circadian clock to initiate and terminate a meal (1,2). An interconnected appetite-regulating network (ARN)4 (3) of neuropeptide Y (NPY) and cohorts in the hypothalamic arcuate nucleus-paraventricular nucleus (ARC-PVN) axis is apparently the primary neuroanatomical substrate for elaborating and emitting orexigenic and anorexigenic signals in circadian and ultradian rhythmic patterns (1–4). Various studies show that reciprocal rhythmicities in 2 peripheral hormones, anorexigenic leptin from adipocytes and orexigenic ghrelin from the stomach, are the major afferent signals for the timely activation of the ARN (2,4–6) (Fig. 1). Our concerted efforts to delineate feedback communication between the periphery and ARN for maintenance of energy homeostasis on a daily basis has provided new insights at several fronts. These include: 1) existence of a temporal causal relation between rhythmic NPY secretion in the ARC-PVN axis and rhythmic afferent hormonal feedback signals (2,5–8), 2) evidence that derangement in onset, periodicity, duration, or magnitude of afferent feedback signaling imposes a corresponding abnormality in periodic NPY discharge that precedes excessive energy intake and fat accretion (3,4,8), 3) identification of leptin as the primary signal that concurrently augments nonshivering thermogenesis and restrains the orexigenic effects of ghrelin at central and peripheral targets (9–13).



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  		FIGURE 1 The dynamics in the feedback circuitry involved in integration of energy intake and expenditure are shown. NPY, GABA, and AgrP produced and released in the ARC-PVN axis regulate the daily episodic pattern of feeding. The 2 rhythmic patterns of NPY release (ultradian and circadian) are directed by 2 functionally opposing rhythmic afferent hormonal signals—leptin from adipocytes and ghrelin from the stomach. Also depicted is the rhythmic feedback relation in the adipocyte-stomach-pancreas axis. {Rightarrow} restraint on orexigenic effects of ghrelin; (+) = stimulatory, (–) = inhibitory, (±) and ? = unresolved. For details see text. Reprinted with permission from ref. (2).

 
These major findings, derived from measurement of dynamic minute-to-minute fluctuations of various signals, correction of central deficits by gene transfer in vivo, and temporal sequencing of molecular and cellular events engaged in initiation and termination of daily meal patterning are summarized in this article.

Ghrelin: a peripheral and central orexigen

Among a spectrum of peripheral afferent hormonal signals examined so far, ghrelin is currently the only known hormone to readily stimulate feeding and promote adiposity after peripheral administration (1,2,14,15). In addition, the ghrelin produced by neurons in the subparaventricular zone of the hypothalamus is also believed to be orexigenic within the ARN (16). Several lines of evidence suggest that ghrelin may serve as one of the physiologically relevant signals in stimula-tion of episodic feeding. A premeal rise in circulating ghrelin levels (17–20), attenuated feeding following pharmacologic suppression of action of this antecedent rise (21), and decline in ghrelin secretion postprandially (22) are in accord with this notion. Perhaps the strongest evidence is provided by the dynamic secretion patterns of ghrelin in accordance with fluctuations in energy reserves. Ghrelin is normally secreted in an episodic fashion (5) (Fig. 2). In sated rats, ghrelin secretory episodes consist of low-amplitude pulses discharged at a regular frequency of about 2 episodes/h. However, robust appetitive drive elicited by the negative energy balance after food deprivation coincides with high-amplitude pulses at accelerated frequency of about 3 episodes/h. Thus, when energy intake and expenditure are balanced, ghrelin secretion is restrained but reduced energy resources rapidly curb this restraint to allow increased episodic ghrelin discharge (5). What are the neural and hormonal signals that propagate rhythmic ghrelin secretion preceding feeding and accelerated rhythms in response to energy insufficiency? Does leptin, an anorexigen, modulate ghrelin secretion?



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  		FIGURE 2 Representative profiles of pulsatile ghrelin secretion in individual AD (ad libitum, solid circles) and food-deprived rats (empty circles). The mean number of pulses, amplitudes, and interpulse intervals in the 2 groups are also depicted. Arrows here and in Figure 3 indicate peaks. *P < 0.05 vs. AD group. Reprinted with permission from ref. (5).

 
Leptin: a peripheral regulator of ghrelin secretion

Rhythmic fluctuations in circulating levels of leptin in sated rats and in response to shifts in energy balance experimentally have also been observed (5,6). Leptin is secreted in a pulsatile manner with a frequency of discharge similar to that of ghrelin (5,6) (Fig. 3). However, in marked contrast to the acceleration in ghrelin secretion, energy deprivation diminishes leptin pulse amplitude, thereby diminishing overall leptin output (5) (Fig. 3). A reciprocal relation between circulating ghrelin and leptin is also seen normally on a daily basis in rats. Premeal ghrelin hypersecretion at the onset of dark-phase ingestive behavior and preceding the time of food availability in a scheduled feeding paradigm is coincident with low circulating levels of leptin (19,23). On the other hand, a gradual rise in leptin hypersecretion precedes the postprandial decline in ghrelin secretion (19,22,23).



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  		FIGURE 3 Representative profiles of pulsatile leptin pattern in individual AD (solid circles) and food-deprived rats (empty circles). The mean number of pulses, amplitudes, and interpulse intervals in the 2 groups are also depicted. *P < 0.05 vs. AD group. Reprinted with permission from (5).

 
We have observed a reciprocal relation in ghrelin and leptin secretion in 2 additional experimental paradigms aimed at increasing or decreasing adiposity. In outbred Sprague-Dawley rats consuming a diet high in energy, the obesity-prone (OP) group of rats displayed accelerated weight gain in a time-related fashion, whereas the obesity-resistant (OR) group maintained weight in the range of control rats consuming normal rat diet (24,25). Analysis of the rhythmic leptin and ghrelin secretion in these rats showed that only the OP rats rapidly developed hyperleptinemia characterized by high-amplitude leptin episodic discharge (24), accompanied by drastically suppressed ghrelin episodes. Leptin and ghrelin secretion patterns were unchanged in OR and control rats. These findings raised the possibility that hyperleptinemia may suppress ghrelin secretion and this may account for the reported suppressed ghrelin secretion in obese patients and rats (12,13,18).

There is also an opposing relation, ghrelin hypersecretion in conjunction with leptinopenia in another experimental model. A nonpathogenic and replicative deficient vector, recombinant adeno-associated virus encoding the leptin gene (rAAV-lep), injected either intracerebroventricularly or microinjected into discrete hypothalamic sites of normal or diet-induced obese rats and mice, suppressed weight gain and adiposity and markedly suppressed circulating leptin levels for over 1 y duration of the experiments (11,13,25–29). Quite unexpectedly, we uniformly observed ghrelin hypersecretion accompanying the prolonged and severe leptinopenia and loss of adiposity in these rats and mice. Remarkably, despite markedly increased circulating ghrelin level in these rAAV-lep-treated rats and mice, food intake was suppressed. Evidently, a central restraint on the appetite-stimulating effects of ghrelin in these leptin transgene–expressing rats and mice was in effect.

Leptinopenia concomitant with increased episodic ghrelin secretion in food-deprived and rAAV-lep treated mice on the one hand and hyperleptinemia associated with diminished intermittent ghrelin output in obese mice on the other, together with the reciprocal relation between these 2 hormones pre- and postprandially, led us to postulate that leptin may exert a tonic restraint on ghrelin secretion from the stomach (12,13). Indeed, in support of this formulation a single systemic leptin injection to rAAV-lep-treated leptinopenic and ghrelin hypersecreting wild-type and ob/ob mice rapidly suppressed ghrelin secretion (12,13) (Fig. 4). In support of this in vivo evidence, leptin also suppresses ghrelin release from isolated stomach in vitro (30).



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  		FIGURE 4 The effect of an i.p. leptin injection on plasma ghrelin, in wild-type (wt, A) and ob/ob (B) mice on d 35–42 post-icv treatment with either rAAV-GFP (green fluorescent protein control) or rAAV-lep. Note the high initial ghrelin levels in wt and ob/ob mice injected with rAAV-lep. *P < 0.05 vs. initial values, #P < 0.05 vs. control (saline) group. Reprinted with permission from ref. (13).

 
Thus, the endocrine cells—adipocytes and oxyntic cells—are endowed with cellular mechanisms to discharge leptin and ghrelin intermittently at a basal rate, and each is vulnerable to modulation by converging metabolic, hormonal, and neural information (2,4–10). Further, an exquisite temporal relation exists between ghrelin and leptin in the periphery, and the restraining influence of leptin on gastric ghrelin output governs the strength of their reciprocal feedback signaling to the hypothalamic ARN (2,4,12,13,24).

Ghrelin and leptin interplay in the ARC-PVN axis for energy homeostasis

The current view holds that gastric ghrelin crosses the blood brain barrier and, in concert with ghrelin produced locally in the hypothalamus, engages the network of NPY and cohorts in the ARC-PVN axis to evoke the appetitive drive (2,31). NPY neurons coexpress ghrelin receptors and the orexigens, agouti-related peptide (AgrP) and {gamma}-aminobutyric acid (GABA) (1–3,8). On the basis of the cumulative evidence that leptinemia after fasting or preceding the onset of a meal is contemporaneous with enhanced pulsatile ghrelin secretion in the periphery as well as NPY synthesis and episodic NPY release in the ARC-PVN axis (7,32) and blockade of ghrelin induced-appetite with NPY Y1 receptor antagonist (14,15), we postulated that appetite stimulation by ghrelin is propagated by dynamic NPY signaling in the ARC-PVN axis (1–4,8). These effects are apparently supplemented by augmented corelease of AgrP because ghrelin is completely ineffective in NPY and AgrP null mice (33). Seemingly, the premeal ghrelin rise triggers a sequence of events in the ARN. Initiation of synthesis in the ARC is followed by the timely release in the PVN of NPY, AgrP, and GABA, which activate Y1/Y5 and GABAA receptors and block MC4 receptors on NPY target neurons in the magnocellular PVN (mPVN, Fig. 1). These sequalae induce a robust appetitive drive (1–4,8,34–38).

A central effect of leptin is to restrain food intake by suppressing NPY synthesis, release, and action in the ARC-PVN axis (1–4). This tonic restraint is mediated through activation of the biologically relevant long form of leptin receptors expressed by NPY neurons in the ARC and by NPY targets sites coexpressing Y1/Y5 receptors in the mPVN (34–37). Is the dynamic site-specific interplay of leptin and ghrelin in the ARC-PVN axis responsible for episodic appetitive drive? Contrary to expectations, we observed that leptinopenic rAAV-lep-treated rats and mice ate less despite markedly elevated blood ghrelin levels (11–13,25,28,29). Because NPY expression in the ARC was drastically suppressed by the locally expressed leptin in these rats and mice (11,26–28), this implied that even a robust peripheral ghrelin signal was incapable of countering the leptin restraint on NPYergic signaling. Indeed, this was the case because exogenous ghrelin that readily stimulated feeding in a dose-dependent manner in control mice was ineffective in mice expressing leptin locally in the hypothalamus (12,13) (Fig. 5). Evidently leptin counteracts the ghrelin-induced activation of NPYergic signaling at the level of the NPY ARC-PVN axis (Fig. 1).



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  		FIGURE 5 The effect of an i.p. ghrelin injection on food intake in untreated and wt mice at 37–49 d post-icv treatment with either rAAV-GFP or rAAV-lep. *P < 0.05 vs. saline group. Reprinted with permission from ref. (13).

 

   CONCLUSIONS
TOP
 ABSTRACT
 CONCLUSIONS
LITERATURE CITED
 
These studies demonstrate that a tonic dual restraint by leptin on gastric ghrelin secretion peripherally and on activation by ghrelin of the orexigenic network of NPY and cohorts centrally is crucial in the dynamic operation of the leptin-ghrelin-NPY feedback loop (Fig. 1). We envision that the daily ebb and flow in the tonic restraint imposed by leptin on peripheral and hypothalamic orexigenic pathways not only generates the daily pattern of energy intake, but also propagates the circadian and, possibly, the ultradian rhythmic patterns of ghrelin and NPY secretion (2–4,39). Further, it is likely that consumption of high-energy diets disrupts 1 or more locus in this feedback communication to culminate in storage of excess energy as fat (1–4,8,24,39). Consequently, to curb the pandemic of obesity, newer interventional therapies should aim at reinstating the physiological homeostatic reciprocal relation between leptin and ghrelin on a moment-to-moment basis.


   FOOTNOTES
 
1 Presented as part of the symposium "Ghrelin: Its Role in Energy Balance" given at the 2004 Experimental Biology meeting on April 19, 2004, Washington, DC. The symposium was sponsored by the American Society for Nutritional Sciences and in part by Abbott Laboratories, Linco Research, Inc., and Merck Research Laboratories. The proceedings are published as a supplement to The Journal of Nutrition. This supplement is the responsibility of the Guest Editors to whom the Editor of The Journal of Nutrition has delegated supervision of both technical conformity to the published regulations of The Journal of Nutrition and general oversight of the scientific merit of each article. The opinions expressed in this publication are those of the authors and are not attributable to the sponsors or the publisher, editor, or editorial board of The Journal of Nutrition. The views expressed herein are those of the authors and do not necessarily reflect those of Abbott Laboratories, Linco Research, Inc., and Merck Research Laboratories. The Guest Editors for the symposium publication are Gary E. Truett, Department of Nutrition, Knoxville, TN, and Elizabeth J. Parks, University of Minnesota, St. Paul, MN. Back

2 Supported by National Institute of Health DK37273 and NS32727. Back

4 Abbreviations used: AgrP, agouti-related peptide; ARC, arcuate nucleus; ARN, appetite-regulating network; GABA, {gamma}-aminobutyric acid; lep, leptin; NPY, neuropeptide Y; OR, obesity resistant; PVN, paraventricular nucleus; rAAV, recombinant adeno-associated virus. Back


   LITERATURE CITED
TOP
 ABSTRACT
 CONCLUSIONS
 LITERATURE CITED
 

1. Kalra, S. P., Dube, M. G., Pu, S., Xu, B., Horvath, T. L. & Kalra, P. S. (1999) Interacting appetite-regulating pathways in the hypothalamic regulation of body weight. Endocr. Rev. 20:68-100.[Abstract/Free Full Text]

2. Kalra, S. P., Bagnasco, M., Otukonyong, E. E., Dube, M. G. & Kalra, P. S. (2003) Rhythmic, reciprocal ghrelin and leptin signaling: new insight in the development of obesity. Regul. Pept. 111:1-11.[Medline]

3. Kalra, S. P. & Kalra, P. S. (2004) NPY: a novel on/off switch for control of appetite and reproduction. Michel, M. C. eds. Neuropeptide Y and Related Peptides 2004:221-249 Springer-Verlag Berlin. .

4. Kalra, S. P. & Kalra, P. S. (2004) Neuropeptide Y: a physiological orexigen modulated by the feedback action of ghrelin and leptin. Endocrine 22:49-56.

5. Bagnasco, M., Kalra, P. S. & Kalra, S. P. (2002) Ghrelin and leptin pulse discharge in fed and fasted rats. Endocrinology 143:726-729.[Abstract]

6. Bagnasco, M., Kalra, P. S. & Kalra, S. P. (2002) Plasma leptin levels are pulsatile in adult rats: effects of gonadectomy. Neuroendocrinology 75:257-263.[Medline]

7. Kalra, S. P., Dube, M. G., Sahu, A., Phelps, C. P. & Kalra, P. S. (1991) Neuropeptide Y secretion increases in the paraventricular nucleus in association with increased appetite for food. Proc. Natl. Acad. Sci. U.S.A. 88:10931-10935.[Abstract/Free Full Text]

8. Kalra, S. P. & Kalra, P. S. (2004) NPY and cohorts in regulating appetite, obesity and metabolic syndrome: beneficial effects of gene therapy. Neuropeptides 38:201-211.[Medline]

9. Kalra, P. S. & Kalra, S. P. (2002) Obesity and metabolic syndrome: long-term benefits of central leptin gene therapy. Prous, J. R. eds. Drugs of Today 2002:745-757 Prous Science Barcelona, Spain. .

10. Kalra, S. P. & Kalra, P. S. (2003) Keeping obesity and metabolic syndrome at bay with central leptin and cytokine gene therapy. Hamilton, I. eds. Current Medicinal Chemistry—Central Nervous System Agent 2003:189-199 Bentham Science Publications Ltd. San Francisco, CA. .

11. Dhillon, H., Ge, Y., Minter, R. M., Prima, V., Moldawer, L. L., Muzyczka, N., Zolotukhin, S., Kalra, P. S. & Kalra, S. P. (2000) Long-term differential modulation of genes encoding orexigenic and anorexigenic peptides by leptin delivered by rAAV vector in ob/ob mice. Relationship with body weight change. Regul. Pept. 92:97-105.[Medline]

12. Ueno, N., Dube, M. G., Katz, A., Kalra, P. S. & Kalra, S. P. (2003) Leptin inhibits ghrelin-induced obesity by two distinct central and peripheral mechanisms: effects on adiponectin. 33rd Annual Society for Neuroscience Meeting, Nov. 8–12, New Orleans, LA 2003.

13. Ueno, N., Dube, M. G., Inui, A., Kalra, P. S. & Kalra, S. P. (2004) Leptin modulates orexigenic effects of ghrelin and attenuates adiponectin and insulin levels and selectively the dark-phase feeding as revealed by central leptin gene therapy. Endocrinology 145:4176-4184.[Abstract/Free Full Text]

14. Nakazato, M., Murakami, N., Date, Y., Kojima, M., Matsuo, H., Kangawa, K. & Matsukura, S. (2001) A role for ghrelin in the central regulation of feeding. Nature 409:194-198.[Medline]

15. Tschop, M., Smiley, D. L. & Heiman, M. L. (2000) Ghrelin induces adiposity in rodents. Nature 407:908-913.[Medline]

16. Cowley, M. A., Smith, R. G., Diano, S., Tschop, M., Pronchuk, N., Grove, K. L., Strasburger, C. J., Bidlingmaier, M., Esterman, M., Heiman, M. L., Garcia-Segura, L. M., Nillni, E. A., Mendez, P., Low, M. J., Sotonyi, P., Friedman, J. M., Liu, H., Pinto, S., Colmers, W. F., Cone, R. D. & Horvath, T. L. (2003) The distribution and mechanism of action of ghrelin in the CNS demonstrates a novel hypothalamic circuit regulating energy homeostasis. Neuron 37:649-661.[Medline]

17. Cummings, D. E., Purnell, J. Q., Frayo, R. S., Schmidova, K., Wisse, B. E. & Weigle, D. S. (2001) A preprandial rise in plasma ghrelin levels suggests a role in meal initiation in humans. Diabetes 50:1714-1719.[Abstract/Free Full Text]

18. Tschop, M., Weyer, C., Tataranni, P. A., Devanarayan, V., Ravussin, E. & Heiman, M. L. (2001) Circulating ghrelin levels are decreased in human obesity. Diabetes 50:707-709.[Abstract/Free Full Text]

19. Crowley, W. R., Ramoz, G., Keefe, D. A., Torto, R. & Kalra, S. P. (2005) Differential effects of methamphetamine on expression of neuropeptide Y mRNA in hypothalamus and on serum leptin and ghrelin concentrations in ad libitum fed and scheduled fed rats. Neuroscience 132:167-173.[Medline]

20. Ariyasu, H., Takaya, K., Tagami, T., Ogawa, Y., Hosoda, K., Akamizu, T., Suda, M., Koh, T., Natsui, K., Toyooka, S., Shirakami, G., Usui, T., Shimatsu, A., Doi, K., Hosoda, H., Kojima, M., Kangawa, K. & Nakao, K. (2001) Stomach is a major source of circulating ghrelin, and feeding state determines plasma ghrelin-like immunoreactivity levels in humans. J. Clin. Endocrinol. Metab. 86:4753-4758.[Abstract/Free Full Text]

21. Asakawa, A., Inui, A., Kaga, T., Katsuura, G., Fujimiya, M., Fujino, M. A. & Kasuga, M. (2003) Antagonism of ghrelin receptor reduces food intake and body weight gain in mice. Gut 52:947-952.[Abstract/Free Full Text]

22. Tschop, M., Wawarta, R., Riepl, R. L., Friedrich, S., Bidlingmaier, M., Landgraf, R. & Folwaczny, C. (2001) Post-prandial decrease of circulating human ghrelin levels. J. Endocrinol. Invest. 24:RC19-RC21.[Medline]

23. Xu, B., Kalra, P. S., Farmerie, W. G. & Kalra, S. P. (1999) Daily changes in hypothalamic gene expression of neuropeptide Y, galanin, proopiomelanocortin, and adipocyte leptin gene expression and secretion: effects of food restriction. Endocrinology 140:2868-2875.[Abstract/Free Full Text]

24. Otukonyong, E. E., Torto, R., Dube, M. G., Luttge, W. G., Kalra, P. S. & Kalra, S. P. (2003) Altered rhythmicity in peripheral hormonal feedback may encode dietary obesity, p. Su–81, abs. 283.10. 33rd Annual Meeting Society for Neuroscience, Nov. 8–12, New Orleans, LA 2003.

25. Bagnasco, M., Dube, M. G., Katz, A., Kalra, P. S. & Kalra, S. P. (2003) Leptin expression in hypothalamic PVN reverses dietary obesity and hyperinsulinemia but stimulates ghrelin. Obes. Res. 11:1463-1470.[Medline]

26. Dhillon, H., Kalra, S. P. & Kalra, P. S. (2001) Dose-dependent effects of central leptin gene therapy on genes that regulate body weight and appetite in the hypothalamus. Mol. Ther. 4:139-145.[Medline]

27. Beretta, E., Dube, M. G., Kalra, P. S. & Kalra, S. P. (2002) Long-term suppression of weight gain, adiposity, and serum insulin by central leptin gene therapy in prepubertal rats: effects on serum ghrelin and appetite-regulating genes. Pediatr. Res. 52:189-198.[Medline]

28. Bagnasco, M., Dube, M. G., Kalra, P. S. & Kalra, S. P. (2002) Evidence for the existence of distinct central appetite and energy expenditure pathways and stimulation of ghrelin as revealed by hypothalamic site-specific leptin gene therapy. Endocrinology 143:4409-4421.[Abstract/Free Full Text]

29. Dube, M. G., Beretta, E., Dhillon, H., Ueno, N., Kalra, P. S. & Kalra, S. P. (2002) Central leptin gene therapy blocks high fat diet-induced weight gain, hyperleptinemia and hyperinsulinemia: effects on serum ghrelin levels. Diabetes 51:1729-1736.[Abstract/Free Full Text]

30. Kamegai, J., Tamura, H., Shimizu, T., Ishii, S., Sugihara, H. & Oikawa, S. (2004) Effects of insulin, leptin, and glucagon on ghrelin secretion from isolated perfused rat stomach. Regul. Pept. 119:77-81.[Medline]

31. Horvath, T. L., Diano, S., Sotonyi, P., Heiman, M. & Tschop, M. (2001) Minireview: ghrelin and the regulation of energy balance—a hypothalamic perspective. Endocrinology 142:4163-4169.[Abstract/Free Full Text]

32. Sahu, A., White, J. D., Kalra, P. S. & Kalra, S. P. (1992) Hypothalamic neuropeptide Y gene expression in rats on scheduled feeding regimen. Brain Res. Mol. Brain Res. 15:15-18.[Medline]

33. Chen, H. Y., Trumbauer, M. E., Chen, A. S., Weingarth, D. T., Adams, J. R., Frazier, E. G., Shen, Z., Marsh, D. J., Feighner, S. D., Guan, X. M., Ye, Z., Nargund, R. P., Smith, R. G., Van Der Ploeg, L. H., Howard, A. D., MacNeil, D. J. & Qian, S. (2004) Orexigenic action of peripheral ghrelin is mediated by neuropeptide Y (NPY) and agouti-related protein (AgRP). Endocrinology 145:2607-2612.[Abstract/Free Full Text]

34. Bagnasco, M., Tulipano, G., Melis, M. R., Argiolas, A., Cocchi, D. & Muller, E. E. (2003) Endogenous ghrelin is an orexigenic peptide acting in the arcuate nucleus in response to fasting. Regul. Pept. 111:161-167.[Medline]

35. Yokosuka, M., Xu, B., Pu, S., Kalra, P. S. & Kalra, S. P. (1998) Neural substrates for leptin and neuropeptide Y (NPY) interaction: hypothalamic sites associated with inhibition of NPY-induced food intake. Physiol. Behav. 64:331-338.[Medline]

36. Yokosuka, M., Kalra, P. S. & Kalra, S. P. (1999) Inhibition of neuropeptide Y (NPY)-induced feeding and c-Fos response in magnocellular paraventricular nucleus by a NPY receptor antagonist: a site of NPY action. Endocrinology 140:4494-4500.[Abstract/Free Full Text]

37. Yokosuka, M., Dube, M. G., Kalra, P. S. & Kalra, S. P. (2001) The mPVN mediates blockade of NPY-induced feeding by a Y5 receptor antagonist: a c-FOS analysis. Peptides 22:507-514.[Medline]

38. Traebert, M., Riediger, T., Whitebread, S., Scharrer, E. & Schmid, H. A. (2002) Ghrelin acts on leptin-responsive neurones in the rat arcuate nucleus. J. Neuroendocrinol. 14:580-586.[Medline]

39. Pu, S., Dube, M. G., Kalra, P. S. & Kalra, S. P. (2000) Regulation of leptin secretion: Effects of aging on daily patterns of serum leptin and food consumption. Regul. Pept. 92:107-111.[Medline]




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