Glucagon-like peptide-1 (GLP-1), an insulinotropic gastrointestinal peptide that is primarily produced by intestinal endocrine L-cells, stimulates satiety. Ghrelin, a hormone that is produced predominantly by the stomach stimulates hunger. There are two forms of ghrelin: active ghrelin and inactive des-acyl ghrelin. After depriving mice of food for 24？h, we demonstrated that the systemic administration of liraglutide (100？μg/kg), a human GLP-1 analog that binds to the GLP-1 receptor, increased (1.4-fold) the plasma levels of active GLP-1 and suppressed the plasma levels of active and des-acyl ghrelin after 1？h. Despite the elevated plasma levels of active GLP-1 (11-fold), liraglutide had no effect on the plasma levels of active or des-acyl ghrelin after 12？h. These findings demonstrated that liraglutide suppresses the plasma levels of active and des-acyl ghrelin independently of active GLP-1 levels in fasted mice, suggesting a novel in vivo biological effect of liraglutide beyond regulating plasma GLP-1. 1. Introduction Hunger is stimulated by ghrelin, a hormone that is primarily produced by the P/D1 cells that line the fundus of the stomach [1]. Plasma ghrelin levels increase during fasting and decrease after ingesting glucose or lipids but not protein [1]. The efferent vagus nerve contributes to the fasting-induced increase in ghrelin secretion [1, 2]. The ghrelin that is secreted in the stomach stimulates the afferent vagus nerve and promotes food intake [1]. Ghrelin exists in both inactive (des-acyl ghrelin) and active forms. Fasting increases both forms of ghrelin compared with the fed state. Hyperphagia and obesity decrease the plasma levels of des-acyl ghrelin but not of active ghrelin [1]. Satiety is stimulated by glucagon-like peptide-1 (GLP-1), an incretin hormone that is released from intestinal L-cells in response to nutrient ingestion [3–5]. The GLP-1 receptors (GLP-1Rs) are expressed in the central nervous system (CNS) and the afferent vagal nerve terminals and contribute to the anorexic effect of GLP-1 [3–6]. GLP-1 potentiates glucose-dependent insulin secretion by activating the GLP-1Rs that are expressed on pancreatic islet β cells [3–5]. GLP-1 secretion increases after ingesting glucose and lipids but not protein [6]. In the isolated rat stomach, GLP-1 has been reported to suppress ghrelin release [7]. In addition, GLP-1 suppresses plasma ghrelin levels in humans via insulin secretion in the late postprandial period [8]. Once GLP-1 is released from the L cells into the bloodstream, it is rapidly degraded from its active form (7–36) to
References
[1]
K. Nonogaki, “Ghrelin and feedback systems,” Vitamins and Hormones, vol. 77, pp. 149–170, 2007.
[2]
D. L. Williams, H. J. Grill, D. E. Cummings, and J. M. Kaplan, “Vagotomy dissociates short- and long-term controls of circulating ghrelin,” Endocrinology, vol. 144, no. 12, pp. 5184–5187, 2003.
[3]
J. J. Holst, “The physiology of glucagon-like peptide 1,” Physiological Reviews, vol. 87, no. 4, pp. 1409–1439, 2007.
[4]
J. A. Lovshin and D. J. Drucker, “Incretin-based therapies for type 2 diabetes mellitus,” Nature Reviews Endocrinology, vol. 5, no. 5, pp. 262–269, 2009.
[5]
M. R. Hayes, B. C. de Jonghe, and S. E. Kanoski, “Role of the glucagon-like-peptide-1 receptor in the control of energy balance,” Physiology and Behavior, vol. 100, no. 5, pp. 503–510, 2010.
[6]
G. Carrel, L. Egli, C. Tran et al., “Contributions of fat and protein to the incretin effect of a mixed meal,” American Journal of Clinical Nutrition, vol. 94, no. 4, pp. 997–1003, 2011.
[7]
F. Lippl, F. Kircher, J. Erdmann, H.-D. Allescher, and V. Schusdziarra, “Effect of GIP, GLP-1, insulin and gastrin on ghrelin release in the isolated rat stomach,” Regulatory Peptides, vol. 119, no. 1-2, pp. 93–98, 2004.
[8]
D. Hagemann, J. J. Holst, A. Gethmann, M. Banasch, W. E. Schmidt, and J. J. Meier, “Glucagon-like peptide 1 (GLP-1) suppresses ghrelin levels in humans via increased insulin secretion,” Regulatory Peptides, vol. 143, no. 1–3, pp. 64–68, 2007.
[9]
D. J. Drucker, A. Dritselis, and P. Kirkpatrick, “Liraglutide,” Nature Reviews Drug Discovery, vol. 9, no. 4, pp. 267–268, 2010.
[10]
K. Nonogaki, M. Suzuki, M. Sanuki, M. Wakameda, and T. Tamari, “The contribution of serotonin 5-HT2C and melanocortin-4 receptors to the satiety signaling of glucagon-like peptide 1 and liragultide, a glucagon-like peptide 1 receptor agonist, in mice,” Biochemical and Biophysical Research Communications, vol. 411, no. 2, pp. 445–448, 2011.
[11]
K. Nonogaki, K. Nozue, and Y. Oka, “Hyperphagia alters expression of hypothalamic 5-HT2C and 5-HT1B receptor genes and plasma des-acyl ghrelin levels in Ay mice,” Endocrinology, vol. 147, no. 12, pp. 5893–5900, 2006.
[12]
S. Nagamatsu, M. Ohara-Imaizumi, Y. Nakamichi, K. Aoyagi, and C. Nishiwaki, “DPP-4 inhibitor des-F-sitagliptin treatment increased insulin exocytosis from db/db mice β cells,” Biochemical and Biophysical Research Communications, vol. 412, no. 4, pp. 556–560, 2011.
[13]
G. M. E. Hussein, H. Matsuda, S. Nakamura et al., “Mate tea (Ilex paraguariensis) promotes satiety and body weight lowering in mice: involvement of glucagon-like peptide-1,” Biological and Pharmaceutical Bulletin, vol. 34, no. 12, pp. 1849–1855, 2011.
[14]
P. J. Larsen, C. Fledelius, L. B. Knudsen, and M. Tang-Christensen, “Systemic administration of the long-acting GLP-1 derivative NN2211 induces lasting and reversible weight loss in both normal and obese rats,” Diabetes, vol. 50, no. 7–12, pp. 2530–2539, 2001.
[15]
K. J. Griffioen, R. Wan, E. Okun et al., “GLP-1 receptor stimulation depresses heart rate variability and inhibits neurotransmission to cardiac vagal neurons,” Cardiovascular Research, vol. 89, no. 1, pp. 72–78, 2011.
[16]
S. E. Kanoski, S. M. Fortin, M. Arnold, H. J. Grill, and M. R. Hayes, “Peripheral and central GLP-1 receptor populations mediate the anorectic effects of peripherally administered GLP-1 receptor agonists, liraglutide and exendin-4,” Endocrinology, vol. 152, no. 8, pp. 3103–3112, 2011.
[17]
T. P. Vahl, M. Tauchi, T. S. Durler et al., “Glucagon-Like Peptide-1 (GLP-1) receptors expressed on nerve terminals in the portal vein mediate the effects of endogenous GLP-1 on glucose tolerance in rats,” Endocrinology, vol. 148, no. 10, pp. 4965–4973, 2007.
[18]
E. M. Sisson, “Liraglutide: clinical pharmacology and considerations for therapy,” Pharmacotherapy, vol. 31, no. 9, pp. 896–911, 2011.
[19]
M. R. Hayes, S. E. Kanoski, B. C. de Jonghe et al., “The common hepatic branch of the vagus is not required to mediate the glycemic and food intake suppressive effects of glucagon-like-peptide-1,” American Journal of Physiology—Regulatory Integrative and Comparative Physiology, vol. 301, no. 5, pp. R1479–R1485, 2011.
