Grill HJ, Hayes MR. The nucleus tractus solitarius: a portal for visceral afferent signal processing, energy status assessment and integration of their combined effects on food intake. Int J Obes (Lond) 33(Suppl 1): S11-S15

Psychology and Neuroscience, University of Pennsylvania, Philadelphia, PA, USA.
International journal of obesity (2005) (Impact Factor: 5). 05/2009; 33 Suppl 1(Suppl 1):S11-5. DOI: 10.1038/ijo.2009.10
Source: PubMed

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.

Download full-text


Available from: Harvey Grill, Jun 16, 2015
8 Reads
  • Source
    • "Their brainstem is at the core of the neuroinflammatory process with high immunoreactivity for 8 hydroxi-deoxyguanosine , activated microglia and accumulation of alpha synuclein involving the ventral tegmental area, substantia nigrae, nucleus ambiguus, and the dorsal motor nucleus of the vagus, among others. The anatomical areas involved in Mexico City children overlap the well described leptin cellular targets (Steppan and Swick, 1999; Grill and Hayes, 2009; Scott et al., 2009; Bouret, 2013). The arcuate nucleus of the hypothalamus, hippocampus, cortical neurons, insular cortex, lateral septal nucleus, ventral tegmental area and midbrain dopaminergic neurons express leptin receptors and are influenced by signals that carry information Table 2 Means and standard deviations for vitamin D, adipokines and food reward hormones values in Control and Metropolitan Mexico City area children. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Millions of Mexico, US and across the world children are overweight and obese. Exposure to fossil-fuel combustion sources increases the risk for obesity and diabetes, while long-term exposure to fine particulate matter (PM2.5) and ozone (O3) above US EPA standards is associated with increased risk of Alzheimer's disease (AD). Mexico City Metropolitan Area children are chronically exposed to PM2.5 and O3 concentrations above the standards and exhibit systemic, brain and intrathecal inflammation, cognitive deficits, and Alzheimer disease neuropathology. We investigated adipokines, food reward hormones, endothelial dysfunction, vitamin D and apolipoprotein E (APOE) relationships in 80 healthy, normal weight 11.1±3.2 year olds matched by age, gender, BMI and SES, low (n: 26) versus high (n:54) PM2.5 exposures. Mexico City children had higher leptin and endothelin-1 (p<0.01 and p<0.000), and decreases in glucagon-like peptide-1 (GLP 1), ghrelin, and glucagon (<0.02) versus controls. BMI and leptin relationships were significantly different in low versus high PM2.5 exposed children. Mexico City APOE 4 versus 3 children had higher glucose (p=0.009). Serum 25-hydroxyvitamin D<30ng/mL was documented in 87% of Mexico City children. Leptin is strongly positively associated to PM 2.5 cumulative exposures. Residing in a high PM2.5 and O3 environment is associated with 12h fasting hyperleptinemia, altered appetite-regulating peptides, vitamin D deficiency, and increases in ET-1 in clinically healthy children. These changes could signal the future trajectory of urban children towards the development of insulin resistance, obesity, type II diabetes, premature cardiovascular disease, addiction-like behavior, cognitive impairment and Alzheimer's disease. Increased efforts should be made to decrease pediatric PM2.5 exposures, to deliver health interventions prior to the development of obesity and to identify and mitigate environmental factors influencing obesity and Alzheimer disease.
    Environmental Research 05/2015; 140:579-592. DOI:10.1016/j.envres.2015.05.012 · 4.37 Impact Factor
  • Source
    • "The central sites integrating hunger and satiety signals such as the hypothalamus and brainstem are potential drug target areas to treat eating disorders and obesity (Grill and Hayes, 2009; Berthoud, 2012). Among the involved signals is a-melanocyte-stimulating hormone (a-MSH), a 13 amino acid acylated neuropeptide produced in the arcuate nucleus of the hypothalamus (Harris and Lerner, 1957). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Chronic delivery of neuropeptides in the brain is a useful experimental approach to study their long-term effects on various biological parameters. In this work, we tested albumin-alginate microparticles, as a potential delivery system, to study if continuous release in the hypothalamus of α-melanocyte-stimulating hormone (α-MSH), an anorexigenic neuropeptide, may result in a long-term decrease in food intake and body weight. The 2-week release of α-MSH from peptide-loaded particles was confirmed by an in vitro assay. Then, daily food intake and body weight were studied for 18 days in rats injected bilaterally into the paraventricular hypothalamic nucleus with particles loaded or not with α-MSH. A decrease in body weight gain, persisting throughout the study, was found in rats injected with α-MSH-charged particles as compared with rats receiving non-charged particles and with rats injected with the same dose of α-MSH in solution. Food intake was significantly decreased for 3 days in rats receiving α-MSH-loaded particles and it was not followed by the feeding rebound effect which appears after food restriction. The presence of α-MSH-loaded particles in the hypothalamus was confirmed by immunohistochemistry. In conclusion, our study validates albumin-alginate microparticles as a new carrier system for long-term delivery of neuropeptides in the brain and demonstrates that chronic delivery of α-MSH in the hypothalamus results in a prolonged suppression of food intake and a decrease of body weight gain in rats. Copyright © 2015. Published by Elsevier Ltd.
    Neuroscience 01/2015; 290. DOI:10.1016/j.neuroscience.2015.01.037 · 3.36 Impact Factor
  • Source
    • "The NTS is formed by heterogeneous groups of neurons located in the dorsolateral medulla, extending from the level of caudal portion of the facial nucleus to the caudal portion of the pyramidal decussation (Loewy, 1990; Dampney, 1994). Previous studies have demonstrated that the NTS plays a key role in the processing of visceral afferent information and transmission to other nuclei in the brainstem, forebrain and spinal cord (for review, see Andresen and Kunze, 1994; Sapru, 1996; Johnson and Thunhorst, 1997; Grill and Hayes, 2009). With respect to the cardiovascular and respiratory systems, the majority of the cardiorespiratory afferents converges preferentially to two different regions of the NTS: the intermediate NTS (iNTS), at the level of the area postrema, and the caudal NTS (cNTS), located caudal to the calamus scriptorius (Kumada et al., 1990; Loewy, 1990; Van Giersbergen et al., 1992). "
    [Show abstract] [Hide abstract]
    ABSTRACT: It is well known that breathing introduces rhythmical oscillations in the heart rate and arterial pressure levels. Sympathetic oscillations coupled to the respiratory activity have been suggested as an important homeostatic mechanism optimizing tissue perfusion and blood gas uptake/delivery. This respiratory-sympathetic coupling is strengthened in conditions of blood gas challenges (hypoxia and hypercapnia) as a result of the synchronized activation of brainstem respiratory and sympathetic neurons, culminating with the emergence of entrained cardiovascular and respiratory reflex responses. Studies have proposed that the ventrolateral region of the medulla oblongata is a major site of synaptic interaction between respiratory and sympathetic neurons. However, other brainstem regions also play a relevant role in the patterning of respiratory and sympathetic motor outputs. Recent findings suggest that the neurons of the nucleus of the solitary tract (NTS), in the dorsal medulla, are essential for the processing and coordination of respiratory and sympathetic responses to hypoxia. The NTS is the first synaptic station of the cardiorespiratory afferent inputs, including peripheral chemoreceptors, baroreceptors and pulmonary stretch receptors. The synaptic profile of the NTS neurons receiving the excitatory drive from afferent inputs is complex and involves distinct neurotransmitters, including glutamate, ATP and acetylcholine. In the present review we discuss the role of the NTS circuitry in coordinating sympathetic and respiratory reflex responses. We also analyze the neuroplasticity of NTS neurons and their contribution for the development of cardiorespiratory dysfunctions, as observed in neurogenic hypertension, obstructive sleep apnea and metabolic disorders.
    Frontiers in Physiology 06/2014; 5:238. DOI:10.3389/fphys.2014.00238 · 3.53 Impact Factor
Show more