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Am J Physiol Regul Integr Comp Physiol. 2016 May 15;310(10):R885-95. doi: 10.1152/ajpregu.00520.2015. Epub 2016 Mar 30.

GLP-1 and weight loss: unraveling the diverse neural circuitry.

Author information

1
Human and Evolutionary Biology Section, Department of Biological Sciences, University of Southern California, Los Angeles, California; kanoski@usc.edu.
2
Translational Neuroscience Program, Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia Pennsylvania; and.
3
Department of Physiology/Metabolic Physiology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.

Abstract

Glucagon-like peptide-1 (GLP-1) is currently one of the most promising biological systems for the development of effective obesity pharmacotherapies. Long-acting GLP-1 analogs potently reduce food intake and body weight, and recent discoveries reveal that peripheral administration of these drugs reduces food intake largely through humoral pathways involving direct action on brain GLP-1 receptors (GLP-1R). Thus, it is of critical importance to understand the neural systems through which GLP-1 and long-acting GLP-1 analogs reduce food intake and body weight. In this review, we discuss several neural, physiological, cellular and molecular, as well as behavioral mechanisms through which peripheral and central GLP-1R signaling reduces feeding. Particular attention is devoted to discussion regarding the numerous neural substrates through which GLP-1 and GLP-1 analogs act to reduce food intake and body weight, including various hypothalamic nuclei (arcuate nucleus of the hypothalamus, periventricular hypothalamus, lateral hypothalamic area), hindbrain nuclei (parabrachial nucleus, medial nucleus tractus solitarius), hippocampus (ventral subregion; vHP), and nuclei embedded within the mesolimbic reward circuitry [ventral tegmental area (VTA) and nucleus accumbens (NAc)]. In some of these nuclei [VTA, NAc, and vHP], GLP-1R activation reduces food intake and body weight without concomitant nausea responses, suggesting that targeting these specific pathways may be of particular interest for future obesity pharmacotherapy. The widely distributed neural systems through which GLP-1 and GLP-1 analogs act to reduce body weight highlight the complexity of the neural systems regulating energy balance, as well as the challenges for developing effective obesity pharmacotherapies that reduce feeding without producing parallel negative side effects.

KEYWORDS:

Byetta; Saxenda; dipeptidyl peptidase-4; exendin-4; food reward; glucagon-like peptide-1; liraglutide; obesity

PMID:
27030669
PMCID:
PMC4888559
DOI:
10.1152/ajpregu.00520.2015
[Indexed for MEDLINE]
Free PMC Article

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