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 a humoral pathways involving direct action on brain GLP-1 receptors. 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 (ARH, PVH, LHA), hindbrain nuclei (PBN, mNTS), hippocampus (ventral subregion; vHP), and nuclei embedded within the mesolimbic reward circuitry (VTA, NAc). In some of these nuclei (VTA, NAc, 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 highlights 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.
- glucagon-like peptide-1
- food reward
- Copyright © 2015, American Journal of Physiology - Regulatory, Integrative and Comparative Physiology