Peripheral and Central GLP-1 Receptor Populations Mediate the Anorectic Effects of Peripherally Administered GLP-1 Receptor Agonists, Liraglutide and Exendin-4

被引:299
作者
Kanoski, Scott E. [1 ]
Fortin, Samantha M.
Arnold, Myrtha [3 ]
Grill, Harvey J.
Hayes, Matthew R. [2 ]
机构
[1] Univ Penn, Dept Psychol, Solomon Labs, Sch Arts & Sci, Philadelphia, PA 19104 USA
[2] Univ Penn, Sch Med, Dept Psychiat, Philadelphia, PA 19104 USA
[3] Swiss Fed Inst Technol, Inst Anim Sci, Physiol & Behav Grp, CH-8603 Schwerzenbach, Switzerland
基金
美国国家卫生研究院;
关键词
GLUCAGON-LIKE PEPTIDE-1; DIET-INDUCED OBESE; FOOD-INTAKE; BODY-WEIGHT; MEAL SIZE; GLUCAGON-LIKE-PEPTIDE-1; RECEPTOR; DIFFERENT MECHANISMS; VAGAL AFFERENTS; ENERGY-BALANCE; RAT;
D O I
10.1210/en.2011-0174
中图分类号
R5 [内科学];
学科分类号
100201 [内科学];
摘要
The long-acting glucagon-like peptide-1 receptor (GLP-1R) agonists, exendin-4 and liraglutide, suppress food intake and body weight. The mediating site(s) of action for the anorectic effects produced by peripheral administration of these GLP-1R agonists are not known. Experiments addressed whether food intake suppression after ip delivery of exendin-4 and liraglutide is mediated exclusively by peripheral GLP-1R or also involves direct central nervous system (CNS) GLP-1R activation. Results showed that CNS delivery [ third intracerebroventricular (3(rd) ICV)] of the GLP-1R antagonist exendin-(9-39) (100 mu g), attenuated the intake suppression by ip liraglutide (10 mu g) and exendin-4 (3 mu g), particularly at 6 h and 24 h. Control experiments show that these findings appear to be based neither on the GLP-1R antagonist acting as a nonspecific competing orexigenic signal nor on blockade of peripheral GLP-1R via efflux of exendin-(9-39) to the periphery. To assess the contribution of GLP-1R expressed on subdiaphragmatic vagal afferents to the anorectic effects of liraglutide and exendin-4, food intake was compared in rats with complete subdiaphragmatic vagal deafferentation and surgical controls after ip delivery of the agonists. Both liraglutide and exendin-4 suppressed food intake at 3 h, 6 h, and 24 h for controls; for subdiaphragmatic vagal deafferentation rats higher doses of the GLP-1R agonists were needed for significant food intake suppression, which was observed at 6 h and 24 h after liraglutide and at 24 h after exendin-4. Conclusion: Food intake suppression after peripheral administration of exendin-4 and liraglutide is mediated by activation of GLP-1R expressed on vagal afferents as well as direct CNS GLP-1R activation. (Endocrinology 152: 3103-3112, 2011)
引用
收藏
页码:3103 / 3112
页数:10
相关论文
共 54 条
[1]
The inhibitory effects of peripheral administration of peptide YY3-36 and glucagon-like peptide-1 on food intake are attenuated by ablation of the vagal-brainstem-hypothalamic pathway [J].
Abbott, CR ;
Monteiro, M ;
Small, CJ ;
Sajedi, A ;
Smith, KL ;
Parkinson, JRC ;
Ghatei, MA ;
Bloom, SR .
BRAIN RESEARCH, 2005, 1044 (01) :127-131
[2]
The Extrapancreatic Effects of Glucagon-Like Peptide-1 and Related Peptides [J].
Abu-Hamdah, Rania ;
Rabiee, Atoosa ;
Meneilly, Graydon S. ;
Shannon, Richard P. ;
Andersen, Dana K. ;
Elahi, Dariush .
JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM, 2009, 94 (06) :1843-1852
[3]
The pharmacokinetics, pharmacodynamics, safety and tolerability of NN2211, a new long-acting GLP-1 derivative, in healthy men [J].
Agerso, H ;
Jensen, LB ;
Elbrond, B ;
Rolan, P ;
Zdravkovic, M .
DIABETOLOGIA, 2002, 45 (02) :195-202
[4]
[Anonymous], 2009, OV OB DAT STAT
[5]
Gut vagal afferents are not necessary for the eating-stimulatory effect of intraperitoneally injected Ghrelin in the rat [J].
Arnold, Myrtha ;
Mura, Anna ;
Langhans, Wolfgang ;
Geary, Nori .
JOURNAL OF NEUROSCIENCE, 2006, 26 (43) :11052-11060
[6]
Effects of liraglutide in the treatment of obesity: a randomised, double-blind, placebo-controlled study [J].
Astrup, Arne ;
Rossner, Stephan ;
Van Gaal, Luc ;
Rissanen, Aila ;
Niskanen, Leo ;
Al Hakim, Mazin ;
Madsen, Jesper ;
Rasmussen, Mads F. ;
Lean, Michael E. J. .
LANCET, 2009, 374 (9701) :1606-1616
[7]
Brain uptake of the glucagon-like peptide-1 antagonist exendin(9-39) after intranasal administration [J].
Banks, WA ;
During, MJ ;
Niehoff, ML .
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, 2004, 309 (02) :469-475
[8]
Lesions of area postrema and subfornical organ alter exendin-4-induced brain activation without preventing the hypophagic effect of the GLP-1 receptor agonist [J].
Baraboi, Elena-Dana ;
Smith, Pauline ;
Ferguson, Alastair V. ;
Richard, Denis .
AMERICAN JOURNAL OF PHYSIOLOGY-REGULATORY INTEGRATIVE AND COMPARATIVE PHYSIOLOGY, 2010, 298 (04) :R1098-R1110
[9]
Hepatic-Portal Vein Infusions of Glucagon-Like Peptide-1 Reduce Meal Size and Increase c-Fos Expression in the Nucleus Tractus Solitarii, Area Postrema and Central Nucleus of the Amygdala in Rats [J].
Baumgartner, I. ;
Pacheco-Lopez, G. ;
Ruettimann, E. B. ;
Arnold, M. ;
Asarian, L. ;
Langhans, W. ;
Geary, N. ;
Hillebrand, J. J. G. .
JOURNAL OF NEUROENDOCRINOLOGY, 2010, 22 (06) :557-563
[10]
Lesion of the lateral parabrachial nucleus attenuates the anorectic effect of peripheral amylin and CCK [J].
Becskei, Csilla ;
Grabler, Valerie ;
Edwards, Gaylen L. ;
Riediger, Thomas ;
Lutz, Thomas A. .
BRAIN RESEARCH, 2007, 1162 :76-84