Central GLP-1 Actions on Energy Metabolism

Provided for non-commercial research and educational use only. Not for reproduction, distribution or commercial use. This chapter was originally published in the book Vitamins and Hormones, Vol. 84, published by Elsevier, and the attached copy is provided by Elsevier for the author's benefit and for the benefit of the author's institution, for non-commercial research and educational use including without limitation use in instruction at your institution, sending it to specific colleagues who know you, and providing a copy to your institution’s administrator.

All other uses, reproduction and distribution, including without limitation commercial reprints, selling or licensing copies or access, or posting on open internet sites, your personal or institution’s website or repository, are prohibited. For exceptions, permission may be sought for such use through Elsevier's permissions site at: http://www.elsevier.com/locate/permissionusematerial From: Douglas A. Vela´squez, Daniel Beiroa, Marı´a J. Va´zquez, Amparo Romero, Miguel Lo´pez, Carlos Die´guez, and Ruben Nogueiras, Central GLP-1 Actions on Energy Metabolism. In Gerald Litwack, editor: Vitamins and Hormones, Vol. 84, Burlington: Academic Press, 2010, pp. 303-317 ISBN: 978-0-12-381517-0 © Copyright 2010 Elsevier Inc. Academic Press.

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Central GLP-1 Actions on Energy Metabolism Douglas A. Vela´squez,*,† Daniel Beiroa,*,† Marı´a J. Va´zquez,*,† Amparo Romero,*,† Miguel Lo´pez,*,† Carlos Die´guez,*,† and Ruben Nogueiras*,† Contents 304 305 308 310 311 313 313

I. Introduction II. CNS Glucagon-Like Peptide 1 and Energy Intake III. CNS Glucagon-Like Peptide 1 and Glucose Metabolism IV. CNS Glucagon-Like Peptide 1 and Lipid Metabolism V. Future Directions Acknowledgments References

Abstract Glucagon-like peptide 1 (GLP-1) is secreted mainly by the intestine in a nutrientdependent manner and stimulates glucose-induced insulin secretion, inhibits gastric emptying, food intake, and glucagon secretion. All these beneficial effects make GLP-1 as a promising, and currently in the market, drug candidate for the treatment of type 2 diabetes. More recently, it has been also demonstrated that within the central nervous system, GLP-1 also exerts important metabolic actions inhibiting food intake, increasing insulin secretion, and modulating behavioral responses. In this review, we will focus on the metabolic actions and mechanisms of the central GLP-1 system: modulation of energy intake, glucose metabolism, and fatty acid metabolism. ß 2010 Elsevier Inc.

* Department of Physiology, School of Medicine, University of Santiago de Compostela—Instituto de Investigacio´n Sanitaria, Santiago de Compostela, A Corun˜a, Spain CIBER Fisiopatologı´a de la Obesidad y Nutricio´n (CIBERobn), Santiago de Compostela, A Corun˜a, Spain

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Vitamins and Hormones, Volume 84 ISSN 0083-6729, DOI: 10.1016/S0083-6729(10)84007-5

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2010 Elsevier Inc. All rights reserved.

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Douglas A. Vela´squez et al.

I. Introduction Glucagon-like peptide 1 (GLP-1) is a posttranslational product of proglucagon, that is, endogenously released mainly from two organs: (a) “L” cells within the gastrointestinal tract, mainly in the ileum, after the ingestion of nutrients and (b) neurons of the nucleus tractus solitarius (NTS) in the caudal brainstem, reviewed in Drucker (2006, 2007) and Goke et al. (1991). A small percentage of GLP-1 is also secreted from the pancreas following the ingestion of food. The amino acid sequence differs depending on the origin of the peptide. GLP-1(7-36) is derived from the intestine and represents the majority of circulating GLP-1 in plasma, whereas GLP-1 (1-36) is derived from the pancreas (Orskov et al., 1994). The metabolism and degradation of endogenous GLP-1 by the enzyme dipeptidyl-peptidase-4 (DPP-IV) is very rapid. It is estimated that