The nucleus tractus solitarius: a portal for visceral afferent signal processing, energy status assessment and integration of their combined effects on food intake.
ABSTRACT For humans and animal models alike there is general agreement that the central nervous system processing of gastrointestinal (GI) signals arising from ingested food provides the principal determinant of the size of meals and their frequency. Despite this, relatively few studies are aimed at delineating the brain circuits, neurochemical pathways and intracellular signals that mediate GI-stimulation-induced intake inhibition. Two additional motivations to pursue these circuits and signals have recently arisen. First, the success of gastric-bypass surgery in obesity treatment is highlighting roles for GI signals such as glucagon-like peptide-1 (GLP-1) in intake and energy balance control. Second, accumulating data suggest that the intake-reducing effects of leptin may be mediated through an amplification of the intake-inhibitory effects of GI signals. Experiments reviewed show that: (1) the intake-suppressive effects of a peripherally administered GLP-1 receptor agonist is mediated by caudal brainstem neurons and that forebrain-hypothalamic neural processing is not necessary for this effect; (2) a population of medial nucleus tractus solitarius (NTS) neurons that are responsive to gastric distention is also driven by leptin; (3) caudal brainstem-targeted leptin amplifies the food-intake-inhibitory effects of gastric distention and intestinal nutrient stimulation; (4) adenosine monophosphate-activated protein kinase (AMPK) activity in NTS-enriched brain lysates is elevated by food deprivation and reduced by refeeding and (5) the intake-suppressive effect of hindbrain-directed leptin is reversed by elevating hindbrain AMPK activity. Overall, data support the view that the NTS and circuits within the hindbrain mediate the intake inhibition of GI signals, and that the effects of leptin on food intake result from the amplification of GI signal processing.
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ABSTRACT: Early islet graft survival is crucial in determining the outcome after clinical islet transplantation. Exendin-4 has anti-apoptotic and beta cell proliferative properties, which could improve islet graft survival and function. The aim of these studies was to evaluate the effect of exendin-4 on graft function after islet transplantation. Rat islets were transplanted under the kidney capsule of diabetic athymic mice. First, we performed a dose-finding study and found that 30 islets just failed to cure diabetic mice. In the following two studies, we transplanted 30 islets and treated the mice that had received these islets with exendin-4 i.p. (100 ng/mouse) once daily for 1 week. Blood glucose levels and body weights were used as evaluation criteria. In the short-term study evaluation was done at day 8. This study was followed by a long-term study that was evaluated at 4 weeks. In this study, islets were precultured with exendin-4 (0.1 nmol/l) in addition to the treatment given to mouse-recipients of transplanted islets. The cured mice underwent an intraperitoneal glucose tolerance test (IPGTT). In the short-term study, 63% of exendin-4-treated mice achieved graft function compared with 21% of untreated mice (p = 0.033). In the long-term study, 88% of treated mice had functioning grafts compared with 22% of controls (p = 0.015). Cured mice showed a normal response in the IPGTT, comparable to that of healthy mice. Exendin-4-treated mice gained significantly more weight than their untreated counterparts. Islet preculture and a short course of therapy with exendin-4 improves metabolic control after rat islet transplantation in athymic mice. The beneficial effect lasts beyond the treatment period.Diabetologia 07/2006; 49(6):1247-53. · 6.49 Impact Factor
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ABSTRACT: Intracerebroventricular administration of glucagon-like peptide-1 (7-36) amide (GLP-1) reduces food intake and produces symptoms of visceral illness, such as a conditioned taste aversion (CTA). The central hypothesis of the present work is that separate populations of GLP-1 receptors mediate the anorexia and taste aversion associated with GLP-1 administration. To test this hypothesis, we first compared the ability of various doses of GLP-1 to induce anorexia or CTA when administered into either the lateral or fourth ventricle. Lateral and fourth ventricular GLP-1 resulted in reduction of food intake at similar doses, whereas only lateral ventricular GLP-1 resulted in a CTA. Such data indicate that both hypothalamic and caudal brainstem GLP-1 receptors are likely to participate in the ability of GLP-1 to reduce food intake. We also hypothesized that the site that must mediate the ability of GLP-1 to induce visceral illness is in the central nucleus of the amygdala (CeA). Administration of 0.2 or 1.0 microg of GLP-1 (7-36) but not the inactive GLP-1 (9-36) resulted in a strong CTA with no accompanying anorexia. In addition, bilateral CeA administration of 2.5 microg of a GLP-1 receptor antagonist before intraperitoneal administration of the toxin lithium chloride resulted in a diminished CTA. Together, these data indicate that separate GLP-1 receptor populations mediate the multiple responses to GLP-1. These results indicate that GLP-1 is a flexible system that can be activated under various circumstances to alter the ingestion of nutrients and/or produce other visceral illness responses, depending on the ascending pathways of the GLP-1 system that are recruited.Journal of Neuroscience 01/2003; 22(23):10470-6. · 6.91 Impact Factor
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ABSTRACT: The rat's willingness to ingest glucose after an initial intraoral intake test was probed by beginning a 2nd intraoral intake test at variable durations (1-120 min). In Experiment 1, after an initial meal of 12.5% glucose solution averaging 26.9 +/- 1.7 ml (SEM, n = 10), the size of the 2nd (probe) meal of the same stimulus increased linearly from 4.0 +/- 0.9 ml after a 1-min delay to 15.4 +/- 2.7 ml after a 120-min delay. In Experiment 2, intraoral intake of a more concentrated (37.5%) glucose solution rose more slowly as a function of delay from 2.4 +/- 2.7 ml (SEM, n = 12) to 4.9 +/- 0.6 ml. For each glucose concentration, the linear recovery function and a slope that depends on stimulus concentration are consistent with a role for gastric emptying during the delay in intake recovery. In Experiment 3, rats ingested 12.5% or 37.5% glucose to satiety in an initial test and received, after a variable delay, either the same or the other concentration as the probe stimulus. The same volumes were ingested at each delay whether the glucose concentration of the probe stimulus was the same or was switched from that presented in the initial test. This result shows that the taste and caloric properties of the probe stimulus played no role in determining how much of it would be ingested. Rather, the satiety criterion for the probe test was reached on the basis of the volume ingested.(ABSTRACT TRUNCATED AT 250 WORDS)Behavioral Neuroscience 05/1994; 108(2):353-61. · 2.63 Impact Factor