Leptin and the Control of Food Intake: Neurons in the Nucleus of the Solitary Tract (NTS) are Activated by Both Gastric Distension and Leptin

Harvard University, Cambridge, Massachusetts, United States
Endocrinology (Impact Factor: 4.5). 06/2007; 148(5):2189-97. DOI: 10.1210/en.2006-1572
Source: PubMed


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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    • "For non-fluorescent light microscopy, free-floating brain sections were incubated with biotinylated secondary antibodies, followed by avidin-biotin complex labeling, and developed with nickel-diaminobenzidine (DAB), generating a brown-black precipitate for analyses by light microscopy (LM)[19,30]. For fluorescence microscopy, the free-floating sections were incubated with fluorescent-labeled secondary antibodies [44,45]. In the case of HA immunofluorescence, TSA procedures were applied to enhance sensitivity (Perkin Elmer). "
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    ABSTRACT: Leptin acts via neuronal leptin receptors to control energy balance. Hypothalamic pro-opiomelanocortin (POMC) and agouti-related peptide (AgRP)/Neuropeptide Y (NPY)/GABA neurons produce anorexigenic and orexigenic neuropeptides and neurotransmitters, and express the long signaling form of the leptin receptor (LepRb). Despite progress in the understanding of LepRb signaling and function, the sub-cellular localization of LepRb in target neurons has not been determined, primarily due to lack of sensitive anti-LepRb antibodies. Here we applied light microscopy (LM), confocal-laser scanning microscopy (CLSM), and electron microscopy (EM) to investigate LepRb localization and signaling in mice expressing a HA-tagged LepRb selectively in POMC or AgRP/NPY/GABA neurons. We report that LepRb receptors exhibit a somato-dendritic expression pattern. We further show that LepRb activates STAT3 phosphorylation in neuronal fibers within several hypothalamic and hindbrain nuclei of wild-type mice and rats, and specifically in dendrites of arcuate POMC and AgRP/NPY/GABA neurons of Leprb (+/+) mice and in Leprb (db/db) mice expressing HA-LepRb in a neuron specific manner. We did not find evidence of LepRb localization or STAT3-signaling in axon-fibers or nerve-terminals of POMC and AgRP/NPY/GABA neurons. Three-dimensional serial EM-reconstruction of dendritic segments from POMC and AgRP/NPY/GABA neurons indicates a high density of shaft synapses. In addition, we found that the leptin activates STAT3 signaling in proximity to synapses on POMC and AgRP/NPY/GABA dendritic shafts. Taken together, these data suggest that the signaling-form of the leptin receptor exhibits a somato-dendritic expression pattern in POMC and AgRP/NPY/GABA neurons. Dendritic LepRb signaling may therefore play an important role in leptin's central effects on energy balance, possibly through modulation of synaptic activity via post-synaptic mechanisms.
    PLoS ONE 12/2013; 8(10):e77622. DOI:10.1371/journal.pone.0077622 · 3.23 Impact Factor
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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 · 5.11 Impact Factor
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    • "More recently, we have shown that GLP-1R expressed specifically within the medial subnucleus of the NTS (mNTS), at the level of the area postrema, are critical to food intake regulation 19–20. It is interesting to note that neurons in this region of the mNTS also process: 1] vagally mediated satiation signals that arise from the gastrointestinal (GI) tract following ingestion of food 21–22, and 2] signals conveying long-term energy storage, such as the adipose-tissue derived hormone leptin 23–24. Therefore, it may be that GLP-1R signaling specific to the mNTS participates in the control of food intake by interacting with and enhancing the intake inhibitory effects of these other anorectic signals that require mNTS processing. "
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    ABSTRACT: Background The physiological control of feeding behavior involves modulation of the intake inhibitory effects of gastrointestinal satiation signaling via endogenous hindbrain leptin receptor (LepR) and glucagon-like-peptide-1 receptor (GLP-1R) activation. Design and Results Using a variety of dose-combinations of hindbrain delivered (4th icv) leptin and the GLP-1R agonist exendin-4, experiments demonstrate that hindbrain LepR and GLP-1R signaling interact to control food intake and body weight in an additive fashion. In addition, the maximum intake suppressive response that could be achieved by 4th icv leptin alone in non-obese rats (~33%) was shown to be further suppressed when exendin-4 was co-administered. Importantly, it was determined that the interaction between hindbrain LepR signaling and GLP-1R signaling is relevant to endogenous food intake control, as hindbrain GLP-1R blockade by the selective antagonist exendin-(9–39) attenuated the intake inhibitory effects of hindbrain leptin delivery. Conclusions Collectively, the findings reported here show that hindbrain LepR and GLP-1R activation interact in at least an additive fashion to control food intake and body weight. As evidence is accumulating that combination pharmacotherapies offer greater sustained food intake and body weight suppression in obese individuals when compared to mono-drug therapies or lifestyle modifications alone, these findings highlight the need for further examination of combined CNS GLP-1R and LepR signaling as a potential drug target for obesity treatment.
    International journal of obesity (2005) 01/2012; 36(12). DOI:10.1038/ijo.2011.265 · 5.00 Impact Factor
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