The nucleus tractus solitarius: a portal for visceral
afferent signal processing, energy status assessment
and integration of their combined effects on food
HJ Grill and MR Hayes
Psychology and Neuroscience, University of Pennsylvania, Philadelphia, PA, USA
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.
International Journal of Obesity (2009) 33, S11–S15; doi:10.1038/ijo.2009.10
Keywords: GLP-1; leptin; vagus; caudal brainstem; AMP kinase
The ingestion of food gives rise to mechanical and chemical
stimulation of the gastrointestinal (GI) tract and, in turn, to
the secretion of a variety of GI hormones. These events
activate vagal afferent neurons, which project to and
stimulate the central–visceral afferent pathway, which in
turn includes neurons located in the medulla, pons,
hypothalamus and ventral forebrain. Specific subnuclei of
the nucleus tractus solitarius (NTS) are the first central
neurons to process ingestion-related vagal afferent signals.
Central processing of these signals is widely regarded as the
primary determinant of the reduced food intake that follows
meal consumption.1For this reason, research aimed at
defining the central nervous system (CNS) circuits and
neurochemical events that mediate the intake-inhibitory
action of GI signals is likely to provide clues to the
development of new obesity treatments. The clinical rele-
vance of GI signals and their central processing is under-
scored by the success of gastric-bypass surgery in treating
morbid obesity and type 2 diabetes mellitus. Analyses of
large numbers of gastric-bypass cases show that on average,
patients lose B35% of their pre-surgery body weight within
the initial year and that 10 years post-surgery, the majority of
the lost weight is not regained.2,3Recent attention to the
factors contributing to the efficacy of bypass surgery focuses
on the combination of increased circulating levels of the
distal gut hormones glucagon-like peptide-1 (GLP-1) and
peptide YY 3–36, as well as on the reduced stimulation of the
‘bypassed’ stomach and duodenum as causal in the clinical
Correspondence: Professor HJ Grill, Psychology and Neuroscience, University
of Pennsylvania, Philadelphia, PA, USA.
International Journal of Obesity (2009) 33, S11–S15
& 2009 Macmillan Publishers Limited All rights reserved 0307-0565/09 $32.00
outcomes. Further support for the contribution of GI signals
and their CNS-mediated effects to the physiological control
of energy balance comes from the recent success of the
GLP-1 analog, exendin-4 (Ex-4), a modified peptidase-
resistant GLP-1 analog, in the treatment of type 2 diabetes
and from the indications that this treatment also results in
body weight loss.4,5This paper focuses on CNS neurons that
mediate the intake-reducing effects that arise from the action
of nutrients on the GI tract. Ligand activation of glucagon-
like peptide-1 receptors (GLP-1R) in the abdomen serves as a
model. In addition to the direct contribution of satiation
signals arising from the GI tract,1other energy status signals
also play a critical role in determining meal consumption.
Treatment with leptin, an adipose tissue-derived energy
status signal, reduces food intake through an action on CNS
neurons. Although the mechanism(s) and the CNS neurons
mediating leptin’s intake-reducing effects remain unspeci-
fied, insight into a possible mechanism comes from the
finding that the reduced feeding triggered by leptin results
from an effect on meal size.6–8This result suggests that
leptin’s intake suppressive action involves an amplification
of the processing of GI signals in the central neurons. Data
that are consistent with this perspective are discussed below.
Glucagon-like peptide-1, released from ‘L’-type enteroendo-
crine cells in the distal small intestine in response to nutrient
stimulation, acts on peripheral GLP-1R.9,10Endogenous
release or intraperitoneal GLP-1R agonist delivery triggers a
set of responses that include reduced food intake,11–14
inhibition of gastric emptying,9,14stimulation of glucose-
dependent insulin secretion15,16and tachycardia.17–21GLP-
1R ligand is also supplied by proglucagon-expressing neu-
rons of the caudal brainstem that project to GLP-1Rs, which
are distributed throughout the brain.22–24It is interesting to
note that stimulation of central GLP-1R results in many of
the same responses, for example, inhibition of food intake
and increased insulin secretion, as are observed following
peripheral ligand injection. It is, however, still unclear
whether the central GLP-1 system contributes to the control
of energy balance and whether the peripheral and central
GLP-1 systems are functionally related.
The effects of peripheral GLP-1R stimulation are trans-
mitted to the CNS by vagal afferent transmission. The
feeding and gastric emptying inhibition triggered by periph-
eral GLP-1R ligand injections is blocked by vagotomy or by
vagal de-afferentation with capsaicin treatment,9–11suggest-
ing that peripherally administered ligand does not produce
its functional effects through direct activation of central
GLP-1Rs. The vagally transmitted effects of peripheral
GLP-1R stimulation therefore involve behavioral and auto-
nomic effector pathways that are downstream of CNS
processing.17–19,21,25Structures in the ascending visceral
afferent pathway, which includes nuclei of the caudal
brainstem (NTS; parabrachial nucleus), hypothalamus (lat-
eral hypothalamus; paraventricular nucleus) and basal fore-
brain (bed nucleus of stria terminalis; central nucleus of the
amygdala),26,27may therefore play a role in mediating
responses triggered by peripheral GLP-1R agonist treatmentA
role. Similarly for the central GLP-1 system, direct central
GLP-1R ligand administration activates neurons in many of
the same central structures that show GLP-1-binding23
and/or express GLP-1R mRNA.24Moreover, many of the
aforementioned nuclei in the visceral afferent pathway
project to other GLP-1 binding and/or GLP-1R-expressing
structures involved in energy balance control (area postrema,
ventral tegmental area, arcuate nucleus, medial preoptic
area) (see the reviews by Goke et al.23and Merchenthaler
et al.24). A determination of which of these implicated
structures are necessary for GLP-1R-mediated response
production has not been made. Nonetheless, it is often
asserted that hypothalamic/forebrain processing is critical
for mediating the effects of peripheral GLP-1R stimulation as
well as central activation.11,28–32
We review the results from experiments that used
complete supracollicular transection of the rat brain to:
(1) block the ascending projections to the hypothalamus
and ventral forebrain that originate in the caudal brainstem;
(2) remove descending projections from the hypothalamus
and basal forebrain to hindbrain behavioral and autonomic
effectors and thereby (3) eliminate forebrain–caudal brain-
stem communication.33This strategy was used to directly
investigate the importance of hypothalamic/forebrain and
caudal brainstem processing in the mediation of behavioral,
sympathetic and parasympathetic responses generated by
peripheral or central GLP-1R agonist treatment. The selective
agonist to the GLP-1 receptor, Ex-4, was selected as the
ligand of choice to examine GLP-1R-mediated control of
food intake and gastric emptying, as this compound is used,
both experimentally and clinically in the treatment of
diabetes mellitus and obesity.34–38Control and chronic
supracollicular decerebrate rats received Ex-4 or vehicle
through IP injection or through the fourth intracerebroven-
tricular cannula. Food intake was assessed using direct oral
delivery of liquid nutrient. The intraoral intake method is
required for the assessment of intake in chronic decerebrate
rats and has been validated for the assessment of intake in
intact rats.39,40Gastric emptying was measured using dye-
Inhibition for food intake and gastric emptying in
response to peripheral Ex-4 was comparable to intact control
and decerebrate rats, as were the dose–response relation-
ships, indicating the caudal brainstem is sufficient for
mediating response production.33Hypothalamic processing
had been hypothesized to mediate the profile of responses
evoked by peripheral GLP-1R ligand delivery.11,30,42Periph-
eral administration of GLP-1R agonists induces central
neuronal activation, as indicated by Fos-like immunoreac-
tivity10,11,18,42and a magnetic resonance imaging signal,30in
The nucleus tractus solitarius
HJ Grill and MR Hayes
International Journal of Obesity
the paraventricular nucleus and, in some reports, the arcuate
nucleus and ventral medial hypothalamus nuclei. The neural
mediation of the intake inhibition resulting from peripheral
GLP-1R stimulation was examined earlier11by interrupting
connections between the caudal brainstem and hypothala-
mus with midbrain knife-cuts. The authors conclude12that
hypothalamic processing is required for GLP-1R-induced
anorexia, as rats with knife-cuts (histological details were not
provided) did not show this response. By contrast, decere-
brate rats lacking all neural communication between the
caudal brainstem and hypothalamus (histologically con-
firmed complete transections) showed the same suppression
of intake and gastric emptying rate for peripheral GLP-1R
agonists as that observed in neurologically intact control
rats. These results thereby show that neuronal activation of
paraventricular nucleus, arcuate nucleus or other hypotha-
lamic/forebrain neurons by peripheral GLP-1R treatment
observed in intact rats10,11,18,42is not required for suppres-
sion of intake and gastric emptying rate as is clear from the
This result is consistent with a body of other work from
our laboratory from which we conclude that in the absence
of connections between forebrain and caudal brainstem
neurons, integrations carried out in the isolated caudal
brainstem of the chronic decerebrate rat and efferent
projections from this region are, (1) sufficient for a
fundamentally normal oropharyngeal organization of meal
consumption and, moreover, (2) mediate the integration of
food taste and GI afferent signals (for example, nutrient load,
cholecystokinin treatment) that codetermine meal size
control in neurologically intact rats.43
Central delivery of Ex-4 with hindbrain-directed fourth
intracerebroventricular injections produced similar intake-
suppressive effects in chronic decerebrate and neurologically
intact controls. These findings show that caudal brainstem
processing is sufficient to mediate feeding effects triggered
by stimulation of hindbrain GLP-1R, and that hypothalamic/
forebrain processing is not necessary for this centrally
evoked response. At the same time, however, it is known
that intake inhibition is observed following ventral forebrain
application of GLP-1R ligands. As ligands are accessible to
both forebrain and hindbrain GLP-1Rs with forebrain
ventricular GLP-1R agonist delivery, it is difficult to ascribe
this to the CNS sites mediating this effect, but ventral
forebrain parenchymal application of GLP-1R ligands does
elicit behavioral responses, and this result does support a
direct role for forebrain GLP-1R and forebrain neural
processing in for the observed effects.44,45Neither our
others28,44,45address the sites of central mediation of
responses resulting from endogenous activation of central
GLP-1Rs. Although the source of the proglucagon-expressing
neurons is located in the NTS of the caudal brainstem, these
neurons project to both hindbrain and forebrain nuclear
targets.46Further investigations are required to determine
the role of endogenous activation of caudal brainstem and
ventral forebrain GLP-1R in the mediation of responses
resulting from endogenous central GLP-1. For responses
generated by exogenous hindbrain-directed central delivery
of GLP-1R ligands, by contrast, the findings are clear;
responses induced by exogenous hindbrain application of
GLP-1R agonists do not require forebrain processing or
caudal brainstem–forebrain communication.33
Leptin interacts with GI signal processing
Leptin, the adipose tissue-derived hormone, is a major
contributor to energy balance control, largely through its
actions on CNS receptors.47Leptin administration reduces
food intake, and despite intense research its neural basis
remains unexplained. Leptin signaling in the neuropeptide-
containing neurons of the arcuate nucleus was the initial
focus of the field;48however, the scope of more recent work
has expanded to include functional assessments of leptin
signaling in the ventral medial hypothalamus and the
midbrain ventral tegmental area.49–51Our attention was
drawn to leptin signaling in NTS neurons by behavioral
findings that suggest leptin’s effect on feeding results from
amplification of the neural processing of intake-inhibitory
GI signals,52,53and by the electrophysiological data of
Schwartz and Moran54that show leptin potentiation of the
NTS response to gastric distention.
In collaboration with Christian Bjorbaek and Lihong
Huo,53we undertook a detailed anatomical analysis of the
NTS subnuclear expression of intraperitoneal leptin-induced
pSTAT3 immunoreactivity (IR) and showed that IR was
limited to a portion of single subnucleus neurons of the
medial NTS, specifically at the level of the area postrema. We
were struck by this expression pattern, as medial NTS
neurons were also known to process GI vagal afferent signals
arising from ingesta interacting with the stomach and
intestine,54–59and set out to address whether leptin signal-
ing (intraperitoneal leptin-induced pSTAT3-IR) and physio-
logical levels of gastric distension-induced Fos-IR were
expressed by the same NTS neurons. We found that B40%
of pSTAT3-IR medial NTS neurons are also responsive to
gastric distention.53The results of two behavioral studies are
consistent with the hypothesis that hindbrain leptin signal-
ing potentiates the intake-inhibitory effects of GI signals.
A volume of gastric distention53or a caloric concentration of
intraduodenal intralipid (triglyceride emulsion) infusion
(Hayes and Grill, unpublished) without effect on intake
were combined with a behaviorally ineffective dose of fourth
intracerebroventricular leptin. In the two studies, neither the
leptin alone nor the GI treatment alone reduced intake.
When leptin and GI treatment were combined, however,
food intake was significantly suppressed. The observed food
intake suppression suggests that leptin signaling directed to
the caudal brainstem neurons resulted in an amplification of
the intake-suppressive action of GI stimulation. These
behavioral results and the expression of distention-induced
The nucleus tractus solitarius
HJ Grill and MR Hayes
International Journal of Obesity
Fos-IR and pSTAT3-IR in the same medial NTS neurons
suggest a siteFmedial NTS neuronsFand a mechanismF
potentiation of GI satiation signals by leptinFto explain the
intake-reducing action of leptin.
Given the growing interest in brain adenosine monophos-
phate-activated protein kinase (AMPK) as a cellular fuel
gauge that regulates energy balance,60,61as well as evidence
from hypothalamic tissues that show leptin and refeeding
(associated with GI stimulation) decrease the elevated AMPK
activity induced by food deprivation, we have been pursuing
the hypothesis that leptin and GI signals processed in NTS
neurons combine to affect intracellular AMPK activity. Using
western blots and activity assays we show that food
deprivation elevates and refeeding reduces AMPK activity
in NTS-enriched lysates.62Moreover, we show that the intake
reduction resulting from hindbrain-directed leptin is re-
versed by hindbrain-directed treatment with AICA, an AMP-
mimicking promoter of AMPK activity. Our data are
consistent with the hypothesis that the intake-inhibitory
effect of leptin is mediated in part by the synergistic actions
of leptin and GI vagal afferent signaling in medial NTS
neurons, and that AMPK activity in these neurons may be a
signal common to both effects.
Overall, the data reviewed here support the view that NTS
and circuits present within the hindbrain mediate the intake
inhibition of GI signals such as GLP-1, and that the intake-
suppressive effect of leptin results, at least in part, from the
amplification of GI signal processing.
Conflict of interest
MR Hayes and HJ Grill have received grant support from the
The work described was supported by NIH Grant DK-21397.
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