The discovery of the peptide hormone ghrelin, an endogenous ligand for the growth hormone secretagogue (GHS) receptor1,2, yielded the surprising result3 that the principal site of ghrelin synthesis is the stomach and not the hypothalamus. Although ghrelin is likely to regulate pituitary growth hormone (GH) secretion3,4 along with GH-releasing hormone and somatostatin, GHS receptors have also been identified on hypothalamic neurons5 and in the brainstem6. Apart from potential paracrine effects, ghrelin may thus offer an endocrine link between stomach, hypothalamus and pituitary, suggesting an involvement in regulation of energy balance. Here we show that peripheral daily administration of ghrelin caused weight gain by reducing fat utilization in mice and rats. Intracerebroventricular administration of ghrelin generated a dose-dependent increase in food intake and body weight. Rat serum ghrelin concentrations were increased by fasting and were reduced by re-feeding or oral glucose administration, but not by water ingestion. We propose that ghrelin, in addition to its role in regulating GH secretion, signals the hypothalamus when an increase in metabolic efficiency is necessary.
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McKee, K. K. et al. Molecular analysis of rat pituitary and hypothalamic growth hormone secretagogue receptors. Mol. Endocrinol. 11 , 415–423 (1997).
Howard, A. D. et al. A receptor in pituitary and hypothalamus that functions in growth hormone release. Science 273, 974 –977 (1996).
Kojima, M. et al. Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature 402, 656–660 (1999).
Hosoda, H., Kojima, M., Matsuo, H. & Kangawa, K. Purification and characterization of rat des-Gln14-ghrelin, a second endogenous ligand for the growth hormone secretagogue receptor. J. Biol. Chem. 275, 21995–22000 (2000).
Guan, X. M. et al. Distribution of mRNA encoding the growth hormone secretagogue receptor in brain and peripheral tissues. Brain Res. 48, 23–29 (1997).
Bailey, A. R., Von Englehardt, N., Leng, G., Smith, R. G. & Dickson, S. L. Growth hormone secretagogue activation of the arcuate nucleus and brainstem occurs via a non-noradrenergic pathway. J. Neuroendocrinol. 12, 191– 197 (2000).
Scheurink, A. J., Leuvenink, H., Benthem, B. & Steffens, A. B. Dexfenfluramine treatment influences plasma catecholamines and energy substrate metabolism in rats. Physiol. Behav. 53, 879–887 (1993).
Snitker, S., Tataranni, P. A. & Ravussin, E. Respiratory quotient is inversely associated with muscle sympathetic nerve activity. J. Clin. Endocrinol. Metab. 83, 3977–3979 (1998).
Atrens, D. M., Sinden, J. D., Penicaud, L., Devos, M. & Le Magnen, J. Hypothalamic modulation of energy expenditure. Physiol. Behav. 35, 15– 20 (1985).
Kuriyama, H., Hotta, M., Wakabayashi, I. & Shibasaki, T. A 6-day intracerebroventricular infusion of the growth hormone-releasing peptide KP-102 stimulates food intake in both non-stressed and intermittently-stressed rats. Neurosci. Lett. 282, 109– 112 (2000).
Okada, K. et al. Intracerebroventricular administration of the growth hormone-releasing peptide KP-102 increases food intake in free-feeding rats. Endocrinology 137, 5155–5158 ( 1996).
Salomon, F., Cuneo, R. C., Hesp, R. & Sonksen, P. H. The effects of treatment with recombinant human growth hormone on body composition and metabolism in adults with growth hormone deficiency. N. Engl. J. Med. 321, 1797–1803 ( 1989).
Vernon, R. G. GH inhibition of lipogenesis and stimulation of lipolysis in sheep adipose tissue: involvement of protein serine phosphorylation and dephosphorylation and phospholipase C. J. Endocrinol. 150, 129–140 (1996).
Charlton, H. M. et al. Growth hormone-deficient dwarfism in the rat: a new mutation. J. Endocrinol. 119, 51– 58 (1988).
Willesen, M. G., Kristensen, P. & Romer, J. Co-localization of growth hormone secretagogue receptor and NPY mRNA in the arcuate nucleus of the rat. Neuroendocrinology 70, 306–316 ( 1999).
Bailey, A. R. et al. Chronic central infusion of growth hormone secretagogues: effects on fos expression and peptide gene expression in the rat arcuate nucleus. Neuroendocrinology 70, 83– 92 (1999).
Luckman, S. M., Rosenzweig, I. & Dickson, S. L. Activation of arcuate nucleus neurons by systemic administration of leptin and growth hormone-releasing peptide-6 in normal and fasted rats. Neuroendocrinology 70, 93–100 (1999).
Erickson, J. C., Clegg, K. E. & Palmiter, R. D. Sensitivity to leptin and susceptibility to seizures of mice lacking neuropeptide Y. Nature 381, 415–421 (1996).
Chen, Y. & Heiman, M. L. Chronic leptin administration promotes lipid utilization until fat mass is greatly reduced and preserves lean mass of normal female rats. Regul. Pept. (in the press).
Elia, M. & Livesey, G. Energy expenditure and fuel selection in biological systems: the theory and practice of calculations based on indirect calorimetry and tracer methods. World Rev. Nutr. Diet 70, 68–131 (1992).
Flatt, J. P. Assessment of daily and cumulative carbohydrate and fat balances in mice. J. Nutr. Biochem. 2, 193– 202 (1991).
Rose, B. S., Flatt, W. P., Martin, R. J. & Lewis, R. D. Whole body composition of rats determined by dual energy X-ray absorptiometry is correlated with chemical analysis. J. Nutr. 128, 246–250 (1998).
Hsiung, H. M. & MacKellar, W. C. Expression of bovine growth hormone derivatives in Escherichia coli and the use of the derivatives to produce natural sequence growth hormone by cathepsin C cleavage. Methods Enzymol. 153, 390–401 (1987).
Heiman, M. L., Nekola, M. V., Murphy, W. A., Lance, V. A. & Coy, D. H. An extremely sensitive in vitro model for elucidating structure-activity relationships of growth hormone-releasing factor analogs. Endocrinology 116, 410– 415 (1985).
We thank J. Caro, G. Cutler Jr, E. Ravussin, R. Al-Awar, C.J. Strasburger and A. Tashjian Jr for critical review, R. Palmiter for providing NPY-deficient mice and L. Craft, J. Baker, J. Bridwell, J. Jacobs, W.T. Johnson, P. Surface, F. Tinsley and T. Butler for technical assistance.
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Tschöp, M., Smiley, D. & Heiman, M. Ghrelin induces adiposity in rodents. Nature 407, 908–913 (2000). https://doi.org/10.1038/35038090
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