Journal ArticleDOI
Interactions of glucagon-like peptide-1 (GLP-1) with the blood-brain barrier.
TLDR
It is concluded that [Ser8]GLp-1 and the endogenous peptide GLP-1 can gain access to the brain from the periphery by simple diffusion and thus contribute to the regulation of feeding.Abstract:
Glucagon-like peptide-1 (GLP-1) reduces insulin requirement in diabetes mellitus and promotes satiety. GLP-1 in the periphery (outside the CNS) has been shown to act on the brain to reduce food ingestion. As GLP-1 is readily degraded in blood, we focused on the interactions of [Ser 8 ]GLP-1, an analog with similar biological effects and greater stability, with the blood-brain barrier (BBB). The influx of radiolabeled [Ser 8 ]GLP-1 into brain has several distinctive characteristics: 1. A rapid influx rate of 8.867 ± 0.798 × 10 4 mL/g-min as measured by multiple-time regression analysis after iv injection in mice. 2. Lack of self-inhibition by excess doses of the unlabeled [Ser 8 ]GLP-1 either iv or by in situ brain perfusion, indicating the absence of a saturable transport system at the BBB. 3. Lack of modulation by short-term fasting and some other ingestive peptides that may interact with GLP-1, including leptin, glucagon, insulin, neuropeptide Y, and melanin-concentrating hormone. 4. No inhibition of influx by the selective GLP-1 receptor antagonist exendin(9–39), suggesting that the GLP-1 receptor is not involved in the rapid entry into brain. Similarly, there was no efflux system for [Ser 8 ]GLP-1 to exit the brain other than following the reabsorption of cerebrospinal fluid (CSF). The fast influx was not associated with high lipid solubility. Upon reaching the brain compartment, substantial amounts of [Ser 8 ]GLP-1 entered the brain parenchyma, but a large proportion was loosely associated with the vasculature at the BBB. Finally, the influx rate of [Ser 8 ]GLP-1 was compared with that of GLP-1 in a blood-free brain perfusion system; radiolabeled GLP-1 had a more rapid influx than its analog and neither peptide showed the self-inhibition indicative of a saturable transport system. Therefore, we conclude that [Ser 8 ]GLP-1 and the endogenous peptide GLP-1 can gain access to the brain from the periphery by simple diffusion and thus contribute to the regulation of feeding.read more
Citations
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Journal ArticleDOI
Glucagon-like peptide-1 receptor is involved in learning and neuroprotection
Matthew J. During,Lei Cao,David S. Zuzga,Jeremy S. Francis,Helen L. Fitzsimons,Xiangyang Jiao,Ross J. Bland,Matthias Klugmann,William A. Banks,Daniel J. Drucker,Colin N. Haile +10 more
TL;DR: Systemic administration of [Ser(2)]exendin(1–9) in wild-type animals prevents kainate-induced apoptosis of hippocampal neurons and represents a promising new target for both cognitive-enhancing and neuroprotective agents.
Journal ArticleDOI
Glucagon-like peptide 1 (GLP-1)
Timo D. Müller,Brian Finan,Stephen R. Bloom,David A. D'Alessio,Daniel J. Drucker,Peter R. Flatt,Andreas Fritsche,Fiona M. Gribble,Harvey J. Grill,Joel F. Habener,Jens J. Holst,Wolfgang Langhans,Juris J. Meier,Michael A. Nauck,Diego Perez-Tilve,Alessandro Pocai,Frank Reimann,Darleen A. Sandoval,Thue W. Schwartz,Randy J. Seeley,Kerstin Stemmer,Mads Tang-Christensen,Stephen C. Woods,Richard D. DiMarchi,M.H. Tschöp +24 more
TL;DR: The numerous beneficial effects of GLP-1 render this hormone an interesting candidate for the development of pharmacotherapies to treat obesity, diabetes, and neurodegenerative disorders.
Journal ArticleDOI
The arcuate nucleus mediates GLP-1 receptor agonist liraglutide-dependent weight loss
Anna Secher,Jacob Jelsing,Arian F. Baquero,Jacob Hecksher-Sørensen,Michael A. Cowley,Louise S. Dalbøge,Gitte Hansen,Kevin L. Grove,Charles Pyke,Kirsten Raun,Lauge Schäffer,Mads Tang-Christensen,Saurabh Verma,Brent M. Witgen,Niels Vrang,Lotte Bjerre Knudsen +15 more
TL;DR: These findings indicate that the GLP-1R on POMC/CART-expressing ARC neurons likely mediates liraglutide-induced weight loss.
Journal ArticleDOI
The Diabetes Drug Liraglutide Prevents Degenerative Processes in a Mouse Model of Alzheimer's Disease
TL;DR: In APP/PS1 mice, liraglutide prevented memory impairments in object recognition and water maze tasks, and prevented synapse loss and deterioration of synaptic plasticity in the hippocampus, commonly observed in this model, suggesting that GLP-1 analogs represent a novel treatment strategy for Alzheimer's disease.
Journal ArticleDOI
International Union of Pharmacology. XXXV. The Glucagon Receptor Family
Kelly E. Mayo,Laurence J. Miller,Dominique Bataille,Stéphane Dalle,Burkhard Göke,Bernard Thorens,Daniel J. Drucker,Daniel J. Drucker +7 more
TL;DR: Advances in the understanding of how these peptides exert their biological activities are discussed, with a focus on the biological actions and structural features of the cognate receptors.
References
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Journal ArticleDOI
A role for glucagon-like peptide-1 in the central regulation of feeding
M. D. Turton,Donal O'Shea,I. Gunn,S. A. Beak,C. M. B. Edwards,K Meeran,S. J. Choi,G. M. Taylor,M. M. Heath,P.D. Lambert,John P.H. Wilding,David M. Smith,M. A. Ghatei,J. Herbert,S.R. Bloom +14 more
TL;DR: It is reported here that intracerebroventricular (ICV) GLP-1 powerfully inhibits feeding in fasted rats, and this findings suggest that central GLp-1 is a new physiological mediator of satiety.
Journal ArticleDOI
Glucagon-like peptide 1 promotes satiety and suppresses energy intake in humans.
TL;DR: The results show that GLP-1 enhanced satiety and reduced energy intake and thus may play a physiological regulatory role in controlling appetite and energy intake in humans.
Journal ArticleDOI
Degradation of glucose-dependent insulinotropic polypeptide and truncated glucagon-like peptide 1 in vitro and in vivo by dipeptidyl peptidase IV
TL;DR: It is concluded that DPP IV may be a primary inactivating enzyme of both GIP and tGLP-1 in vivo and reports of circulating hormone levels should be reconsidered.
Journal ArticleDOI
Central administration of GLP-1-(7-36) amide inhibits food and water intake in rats
Mads Tang-Christensen,Philip J. Larsen,Rüdiger Göke,Anders Fink-Jensen,D. S. Jessop,M. Moller,S. P. Sheikh +6 more
TL;DR: In conclusion, GLP-1 may play a physiological role in regulation of both ingestion and the water and salt homeostasis and had no effect in behavioral assays measuring exploratory locomotor activity and conditioned taste aversion.
Journal ArticleDOI
Distribution of glucagon-like peptide-1 and other preproglucagon-derived peptides in the rat hypothalamus and brainstem
TL;DR: Observations substantiate that glucagon-like peptide-1 neurons of the solitary tract constitute a distinct non-catecholaminergic cell group which projects to many targets, one of which is the hypothalamic paraventricular nucleus.