Role of the glucagon-like-peptide-1 receptor in the control of energy balance

Department of Psychology, School of Arts and Sciences, University of Pennsylvania, 3720 Walnut Street, Philadelphia, PA 19104, USA.
Physiology & Behavior (Impact Factor: 2.98). 03/2010; 100(5):503-10. DOI: 10.1016/j.physbeh.2010.02.029
Source: PubMed


The peripheral and central glucagon-like-peptide-1 (GLP-1) systems play an essential role in glycemic and energy balance regulation. Thus, pharmacological targeting of peripheral and/or central GLP-1 receptors (GLP-1R) may represent a potential long-term treatment option for both obesity and type-II diabetes mellitus (T2DM). Uncovering and understanding the neural pathways, physiological mechanisms, specific GLP-1R populations, and intracellular signaling cascades that mediate the food intake inhibitory and incretin effects produced by GLP-1R activation are vital to the development of these potential successful therapeutics. Particular focus will be given to the essential role of the nucleus tractus solitarius (NTS) in the caudal brainstem, as well as the gut-to-brain communication by vagal afferent fibers in mediating the physiological and behavioral responses following GLP-1R activation. The paper represents an invited review by a symposium, award winner or keynote speaker at the Society for the Study of Ingestive Behavior [SSIB] Annual Meeting in Portland, July 2009.

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    • "This interesting finding led us to hypothesize that the VTA–amygdala pathway may be a target of another anorexic hormone, glucagon-like peptide 1 (GLP-1). GLP-1 is secreted from the intestinal tract in response to nutrients and produced in the NTS in the brainstem with projections throughout the central nervous system; it has captivated interest due to its glucoregulatory and anorexic effects [17] [18] [19] [20]. However, much remains to be discovered about the central mechanisms behind GLP-1-induced hypophagia. "
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    ABSTRACT: Mesolimbic dopamine plays a critical role in food-related reward processing and learning. The literature focuses primarily on the nucleus accumbens as the key dopaminergic target in which enhanced dopamine signaling is associated with reward. Here, we demonstrate a novel neurobiological mechanism by which dopamine transmission in the amygdala regulates food intake and reward. We show that food intake was associated with increased dopamine turnover in the amygdala. Next, we assessed the impact of direct intra-amygdala D1 and D2 receptor activation on food intake and sucrose-driven progressive ratio operant conditioning in rats. Amygdala D2 receptor activation reduced food intake and operant behavior for sucrose, whereas D2 receptor blockade increased food intake but surprisingly reduced operant behavior. In contrast, D1 receptor stimulation or blockade did not alter feeding or operant conditioning for food. The glucagon-like peptide 1 (GLP-1) system, a target for type 2 diabetes treatment, in addition to regulating glucose homeostasis, also reduces food intake. We found that central GLP-1R receptor activation is associated with elevated dopamine turnover in the amygdala, and that part of the anorexic effect of GLP-1 is mediated by D2 receptor signaling in the amygdala. Our findings indicate that amygdala dopamine signaling is activated by both food intake and the anorexic brain-gut peptide GLP-1 and that amygdala D2 receptor activation is necessary and sufficient to change feeding behavior. Collectively these studies indicate a novel mechanism by which the dopamine system affects feeding-oriented behavior at the level of the amygdala.
    Full-text · Article · Sep 2014 · Physiology & Behavior
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    • "These released neurohormones activate receptors (5-HT3 and GLP-1 receptors, respectively) on peripheral GI vagal afferent fiber terminals and the resulting excitatory signals are relayed centrally (Raybould, 1998, 1999, 2002; Glatzle et al., 2002; Raybould et al., 2003; Vincent et al., 2011). These sensory signals activate second order neurons within the NTS and, following integration, the subsequent vagal motor response induces gastric relaxation and delayed emptying (Zittel et al., 1994; Ferreira et al., 2001; Raybould et al., 2003; Zhou et al., 2008; Hayes et al., 2010; Vincent et al., 2011). "
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    ABSTRACT: Glucose sensing within autonomic neurocircuits is critical for the effective integration and regulation of a variety of physiological homeostatic functions including the co-ordination of vagally-mediated reflexes regulating gastrointestinal (GI) functions. Glucose regulates GI functions via actions at multiple sites of action, from modulating the activity of enteric neurons, endocrine cells, and glucose transporters within the intestine, to regulating the activity and responsiveness of the peripheral terminals, cell bodies and central terminals of vagal sensory neurons, to modifying both the activity and synaptic responsiveness of central brainstem neurons. Unsurprisingly, significant impairment in GI functions occurs in pathophysiological states where glucose levels are dysregulated, such as diabetes. A substantial obstacle to the development of new therapies to modify the disease, rather than treat the symptoms, are the gaps in our understanding of the mechanisms by which glucose modulates GI functions, particularly vagally-mediated responses and a more complete understanding of disease-related plasticity within these neurocircuits may open new avenues and targets for research.
    Full-text · Article · Nov 2013 · Frontiers in Neuroscience
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    • "Glucagon-like peptide-1 (GLP1), a gastrointestinal hormone produced by L cells in the distal small intestine and colon, is released in response to meal intake and ingested nutrients (Mojsov et al. 1986, Holst 2007). Because GLP1 and its receptors are present in both the CNS and peripheral tissues such as pancreatic b cells and vagal afferents, the effect of GLP1 on energy metabolism could be mediated at central sites, peripheral sites, or both (Holst 2007, Hayes et al. 2010). Indeed, GLP1 reduces food intake after either central or peripheral administration (Williams et al. 2006). "
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    ABSTRACT: Glucagon-like peptide-1 (GLP1) and leptin are anorectic hormones. Previously, we showed that intraperitoneal coadministration of subthreshold GLP1 with leptin dramatically reduced food intake in rats. Here, by using midbrain-transected rats, we investigated the role of the neural pathway from the hindbrain to the hypothalamus in the interaction of GLP1 and leptin to reduce food intake. Food intake reduction induced by coinjection of GLP1 and leptin was blocked in midbrain-transected rats. These findings indicate that the ascending neural pathway from the hindbrain plays an important role in transmitting the anorectic signals provided by coinjection of GLP1 and leptin.
    Full-text · Article · Nov 2013 · Journal of Endocrinology
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