Leptin and the Control of Food Intake: Neurons in the Nucleus of the Solitary Tract are Activated by both Gastric Distention and Leptin

Harvard University, Cambridge, Massachusetts, United States
Endocrinology (Impact Factor: 4.64). 06/2007; 148(5):2189-97. DOI: 10.1210/en.2006-1572
Source: PubMed

ABSTRACT Leptin reduces food intake by an unspecified mechanism. Studies show that forebrain ventricular leptin delivery increases the inhibitory effects of gastrointestinal (GI) stimulation on intake and amplifies the electrophysiological response to gastric distension in neurons of the medial subnucleus of the nucleus tractus solitarius (mNTS). However, forebrain ventricular delivery leaves unspecified the neuroanatomical site(s) mediating leptin's effect on intake. Detailed anatomical analysis in rats and mice by phosphorylated signal transducer and activator of transcription 3 immunohistochemistry shows that hindbrain leptin-responsive neurons are located exclusively within the mNTS. Here, we investigate 1) whether leptin and gastric distension affect the same mNTS neurons and 2) whether the intake-inhibitory action of gastric distension is potentiated by hindbrain leptin delivery. Twenty-five minutes after gastric balloon distension or sham distension, rats were injected with leptin or vehicle and killed 35 min later. Double-fluorescent immunohistochemistry for phosphorylated signal transducer and activator of transcription 3 and c-Fos revealed that about 40% of leptin-responsive cells also respond to gastric distension. A paradigm was then developed to examine the relationship between leptin and gastric distension volume on intake inhibition. At subthreshold levels, hindbrain ventricular leptin or distension volume were without effect. When combined, an interaction occurred that significantly reduced food intake. We conclude that 1) leptin-responsive neurons in the hindbrain are primarily located in the mNTS at the level of the area postrema, a key vagal afferent projection zone of the GI system; 2) a significant proportion of leptin-responsive neurons in the mNTS are activated by stomach distension; and 3) leptin delivered to the hindbrain is sufficient to potentiate the intake-suppressive effects of an otherwise ineffective volume of gastric distension. These results are consistent with the hypothesis that leptin acts directly on neurons within the mNTS to reduce food intake through an interaction with GI signal processing.

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Available from: Christian Bjørbaek, Aug 11, 2015
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    • " et al . , 1998 ) and would suggest the dorsovagal complex as a site where these modalities may interact . Catechol aminergic neurons in NTS were identified as a site of interaction with CCK signaling ( Rinaman , 2003 ) . In a double - labeling study , w40% of leptin - responsive cells in the medial NTS were also responsive to gastric distension ( Huo et al . , 2007 ) . Different modes of esophageal distension map to different loci within the NTS , area postrema and DMX ( Lang et al . , 2011 ) . It thus appears that oppor tunities for complex inter - modal interaction of meal - related signals within dorsovagal circuits are plentiful , and we may expect certain combinations of signals to be synergi"
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    ABSTRACT: The dorsovagal complex comprises: (1) a chemosensory structure, the area postrema (AP), (2) a center for integrating distension, mechanosensory and other inputs from the viscera, the nucleus of the tractus solitarius (NTS), and (3) a center to integrate motor and secretory drive to the viscera, the dorsal motor nucleus of the vagus (DMX). There is recent evidence for considerable autonomy of dorsovagal reflexes traversing this loop in ingestive control, especially in meal-termination/anorexic responses, and in other controls on nutrient flux. The characteristics of this system, including (1) activation of several parallel effector pathways, and (2) glucose-sensitivity (hypoglycemic override) have profound therapeutic implications for anti-diabetic and anti-obesity drug development. Agents acting via the brain structures similar to those activated by amylin promise efficacy via multiple effectors, but, via glucose-dependence of effects, without increased risk of hypoglycemia. Several peptides, including those secreted in response to meals, are sensed at area postrema, and because they degrade to innocuous metabolites (amino acids) are thereby candidates as safe and effective drugs. Recently developed GLP-1 agonists and amylin agonists are examples of the therapeutic potential of such agents for metabolic diseases. Others in development include PYY agonists and MC4 agonists. Especially promising may be combinations of peptides and/or their analogs. Certain pairs of peptides, including those acting via the dorsovagal complex, exhibit surprising synergies (eg amylin + CCK (Bhavsar et al., 1998), amylin + leptin (Roth et al., 2008), CCK + glucagon + bombesin (Hinton et al., 1986), PYY and GLP-1 (Paulik et al., 2011)). Peptide combinations may thus attain transformational efficacy without invoking burdensome toxic risk. This article is part of a Special Issue entitled 'Central Control of Food Intake'.
    Neuropharmacology 03/2012; 63(1):31-45. DOI:10.1016/j.neuropharm.2012.03.019 · 4.82 Impact Factor
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    • "The importance of leptin signaling in the hypothalamus (Balthasar et al, 2004; Dhillon et al, 2006; Leinninger et al, 2009) and the caudal brainstem (Grill et al, 2002; Huo et al, 2007; Hayes et al, 2010) is established for the homeostatic or need-based control of food intake. However, given that the excessive food intake that contributes to human obesity is generally not driven by metabolic need, it is critical to examine and better define the neural basis of nonhomeostatic controls on food intake. "
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    ABSTRACT: The increase in obesity prevalence highlights the need for a more comprehensive understanding of the neural systems controlling food intake; one that extends beyond food intake driven by metabolic need and considers that driven by higher-order cognitive factors. The hippocampus, a brain structure involved in learning and memory function, has recently been linked with food intake control. Here we examine whether administration of the adiposity hormone leptin to the dorsal and ventral sub-regions of the hippocampus influences food intake and memory for food. Leptin (0.1 μg) delivered bilaterally to the ventral hippocampus suppressed food intake and body weight measured 24 h after administration; a higher dose (0.4 μg) was needed to suppress intake following dorsal hippocampal delivery. Leptin administration to the ventral but not dorsal hippocampus blocked the expression of a conditioned place preference for food and increased the latency to run for food in an operant runway paradigm. Additionally, ventral but not dorsal hippocampal leptin delivery suppressed memory consolidation for the spatial location of food, whereas hippocampal leptin delivery had no effect on memory consolidation in a non-spatial appetitive response paradigm. Collectively these findings indicate that ventral hippocampal leptin signaling contributes to the inhibition of food-related memories elicited by contextual stimuli. To conclude, the results support a role for hippocampal leptin signaling in the control of food intake and food-related memory processing.
    Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 05/2011; 36(9):1859-70. DOI:10.1038/npp.2011.70 · 7.83 Impact Factor
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    • "Le premier et principal signal déclenchant le réflexe de satiété est la distension mécanique de l'estomac par l'arrivée d'aliments ingérés, qui stimule des fibres nerveuses sensorielles du nerf vague (ou nerf X, dixième paire de nerfs crâniens) portant des mécanorécepteurs. Ce mécanisme neurosensoriel intervient dès les premières minutes du remplissage de l'estomac ; il peut être mimé expérimentalement chez un animal à jeun par simple gonflement d'un ballonnet introduit à l'intérieur de l'estomac (Huo et al 2007). La présence d'aliments est également détectée par des terminaisons vagales équipées de chimiorécepteurs, qui sont réceptives surtout aux protéines et innervent plutôt l'intestin ; cette chimiosensibilité sert à pondérer l'impact de la mécanoréception sur l'appétit en fonction du contenu calorique des ingestats (Powley & Philips 2004). "
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