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Incretins and Amylin: Neuroendocrine Communication Between the Gut, Pancreas, and Brain in Control of Food Intake and Blood Glucose

Annual Review of Nutrition (Impact Factor: 10.46). 04/2014; 34. DOI: 10.1146/annurev-nutr-071812-161201
Source: PubMed

ABSTRACT Arguably the most fundamental physiological systems for all eukaryotic life are those governing energy balance. Without sufficient energy, an individual is unable to survive and reproduce. Thus, an ever-growing appreciation is that mammalian physiology developed a redundant set of neuroendocrine signals that regulate energy intake and expenditure, which maintains sufficient circulating energy, predominantly in the form of glucose, to ensure that energy needs are met throughout the body. This orchestrated control requires cross talk between the gastrointestinal tract, which senses the incoming meal; the pancreas, which produces glycemic counterregulatory hormones; and the brain, which controls autonomic and behavioral processes regulating energy balance. Therefore, this review highlights the physiological, pharmacological, and pathophysiological effects of the incretin hormones glucagon-like peptide-1 and gastric inhibitory polypeptide, as well as the pancreatic hormone amylin, on energy balance and glycemic control. Expected final online publication date for the Annual Review of Nutrition Volume 34 is July 17, 2014. Please see http://www.annualreviews.org/catalog/pubdates.aspx for revised estimates.

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    • "notion as VTA amylin receptor activation with sCT did not change blood glucose levels in an oral glucose tolerance test, suggesting that other CNS site(s) mediate the ability of amylin to regulate glycemia (Hayes et al, 2014). "
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    ABSTRACT: Amylin acts in the CNS to reduce feeding and body weight. Recently, the ventral tegmental area (VTA), a mesolimbic nucleus important for food intake and reward, was identified as a site-of-action mediating the anorectic effects of amylin. However, the long-term physiological relevance and mechanisms mediating the intake-suppressive effects of VTA amylin receptor activation are unknown. Data show that the core component of the amylin receptor, the calcitonin receptor (CTR), is expressed on VTA dopamine neurons and that activation of VTA amylin receptors reduces phasic dopamine in the nucleus accumbens core (NAcC). Suppression in NAcC dopamine mediates VTA amylin-induced hypophagia, as combined NAcC D1/D2 receptor agonists block the intake-suppressive effects of VTA amylin receptor activation. Knockdown of VTA CTR via AAV-shRNA resulted in hyperphagia and exacerbated body weight gain in rats maintained on high-fat diet. Collectively, findings show that VTA amylin receptor signaling controls energy balance by modulating mesolimbic dopamine signaling.Neuropsychopharmacology accepted article preview online, 18 July 2014; doi:10.1038/npp.2014.180.
    Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 07/2014; 40(2). DOI:10.1038/npp.2014.180 · 7.83 Impact Factor
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    ABSTRACT: Glucagon-like peptide-1 (GLP-1) is produced in the small intestines and in nucleus tractus solitarius (NTS) neurons. Activation of central GLP-1 receptors (GLP-1Rs) reduces feeding and body weight. The neural circuits mediating these effects are only partially understood. Here we investigate the inhibition of food intake and motivated responding for food in rats following GLP-1R activation in the ventral hippocampal formation (HPFv), a region only recently highlighted in food intake control. Increased HPFv GLP-1R activity following exendin-4 administration potently reduced food intake (both chow and Western diet) and body weight, whereas HPFv GLP-1R blockade increased food intake. These hypophagic effects were based on reduced meal size, and likely do not involve nausea as HPFv exendin-4 did not induce a conditioned flavor avoidance. HPFv GLP-1R activation also reduced effort-based responding for food under an operant progressive ratio reinforcement schedule, but did not affect food conditioned place preference expression. To investigate possible routes of HPFv GLP-1 signaling, immunohistochemical analysis revealed the absence of GLP-1 axon terminals in the HPFv, suggesting volume transmission as a mechanism of action. Consistent with this, the presence of active GLP-1 was detected in both the cerebral spinal fluid (CSF) and the HPFv. The source of CSF GLP-1 may be NTS GLP-1-producing neurons, as, 1) ~30% of NTS GLP-1 neurons colocalized with the retrograde tracer fluorogold following lateral ventricle fluorogold injection, and 2) GLP-1-immunoreactive axon terminals were observed adjacent to the ventricular ependymal layer. Collectively these findings illuminate novel neuronal and behavioral mechanisms mediating food intake reduction by GLP-1.Neuropsychopharmacology accepted article preview online, 18 July 2014; doi:10.1038/npp.2014.175.
    Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 07/2014; 40(2). DOI:10.1038/npp.2014.175 · 7.83 Impact Factor
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    ABSTRACT: Nutrient stimulation of the enteroendocrine L-cells induces the release of the glucagon-like peptide-1 (GLP-1), an incretin and satiating peptide. Due to its short half-life, meal-induced GLP-1's effects on food intake and glycemia are likely to be mediated in part by a paracrine signaling mechanism near the site of release. Early and recent findings from vagus nerve lesion studies scrutinized in this review strongly support an important role of the vagus nerve in mediating GLP-1's effects. Peripheral GLP-1 or GLP-1R agonist treatment failed to elicit the full satiating effects and maintain glucose homeostasis in various lesion models. The potential mechanisms underlying the vagal GLP-1R mediated satiation and glycemic control presumably involve the activation of caudal brainstem neurons via glutamatergic signaling, which activate a vagal reflex loop or/and relay the information to higher brain centers. Recent studies also presented here, however, diminish the relevance of the vagus nerve for the pharmacological intervention of obesity and diabetes with chronic GLP-1R agonist treatments, suggesting that endogenous intestinal GLP-1 and GLP-1R agonists may activate different GLP-1R populations. Finally, lesion-based approaches are limited and new technical approaches are discussed to improve the understanding of vagal GLP-1R functions in maintaining normal energy balance and its relevance in pharmacological interventions. Copyright © 2015. Published by Elsevier Inc.
    Physiology & Behavior 06/2015; DOI:10.1016/j.physbeh.2015.06.001 · 3.03 Impact Factor