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Bourne Behavioral Research Laboratory, Department of Psychiatry, WMC Cornell University (G.J.S.), White Plains, New York 10605; and Department of Psychiatry and Behavioral Sciences, The Johns Hopkins University School of Medicine (T.H.M.), Baltimore, Maryland 21205
Address all correspondence and requests for reprints to: Gary J. Schwartz, Ph.D., Bourne Behavioral Research Laboratory, WMC Cornell University, 21 Bloomingdale Road, White Plains, New York 10605. E-mail: gjs2001{at}med.cornell.edu.
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Abstract |
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Introduction |
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MSH. Increasing leptin levels result in decreases in NPY and agouti-related peptide expression and increases in POMC expression, and these expression changes are thought to mediate the actions of leptin on food intake. Leptin’s ability to reduce food intake has been evaluated in terms of its effects on individual meals, the fundamental units of ingestive behavior in humans and rodents. Total daily food intake can be characterized in terms of the number and size of individual meals, and the feeding inhibitory effect of exogenous central leptin administration has been shown to be due to a reduction in meal size without changing meal frequency (3, 4, 5). These data have been interpreted to suggest that leptin reduces food intake by interacting with the neural mechanisms that mediate the negative feedback control of ingestion during a meal.
Physical, chemical, and secretagogue properties of food in the upper gastrointestinal tract have been demonstrated to limit the size of an individual meal. Gastric and intestinal distension, gastrointestinal nutrient infusions, and exogenous application of gut peptides normally released by the presence of food in the gut each have the potential to reduce food intake by reducing meal size (6, 7, 8, 9). The vagus nerve is the major neuroanatomical linkage between gut sites that handle ingested nutrients and the central nervous system sites that mediate the control of ingestion, and surgical or chemical interruption of gut vagal afferent signals 1) increase meal size and 2) block the ability of these meal-related gut stimuli to limit food intake (8, 9, 10). These data demonstrate that the afferent vagus carries signals important in the negative feedback control of food intake and meal size.
Leptin has been shown to alter the efficacy with which a number of meal-related signals reduce food intake. Thus, a dose of leptin that by itself has no effect on intake significantly increases the degree to which exogenous cholecystokinin (CCK) or a gastric nutrient preload reduces intake during a test meal (11, 12, 13). The likely site of action for these effects appears to be at the central nervous system level of the nucleus of the solitary tract (NTS), the site that receives primary vagal afferent input (14), because leptin affects both food intake and NTS neuronal activation in similar ways. Leptin alone does not result in NTS c-Fos activation, but it does increase the degree of c-Fos activation produced by CCK or gastric preload administration (12, 13). Consistent with these data, administration of the orexigenic peptide NPY reduces the degree of NTS c-Fos activation produced by peripheral CCK (15), suggesting that the saliency of meal-related feedback signaling can be increased or decreased by alterations in the activity of hypothalamic feeding-related signaling pathways.
The c-Fos results provide evidence for the effects of leptin and NPY on overall NTS activation, but do not address whether the responsivity of individual neurons to ascending satiety signals is altered by these peptides. To directly assess this issue, we examined the responsivity of NTS neurons to different degrees of gastric distention before and after third ventricular administration of leptin and NPY. The data demonstrate opposite modulatory actions of leptin and NPY on the ability of NTS neurons to respond to gastric distention that are consistent with their opposing actions on food intake.
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Materials and Methods |
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In all central and peripheral recording studies, rats received iv injections of 1 mg/kg atropine methyl nitrate before stimulus administration to selectively block peripheral cholinergic neurotransmission. This was done to minimize the possibility that central administration of leptin or NPY could affect vagal efferent outflow and gastrointestinal motility (16, 17), and thereby alter the responsivity of primary gut vagal afferents. We have previously demonstrated that atropine fails to attenuate the vagal afferent response to gastric loads (18).
Central neurophysiological recordings
Rats were food-deprived for 16 h before the acute neurophysiological studies were performed. Rats were anesthetized with ip urethane (1.0 mg/kg), and a femoral vein catheter was placed in the left vein using 0.12-in. inner diameter x 0.25-in. outer diameter silicone tubing (Hudson Medical Systems, Hudson, NY). Urethane was used because it improved the anesthetic stability of the rat for the relatively longer time required to prepare for central neurophysiological recording compared with peripheral vagal afferent studies. Core temperature was measured via a flexible rectal probe (YSI, Inc., Yellow Springs, OH) and was maintained at 36–37 C with a water-driven heating pad (Baxter Instruments, McGaw Park, IL) and an infrared heating lamp if the pad alone was insufficient. A surgical plane of anesthesia was maintained by 0.1 mg/0.1 ml iv injections of -chloralose (Sigma) dissolved in sterile saline. The ventrum of the rat was exposed, and a 2-cm midline incision was made through the abdominal wall to expose the pyloric sphincter. The sphincter was ligated as described previously (19) using a length of 4-0 silk. The esophagus was then exposed in the neck and an 8-Fr polyethelene feeding tube was guided into the stomach via a small incision in the esophagus. This tube was then tied in place using 4-0 silk. The exterior end of the gastric tube was attached to a 10-ml syringe and stopcock assembly to permit reversible filling and emptying of the ligated stomach using warm 37 C physiological saline. Rats received iv injections of Flaxedil (gallamine triethiode, Sigma; 0.1 mg/kg) as necessary to maintain tail pinch areflexia and immobility. A bilateral thoracostomy was performed using heat-flared PE200 chest tubes to minimize respiratory artifact, and rats were artificially ventilated throughout all experiments with 95% O2 via a heat-flared PE160 trachea tube friction fit to an Oxymax, Inc. (Plymouth, MN) small animal ventilator set at 60 breaths/min, 2.0–2.5 cc/breath. Heart rate and blood oxygenation were monitored throughout all experiments by a tail pulse oximeter (Medical Systems, Greenvale, NY).
Once a stable plane of anesthesia had been reached, rats were placed in a Kopf stereotaxic apparatus (Kopf Instruments, Tujunga, CA), with the head angled downward at 10 degrees. A midline incision was made through the skin and muscle from the back of the head to the interscapular region, and the neck muscles were removed, exposing the posterior skull and cervical vertebrae. A 1-cm segment of the dorsal brain stem, centered at the level of the area postrema, was exposed by removing the occipital plate of the skull and gently aspirating part of the caudal cerebellum when necessary to completely visualize the complete rostrocaudal extent of the area postrema. The lateral edges of the exposed brain stem were packed with gelfoam to minimize bleeding and form a well that held a small pool of warmed 37 C mineral oil over the recording sites on the brain stem.
Teflon-coated tungsten microelectrodes (1–5 MOhm impedance) with 2- to 4-µm exposed tips were used for all central brain stem recordings. A hydraulic micromanipulator (Narishige, Tokyo, Japan) was used to advance the recording electrode. Neuronal potentials were amplified using a high impedance preamplifier in series with a Grass amplifier (Grass Instruments, Quincy, MA). Amplified potentials were monitored on a dual beam storage oscilloscope (Tektronix, Wilsonville, OR) and an audio monitor (FHC, Inc., Bowdoinham, ME), and were fed into a dual time-amplitude window discriminator (BAK Electronics, Inc., Germantown, MD), to confirm the identification of an individual neuron’s time-amplitude spike profile for subsequent experimental testing. Only neurons whose window-discriminated action potentials generating at least 50 identical sweeps were used. The discriminated spike waveform was monitored throughout testing to confirm that the individual unit was continuously well isolated. Neurophysiological activity from each vagal or NTS unit was recorded on digital tape via a CDAT recorder (Cygnus, Inc., Delaware Water Gap, PA) and analyzed off-line for spike rate using digital acquisition hardware and SuperScope analysis software (GW Instruments, Somerville, MA).
The receptive field of each neuron was determined by gently, but firmly, probing the external gastric wall with a blunt-tipped glass rod (tip diameter, 1.2 mm) in the nondistended stomach. A receptive field was defined as a portion of the stomach wall where probing a 5-mm diameter region with a glass rod would elicit a rate of neuronal discharge at least 2 SD above the spontaneous rate. This method of receptive field determination has been used successfully in previous studies (19). Receptive fields were generated for each of the analyzed units in this study, and all were localized to the ventral gastric wall.
Recording electrodes were aimed at the level of the left NTS at depths ranging from 50–250 µm from the surface, at sites 10–300 µm lateral to the observed lateral border of the area postrema. The left NTS was chosen because it receives input from the larger of the two subdiaphragmatic vagal trunks (20).
Histological analysis
After the end of recordings, electrode tip site placement was confirmed by 5-mA, 10-sec constant current electrolytic lesions. This lesion technique typically produced a 30- to 50-µm diameter round site near the electrode tip. Rats were then intracardially perfused with heparinized PBS, followed by 10% formalin. Brains were removed and stored in 20% sucrose/10% formalin as a postfixative, then sectioned at 50 µm on a sliding microtome and stained with cresyl violet. Lesion sites at gastric load-responsive neurons were primarily localized to the gelatinosus, medial, and dorsomedial subnuclei of the NTS at the rostrocaudal level of the area postrema.
Peripheral vagal afferent neurophysiological recordings
Peripheral vagal afferent recordings were made in separate rats (n = 13) to assess whether centrally administered peptide might act peripherally to directly stimulate gut vagal afferents (21), thereby providing an indirect way of altering the NTS response to gastric loads. Peripheral vagal afferent neurophysiological studies were performed in im ketamine (100 mg/ml)/xylazine (20 mg/ml)-anesthetized rats (n = 13) by exposing the cervical vagus in the neck and isolating individual fibers with fine forceps, as described previously (19). Small bundles of decentralized vagal fibers were placed on tungsten hook electrodes (impedance, 5–12 MOhm). Intracerebroventricular (icv) injections were similar to the central neurophysiological methods described above.
Stimulus delivery
Gastric loads of 37 C physiological saline were delivered at approximately 0.5 ml/sec at volumes of 2, 4, 6, 8, and 10 ml and were held in place in the stomach by the ligation at the pyloric sphincter. Load volumes and rates of infusion were chosen based on previous experiments evaluating gastric load-responsive primary vagal afferents (18). Gastric loads were delivered in ascending order, and at least 3 min intervened between the end of one infusion and the beginning of the test. After the gastric load-dose-response function had been determined, either human recombinant leptin (PeproTech, Inc., Rocky Hills, NJ) or NPY (Bachem, Torrance, CA) was administered into the third icv cannula at a dose of 3.5 µg in a volume of 3.5 µl/2 min. Two hours later, the dose-response curve to gastric loads was reassessed. The leptin dose and the 2 h point was chosen to match times at which leptin has been demonstrated to alter feeding and c-Fos responses to CCK and gastric loads (12, 13). The NPY dose was chosen as a subthreshold dose to reduce food intake based on acute studies (15), where NPY has been demonstrated to modulate the feeding inhibitory effects of the gut-brain satiety peptide CCK.
Data analysis
Responses to stimuli were defined as at least a 2-SD increase above the average prestimulation baseline level of activity. Responses for each load were counted beginning at the time that the final volume for each gastric load was reached in each trial. Neural activity was also measured for 30 sec before the administration of each load to examine whether prestimulus baseline spike rates significantly changed over the course of the experiment. Data resulting from gastric load and icv saline vehicle, and leptin or NPY administration were analyzed by two-way repeated measures ANOVA, using load and icv injection treatment as fixed factors and the number of spikes occurring during the 30 sec of each load as the dependent measure. Planned t comparisons using the pooled interaction mean square error term were then used to determine whether individual load responses were significantly affected by the icv injection treatment.
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Results |
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]. Eight of the remaining rats received icv leptin injections, and the other 8 received icv NPY injections. In each set of 8 units, ANOVA revealed a significant effect of gastric load volume on NTS neuron spike rate [leptin group: F(7,35) = 30.5; P < 0.01; NPY group: F(7,35) = 39.8; P < 0.01].
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, top, and Fig. 3 top]. There was no significant interaction between leptin treatment and gastric load volume [F(1,5) = 0.3; P > 0.5]. Planned comparisons revealed that the leptin-induced increase in gastric load response occurred at the 2-, 4-, and 6-ml load volumes (P < 0.05), but the response to the highest volumes tested (8 and 10 ml) were not significantly affected by leptin treatment. In contrast to its action on NTS neurons, icv leptin had no effect on the response to gastric loads in primary vagal afferents with gastric receptive fields [F(1,5) = 1.3; Fig. 3, bottom].
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, top, and Fig. 4, top]. There was no significant interaction between NPY treatment and gastric load volume [F(1,5) = 0.7]. Planned comparisons revealed that the NPY-induced decrease in gastric load response occurred at 2-, 4-, 8-, and 10-ml load volumes (P < 0.05), but the response to 6 ml was not significantly affected. In contrast, icv NPY had no effect on the response to gastric loads in primary vagal afferents with gastric receptive fields [F(1,5) = 0.9; Fig. 4, bottom].
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The present data extend previous findings of leptin- induced increases in brain stem activation produced by meal-elicited negative feedback signals to the level of the individual sensory neuron. Emond et al. (14) showed that third ventricular administration of leptin increased the number of NTS neurons expressing c-Fos in response to gastric loads, and this effect was most prominent at the rostrocaudal level of the area postrema, consistent with the localization of the recording sites in the present study.
The range of gastric load volumes used in this study (2–10 ml) is well within the physiological range of volumes that accumulate in the stomach during ingestion of a liquid meal (24). A functional role for gastric load-stimulated vagal afferent input in the control of meal size has been shown by Phillips and Powley (6), in that both nutrient and nonnutrient gastric load volumes confined to the stomach with a pyloric cuff dose-dependently reduce food intake, and subdiaphragmatic vagotomies that interrupt vagal afferent signals from the stomach block the feeding inhibitory effects of these loads (25).
Although leptin and NPY were administered into the third ventricle, there are multiple possibilities for their site of action. The hypothalamic arcuate nucleus has been identified as a major target site for the feeding inhibitory actions of leptin. Leptin receptors are found on both NPY- and POMC-expressing neurons (1, 2). A projection site for these neurons is the hypothalamic paraventricular nucleus (26, 27), and the paraventricular nucleus (PVN) is a site at which NPY potently stimulates food intake (28). PVN neurons project to the NTS (29), and PVN electrical stimulation has been demonstrated to modify the activity of gastric distention-responsive NTS neurons and dorsal motor nucleus neurons (30). Thus, these peptides could be activating descending hypothalamic pathways to modify NTS reactivity.
Alternatively, both of these peptides could be exerting their effects at hindbrain sites. The NTS contains leptin receptors (17, 31), and fourth ventricular or direct NTS leptin administration has been demonstrated to inhibit food intake (31). Similarly, NPY receptors are found within the NTS (32), and fourth ventricular NPY administration has been demonstrated to potently increase food intake (33). Thus, the ability of third ventricular leptin or NPY to modulate the responsivity of NTS neurons to gastric distention could be mediated at either forebrain or hindbrain sites.
The mechanisms underlying the actions of leptin and NPY on the responsivity of NTS neurons remain to be determined. However, data from experiments examining the actions of NPY and leptin within the hypothalamus provide potential explanations. Leptin has been demonstrated to increase the frequency of action potentials in POMC-expressing neurons through two mechanisms (34). It causes a direct, concentration-dependent depolarization of POMC neurons through the activation of a nonspecific cation channel and reduces the frequency of inhibitory postsynaptic current mediated by local NPY and 
-aminobutyric acid (GABA)-ergic neurons. Thus, leptin appears to have both pre- and postsynaptic actions that each increase the responsivity of hypothalamic POMC neurons. This predicted increase would potentially increase endogenous melanocortin agonist release (e.g. MSH), which could act at melanocortin brain stem receptor sites to modulate the neural processing and behavioral potency of ascending gut vagal afferent signals. In support of this possibility, brain stem application of the melanocortin 3/4 receptor agonist MTII reduces food intake and meal size (35). NPY, in contrast, seems to function as a presynaptic inhibitor of neuronal function in the PVN by increasing inhibitory GABAergic-evoked currents, implying that NPY directly increases GABA release (27). Leptin and NPY could be acting through these hypothalamic mechanisms to modulate NTS neuronal responses to gastric distention by modifying output neurons innervating the NTS or through similar direct mechanisms at the level of the NTS.
Leptin and NPY may also be modulating NTS responses to other ascending meal-related vagal afferent inputs in producing their opposing effects on food intake. Both NTS neurons and primary vagal afferents that respond to gastric distention also respond to administration of the brain gut peptide CCK (19, 36, 37). Thus, leptin and NPY’s ability to modulate feeding and c-Fos responses to CCK may reflect alterations in the responsivity of this same population of NTS neurons. Vagal afferents and NTS neurons also respond to intestinal nutrient infusions (38, 39, 40, 41), and surgical and chemical interruption of intestinal vagal afferent signaling significantly attenuates the reductions in meal size produced by these infusions (8, 9). It seems likely that leptin and NPY would have the ability to alter NTS responsivity to this class of feedback signals in a manner similar to that demonstrated in the current study.
Leptin and leptin activated hypothalamic signaling pathways have now been demonstrated to alter ingestion in a variety of settings, but the neurobiological mechanisms through which activation of these pathways translates into behavioral changes remain unclear. The present results make an important contribution to this question, in that they demonstrate a direct effect of leptin and NPY on the neural responses to within-meal feeding stimuli. Thus, these data provide a conceptual basis for linking forebrain hypothalamic signaling pathways important in overall energy balance to hindbrain sensory systems critical to the negative feedback systems controlling meal size. Such important interactions both increase our understanding of the neural network engaged in the control of food intake and provide a mechanistic framework for considering how food intake is altered by metabolic status. For example, during a fast, leptin levels decrease, whereas NPY levels are increased, and the present data suggest that both of theses changes would be expected to reduce the saliency of meal-elicited negative feedback signals. Consequently, a greater amount of food intake would be required to achieve the normal level of food-elicited negative feedback in the central nervous system. In contrast, in conditions where NPY is reduced and leptin is elevated, such as after a period of overfeeding, the negative feedback signals elicited by food would have a greater impact on NTS activity. This increased activation may mediate the observed reduction in intake following overfeeding.
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Footnotes |
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Abbreviations: CCK, Cholecystokinin; GABA, -aminobutyric acid; icv, intracerebroventricular; NPY, neuropeptide Y; NTS, nucleus of the solitary tract; POMC, proopiomelanocortin; PVN, paraventricular nucleus.
Received March 27, 2002.
Accepted for publication June 5, 2002.
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