Physiology & Behavior 105 (2011) 6270

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Physiology & Behavior

j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / p h b

Nutrient sensing in the gut: interactions between chemosensory cells, visceral

afferents and the secretion of satiation peptides
Robert E. Steinert, Christoph Beglinger
Clinical Research Center, Department of Biomedicine and Division of Gastroenterology, University Hospital Basel, Basel, Switzerland

a r t i c l e i n f o a b s t r a c t

Article history: The chemical environment of the intestinal lumen and the presence of nutrients in the gut result in the
Received 20 December 2010 secretion of regulatory peptides and in the discharge of intestinal sensory afferent bers. Since afferent nerve
Received in revised form 24 February 2011 terminals do not directly extend into the intestinal lumen, their activation presumably depends on
Accepted 25 February 2011
intermediary steps post-absorptive mechanisms, i.e. direct neuronal activation by absorbed substances and
pre-absorptive mechanisms, i.e. neuronal activation by a secondary substance released from the mucosal
Keywords:
Gut
epithelium.
Gastrointestinal satiation peptides Entero-endocrine cells (EEC) are able to taste the luminal content and to function as chemosensory
Taste receptor transducers to provide the interface between the intestinal lumen and the afferent nerve terminals. Their
Nutrient sensing secretory products mainly peptide hormones are released upon stimulation by nutrients into the
extracellular space of the lamina propria to either act 1) locally in a paracrine fashion to activate afferent
terminals or other cells or 2) in an endocrine fashion via intestinal capillaries and the lymphatic system to
bind to specic receptors at more distant targets.
The chemosensory mechanisms by which EEC sense the intestinal lumen remain, however, poorly
understood. Recent information suggest that taste signaling mechanisms known from the oral epithelium
also operate in the mucosal epithelium. Several nutrient-responsive G-protein coupled receptors (GPCRs)
have been identied in EEC including the sweet-taste responsive T1R2/T1R3 heterodimer or GPR120,
responsive to free fatty acids (FFAs).
This review provides a brief overview on gastrointestinal chemosensory mechanisms and their functional
involvement in the secretion of satiation peptides with a focus on human studies albeit most evidence at
present comes from in vitro or animal studies.
2011 Elsevier Inc. All rights reserved.

1. Introduction
Intestinal chemosensitivity is a key element in digestive processes
and has been observed in mechanisms such as the dependence of
gastric emptying on the chemical nature of nutrients or the fact that
oral ingestion of glucose triggers more insulin release than a similar
plasma glucose prole delivered intravenously [1,2].
One of the rst physiologists who proposed a chemosensitivity
hypothesis was Pavlov in the 19th century. Based on his nervism, i.e.
the theory that the nervous system controls the greatest possible
number of bodily activities, he suggested that sensory nerves
are exposed to the intestinal lumen and directly catch chemical
messages of the luminal content at their nerve endings (nerve
antenna theory) [3].
Corresponding author at: Clinical Research Center, Department of Biomedicine,
Division of Gastroenterology, University Hospital Basel, CH-4031 Basel, Switzerland.
Tel.: +41 612653846; fax: +41 612653847.
E-mail address: beglinger@tmr.ch (C. Beglinger).
The rst evidence that nervism was not the only mechanism
controlling gut functions was provided by Bayliss and Starling in 1902
[4]. They observed that the presence of protons in the proximal small
intestine elicited a strong stimulation of pancreatic-uid secretion. By
cutting all the nerves to the pancreas in their experimental animals,
they found that this process was not governed by the nervous system
and showed that a substance secreted by the intestinal lining stimulates
the pancreas after being transported via the bloodstream. They named
the secreted compound 'secretin' and used Hardy's term hormone as a
general designation for blood-borne chemical messengers.
In the 1970s Fujita and Kobayashi [5] proposed the intestinal sensor
cell theory, which was further expanded by Grundy [6]. They described
nutrient-sensing bipolar cells, which contain secretory granules in the
basolateral portion and cytoplasmatic projections to the intestinal
lumen. These cells were thought to interact with the intestinal lumen
and to release peptide hormones and bioactive amines to transfer
information to other organs via endocrine or vagal pathways.
In 1985, N. Mei reviewed the subject of intestinal chemosensitivity
[7]. Available data demonstrated that (i) changes in the chemical
environment of the intestinal lumen (pH, osmolality) and the

0031-9384/$ see front matter 2011 Elsevier Inc. All rights reserved.
doi:10.1016/j.physbeh.2011.02.039
 R.E. Steinert, C. Beglinger / Physiology & Behavior 105 (2011) 6270 63

presence of different nutrients (carbohydrates, protein, lipids) lead to function as the transducer to provide the interface between the GI
a discharge of sensory afferent bers; however (ii) vagal ring is not lumen and nerve terminals [15].
due to a direct intraluminal stimulation of nerve terminals. He
suggested that activation of chemosensory nerve terminals may 3. Chemosensory cells
depend on intermediary steps. To date, intestinal chemosensitivity is
thought to involve a highly specialized and complex system of A major morphological characteristic of chemosensory cells is that
primary afferent neurons, intestinal chemosensory cells and the gut they are scattered along the epithelial lining and that they have direct
immune system. access to the luminal content. Cell types that fulll this requirement
This review summarizes important current data on gastrointesti- include (i) enterocytes, (ii) brush cells and (iii) entero-endocrine cells
nal (GI) chemosensory mechanisms and their functional involvement (EEC). All of them have repeatedly been implicated in intestinal
in the secretion of satiation peptides with a focus on human studies chemosensitivity, and afferent nerve terminals have been visualized
albeit most evidence at present comes from in vitro or animal studies. close to these cells [12,23,24]. Brush cells are characterized by a brush
of rigid apical microvilli and, although the function of these cells has
2. Primary afferent neurons long been unknown, recent data suggest that they comprise a diffuse
chemosensory system that covers large areas of the digestive and
Two classes of primary afferent neurons innervate the GI tract: respiratory tract (for review see ([25])).
intrinsic primary afferent neurons (IPANs) and extrinsic (vagal and Most data, however, imply that EEC are the primary chemosensory
spinal) primary afferent neurons. In addition intestinofugal neurons cells. Although they represent less than 1% of the entire epithelial
are part of the afferent limb [8]. population; in total, they constitute the largest endocrine organ
IPANs innervate both, mucosal and muscular layers of the gut wall secreting multiple peptide hormones and bioactive amines. Results
and originate either in the myenteric (Auerbach) or submucosal obtained from experiments in cultured entero-endocrine GLUTag and
(Meissner) plexus. They are part of the enteric nervous system which NCI-H716 cells indicate that EEC are themselves nutrient-sensitive,
generates reexes affecting GI motility, blood ow and water/ albeit indirect sensing pathways (via brush cells or enterocytes) might
electrolyte secretion. Myenteric IPAN's respond to distortion in also be involved [26,27]. Two groups of EEC can be distinguished
external muscles layers whereas Meissner IPANs detect distortion of according to their epithelial localization: open cells with microvilli
the mucosa. Both also respond to changes in luminal chemistry; they extending into the intestinal lumen, and closed cells that do not reach
synapse with each other and form a dense network that commu- the epithelial surface. Open cells directly sense luminal factors whereas
nicates to interneurons to provide the enteric nervous system the closed cells (e.g. enterochromafn-like cells) are regulated by the
information required for the autonomic control of digestion [9,10]. luminal content indirectly through neural and humoral mechanisms.
Extrinsic primary afferent neurons have their cell bodies lying in Over 20 different EEC types have been classied according to their
dorsal root ganglia (spinal primary afferent neurons) and in jugular content of the secretory granules. The different cell types are variously
and nodose ganglia (vagal primary afferent neurons) [10]. They both distributed along the intestinal tract. For example, I-cells are primarily
innervate the entire length of the GI tract; vagal afferents are more present in the duodenal and jejunal mucosa, whereas the majority of
prevalent in the proximal gut and spinal afferents (particularly pelvic) L-cells are located in the distal ileum and colon (Table 1).
predominate the distal gut. Their nerve terminals are distributed
within the gut wall including mucosa and submucosa, muscle and 4. Nutrient sensing and chemosensory mechanisms
enteric ganglia but also in serosa and mesenteric attachments.
Importantly, 80 to 90% of axons in the vagus nerve are afferent The ndings that different macronutrients have different poten-
nerve bers; therefore, the vagus nerve is the major component of cies to modulate the secretion of gut peptides (e.g. CCK, GLP-1 or PYY)
extrinsic afferent pathways [11]. Vagal afferents have been demon- independently of energy densities suggests that regulatory mecha-
strated to be both mechano- and chemo-sensitive. For mechanosen- nisms are of complex design to generate the appropriate secretory
sitivity, sensory nerve bers may function as contact sensors that responses [2830].
detect the movement of luminal content across the mucosal surface
(e.g. mucosal deformation or villi distension) by stretch-activated ion 4.1. Carbohydrates
channels [12]. Chemosensitivity was rst demonstrated more than
50 years ago by Iggo. He measured the discharge of vagal afferent Carbohydrates in nature include the complex plant products starch
bres with electrophysiological recordings and found a variety of and cellulose, the animal starch (glycogen), and various disaccharide
nutrients to activate the vagus from the gut [13]. and monosaccharide sugars. The complex carbohydrates are further
Although the primary afferent nerve terminals in the mucosal
epithelium are closely associated with the lamina propria, they do,
Table 1
however, not project directly into the intestinal lumen. Tracing
Selected entero-endocrine cells: location and secretory products.
studies demonstrate that they never actually enter the epithelial layer
[14,15]. Thus their activation is thought to depend on postabsorptive Cell type Highest density Peptide released
or preabsorptive mechanisms, respectively. Several vagal chemor- G-cells Stomach Gastrin
eceptors have been described including gluco-, amino acid-, lipid-, X-cells Stomach Ghrelin
pH-, and osmo-receptors as well as receptors sensitive to specic ECL-cells Stomach Histamin
Unamed cells Stomach and duodenum Gastrin Releasing Peptide (GRP)
dietary compounds, suggesting a direct post-absorptive activation of
S-cells Duodenum and jejunum Secretin
the vagus by absorbed substances from the lumen [12,15]. In contrast, I-cells Duodenum and jejunum Cholecystokinin (CCK)
in the 1980s Gibbs and Smith discovered that gut hormones particular K-cells Duodenum and jejunum Glucose-dependent insulinotropic
those, like CCK, that act to control food intake and gastric emptying polypeptide (GIP)
N-cells Ileum Neurotensin
also require the vagus in mediating their action suggesting a neuronal
L-cells Ileum and colon Glucagon-like peptides (GLP's),
vagal activation by secondary substances (e.g. gut peptides) released Peptide YY (PYY)
from the mucosal epithelium [16]. To date, numerous receptors for D-cells Entire GI tract Somatostatin
gut peptides and other bioactive molecules have been identied on EC-cells Entire GI tract 5-hydroxytryptamin (5-HT, Serotonin)
afferent bers, including CCK-1 and -2, GLP-1, Y2, GHS1, CB1, GABAB EC-cells, enterochromafn cells; ECL-cells, enterochromafn-like-cells; glucagon-like
receptors [1722] and specialized chemosensory cells are proposed to peptides (GLP's) include GLP-1, GLP-2, oxyntomodulin, glicentin.
64 R.E. Steinert, C. Beglinger / Physiology & Behavior 105 (2011) 6270
broken down by intestinal enzymes to liberate the simple sugars.
Most studies have focused on glucose as the most important
carbohydrate for human metabolism. Different mechanisms are
thought to be involved in glucose sensing by gut EEC.
4.1.1. Glucose transporter activity
Several studies have documented that the secretion of peptide
hormones may depend on actively absorbed glucose via the sodium-
dependent glucose co-transporter (SGLT-1). Gribble et al. [31]
identied a glucose sensing-pathway in GLUTag cells, whereby sugars
trigger membrane depolarization and GLP-1 secretion via electrogenic
actions of SGLT-1. In the same experiments, GLP-1 release was
impaired when glucose absorption was blocked with phlorizin, a
specic SGLT-1 inhibitor. In rats, glucose-triggered GIP secretion was
markedly reduced by phlorizin [32]. In humans, slowly and rapidly
digestible carbohydrates differed in their ability to stimulate the
release of GLP-1 and GIP; moreover, the rate of intestinal glucose
absorption strongly correlated with GIP plasma concentrations [33].
In addition to SGLT-1, there is evidence that GLUT2, which facilitates
the glucose transport across the basolateral membrane into the
bloodstream, may be involved in glucose sensing. Although GLP-1
secretion was generally thought to be insensitive to plasma glucose
levels, knockout mice models for GLUT2 (GLUT2/) showed
impaired GLP-1 responses to oral glucose [34], suggesting a potential
metabolism-dependent pathway to adjust GLP-1 secretion to plasma
glucose concentration.
4.1.2. KATP channel dependent glucose sensing
KATP channel dependent glucose sensing is well characterized as
glucose sensors in pancreatic -cells but also in cardiac muscle and in
subsets of neurons in the brain [35,36]. In -cells, the metabolism of
glucose leads to the generation of ATP; this triggers the closure of KATP
channels, which leads to membrane depolarization, Ca2+ inux and
nally to the release of insulin [37]. It has been suggested that glucose
may trigger the release of gut peptides from EEC via similar
mechanisms. Glucose-stimulated secretion of GLP-1 from entero-
endocrine GLUTag or NCIH716 cells involves the closure of KATP
channels [31,38,39]; in addition in primary cultures of mouse small
intestine glucose-triggered GIP secretion was dependent on KATP
channel activity [40]. However, in humans, the involvement of KATP
channels has been questioned because sulphonylureas, which
stimulate insulin release in diabetics by their inhibitory action on
KATP channels, do not trigger the release of GLP-1 [38]. Moreover,
Ritzel et al. [41] report that GLP-1 is also secreted in response to non-
metabolizable sugar analogues such as 3-O-methylglucose suggesting
additional mechanisms of glucose sensing.
4.1.3. Taste receptors
Taste receptors were originally described in taste cells of lingual
epithelium and have been identied as ion channels (salty, sour) and
G-protein coupled receptors (GPCRs) responsive to bitter, sweet and
umami [42]. The GPCR type 1 taste receptor (T1R) family includes
three distinct subunits (T1R1, T1R2 and T1R3) that form heterodimers
to mediate either: (i) sweet-taste such as carbohydrate sugars and
articial sweeteners (T1R2 + T1R3) or, (ii) umami and other savory
amino acids (T1R1 + T1R3). The type 2 receptor (T2R) family contains
over 30 genes encoding different receptor transcripts that mediate
bitter taste, such as plant alkaloids. Recent ndings suggest that the
molecular pathways that mediate lingual taste perception also
operate in the gut.
4.1.3.1. Histological evidence for the involvement of taste receptors in
glucose sensing. In 1996, Hfer et al. [43] rst identied taste receptor-
like cells in the rat gut by showing expression of -gustducin, a taste
specic G-protein subunit and marker for chemosensory cells. Wu et
al. [44] demonstrated the presence of transcripts corresponding to
multiple members of the T2R family in mouse gastric and duodenal
mucosa. The proteins were cloned and sequenced, conrming that
they are identical to known taste receptor sequences in lingual
epithelium [45]. In 2005, Dyer et al. [46] reported the expression of
T1R sweet-taste receptors at mRNA and protein levels in mouse small
intestine. In addition, several other taste signalling proteins including
transducin or TRPM5 were detected in gastric or intestinal mucosa of
humans and rodents as well as in EEC in culture [4750]. In human
duodenal biopsy sections, -gustducin, T1R2 and T1R3 were
identied by immunohistochemistry at apical projections of cells
with shapes characteristic of EEC. -gustducin was shown to be
colocalized with: (i) GLP-1-expressing entero-endocrine L-cells,
(ii) GIP-expressing entero-endocrine K-cells, and (iii) GIP and GLP-1
coexpressing entero-endocrine K/L-cells [50]. Independent conrma-
tion of the expression of -gustducin in K and L-cells came from
experiments using laser capture microdissection followed by RT-PCR
and the same technique was used to show that -gustducin was not
present in duodenal enterocytes [50].
In human colonic mucosa, Rozengurt et al. [48] found -gustducin
in entero-endocrine L-cells that express PYY and GLP-1. Recent
studies also demonstrate coexpression of -gustducin with CCK in
entero-endocrine I-cells [45]. Furthermore, most -gustducin positive
cells coexpress chromogranin A, a marker of EEC, but not villin, which
indicates that in humans, -gustducin is present predominantly in
EEC [48]. In contrast, in rodents, -gustducin immunoreactivity has
also been documented in intestinal brush cells (which are character-
ized by villin expression) thus, suggesting a role of these cells in
chemosensory functions in rodents [5153].
4.1.3.2. Functional evidence for the involvement of taste receptors in
glucose sensing. Functional evidence that taste receptor pathways are
involved in gut peptide secretion stems primarily from results
obtained in intestinal cell lines which have been used extensively to
elucidate secretory responses in EEC. EEC models include (i) the
murine STC-1 and GLUTag cell line, (ii) the rat pancreatic acinar tumor
cell line AR42J with neuroendocrine properties and (iii) the human
endocrine intestinal cell lines HuTu-80 and NCI-H716. All of them
express multiple components of taste signaling proteins and secrete
several GI peptides [45,47]. Stimulation of NCI-H716 or GLUTag cells
with sweet receptor agonists, including glucose, sucrose or sucralose,
an articial sweetener, promoted the release of GLP-1 and GIP. More
importantly, the sweet-taste receptor antagonists lactisole and
gurmarin, both blocked the secretion of GLP-1 and GIP from these
cells [50,54]. In addition, bitter ligands were shown to be potent
stimulants of CCK release from STC-1 cells [55]. Major support for a
functional role of taste-signaling pathways in the gut is provided by
Jang et al. [50] Knockout mice lacking -gustducin (-gust/) or
T1R3 (T1R3/) were examined for their responses to carbohydrate
gavage. In contrast to the wild type littermates, the knockout models
showed no increase in glucose-stimulated secretion of GLP-1 and GIP.
In addition, they revealed an impaired release of insulin and elevated
blood glucose level. Young et al. [56] quantied transcript level of
T1R2, T1R3, -gustducin and TRPM5 in the upper GI tract of subjects
with and without type II diabetes mellitus. He found that higher
serum blood glucose concentrations were associated with lower
levels of sweet-taste signaling molecule transcripts. He also demon-
strated in mice that jejunal infusions of glucose signicantly
decreased transcript level of T1R2 compared to control infusions
with 2-deoxy-D-glucose or saline and therefore concluded that taste
transduction in the gut might be under dynamic metabolic and
luminal control [56].
We also performed experiments to determine the functional
involvement of sweet-taste receptors in glucose-stimulated secre-
tions of GLP-1 and PYY in humans. We used lactisole, a competitive
inhibitor of the sweet-taste receptor subunit T1R3, to block sweet-
taste receptor function in the gut. In parallel to the in vitro data by Jang
 R.E. Steinert, C. Beglinger / Physiology & Behavior 105 (2011) 6270
et al. [50], we could demonstrate that lactisole attenuated the regular
glucose-stimulated secretion of GLP-1 and PYY in a dose dependent
manner (Fig. 1).
Taken together, these data suggest that gut-expressed sweet-taste
receptors may be functionally involved in glucose-stimulated secre-
tion of GI peptides with plasticity of receptor expression to adapt to
different nutritional situations.
4.1.3.3. Limitations. We and other groups investigated whether
equisweet solutions of carbohydrate sugars or articial sweetener
have equivalent effects on the release of gut peptides [5760].
Interestingly, we found that in contrast to the in vitro experiments, the
equisweet solutions of either glucose, fructose or articial sweetener
had different effects on gut peptide secretion: only glucose potently
stimulated the secretion of GLP-1 and PYY; in contrast fructose was
much less effective and articial sweetener had no signicant effect
[57]. We infer from these observations that activation of the taste
receptor pathway alone is not sufcient to stimulate GLP-1 and PYY
secretion. The ndings that fructose was much less effective in
stimulating peptides secretion than equisweet glucose further
suggests that different molar loads (25 g fructose vs. 50 g glucose)
may affect peptide secretion differentially. However, previous human
data document that GLP-1 responses to equal doses (75 g) of either
fructose or glucose is less for fructose [61]. The relationship between
Fig. 1. The functional involvement of gut-expressed sweet-taste receptors in glucose-
stimulated secretion of glucagon-like peptide (GLP-1) and peptide tyrosine tyrosine
(PYY) was determined by intragastric infusion of 75 g glucose with or without 150, 300
and 450 ppm lactisole (a sweet-taste receptor antagonist) in a double blind, 4-way
crossover trial including 8 healthy fasted subjects. Lactisole induced a dose-dependent
reduction in glucose-stimulated secretion of GLP-1 and PYY; the reduction was noted
with all three concentrations (the 300 ppm dose is not shown for visual clarity). The
area under the curve for the plasma concentration-time prole of GLP-1 was
signicantly reduced with 450 ppm lactisole (P = 0.043); in contrast, PYY secretion
only trended towards a reduction (P = 0.066) due to the limited number of subjects.
65
the molecular structure of carbohydrate sugars and their ability to
stimulate the release of incretins has been investigated in more detail
by Sirinek et al. [62] and Shima et al. [63]. In analogy to our ndings,
they demonstrate that only glucose and, to a lesser extent, galactose,
but not fructose or mannose can stimulate the release of GLP-1 and
GIP. They propose a special sugar sensor with specic steric require-
ments which may be involved in the secretion of these peptides
[62,63].
Taken together, the current data suggest that additional non-taste
chemosensory mechanisms directed towards certain nutrient mole-
cules (e.g. glucose, a major fuel for the body) may exist to modulate
the secretion of gut peptides (Fig. 2). Also, potential energy sensing
mechanisms or energy thresholds might exist for the secretory
responses, albeit it is unlikely that the release is directly related to the
caloric load in a dose response manner.
In addition, gut-expressed sweet-taste receptors may have
regulatory function aside from gut peptide secretion. The two main
mechanisms of intestinal glucose absorption into enterocytes (SGLT1
and GLUT2) also appear to be regulated by sweet-taste receptor
signaling. Margolskee et al. [54] showed in experiments in mice that
SGLT-1 is upregulated by a high sugar diet or when fed articial
sweetener; in contrast mice decient in either -gustducin or T1R3
failed to increase SGLT-1 expression.
4.2. Lipids
Lipids are major stimuli for the secretion of GI peptides but the
mechanisms of fat-triggered hormone release remain largely un-
known. Long-chain free fatty acids (FFA) (chain length NC12) potently
trigger the release of GLP-1, PYY and CCK. In contrast, C11 or shorter
FFA does not, suggesting that a molecular recognition system for FFA
resides within the GI tract [64,65].
One potential mechanism involves the activation of specic GPCRs,
such as GPR40, GPR41, GPR43, GPR119 and GPR120. GPR40 and
GPR120 are responsive to medium and long-chain FFA [6669]. In
contrast, GPR43 and GPR41 are activated by short chain FFAs such as
acetate or butyrate [69]. GPR40 has been identied in EEC in mice
where it colocalizes predominantly with GLP-1 and GIP (less with
CCK, PYY and ghrelin) suggesting that it mediates FFA stimulated
incretin secretion [66]. GPR41 and 43 have been identied in rat
endocrine cells containing PYY and in mucosal mast cells, which
contain 5-hydroxytryptamine (5-HT). This is consistent with data
demonstrating that FFAs stimulate the release of PYY and 5-HT from
rat ileum and colon [70,71]. In addition, GPR41 decient knockout
mice showed impaired expression of PYY and increased intestinal
transit rate [72]. GPR119 is found in rodent and human L- and K-cells
and is responsive to oleoylethanolamide (OEA), an endogenous fatty
acid derivative [73]. Recent studies have reported that OEA and a
novel GPR119 agonists stimulate the secretion of GLP-1 and GIP in
vitro and in vivo in rodents [74,75].
The best evidence for a role of GPCRs in the sensing of intestinal
lipids is presently available for GPR120. This receptor is abundantly
expressed in human and mouse intestine, as well as in STC-1 cells and
its stimulation has been shown to promote the secretion of GLP-1 and
CCK in mice and humans [67,68,76,77]. Tsujimoto and coworkers
showed that in mice GPR120 is colocalized with GLP-1 predominantly
in colonic endocrine cells. In addition, he showed that colonic, but not
duodenal or ileal administration of -linoleic acid induced a
signicant increase in circulating levels of GLP-1, and therefore
concluded that lipids contained in food may contribute to the later
phase of GLP-1 secretion by direct effects on distal L-cells [68,76].
Moreover, FFA-triggered secretion of GLP-1 was markedly reduced in
GPR120 knockout mice (GPR120/) [68].
We also found GPR120 to be expressed mainly in distal segments
of the human GI tract (Fig. 3), again suggesting that GPR120 is
implicated in the later phase of GI peptide secretion; perhaps involved
66 R.E. Steinert, C. Beglinger / Physiology & Behavior 105 (2011) 6270

Fig. 2. Summary model depicting the ndings that glucose-stimulated secretion of GLP-1 and PYY can blocked by a sweet-taste antagonist suggesting the functional involvement of
the sweet-taste receptor sweet-pathway in glucose-stimulated secretion of these peptides. In contrast, sweetness from articial sweetener (AS) does not affect peptide secretion
suggesting that the activation of the taste receptor pathway alone is not sufcient to stimulate GLP-1 and PYY secretion.

in the ileal break, a physiological mechanism by which the presence of
nutrient in ileal parts delay gastric emptying and thereby reduce
nutrient delivery to the small intestine. However, the majority of
ingested food does not transit to distal segments of the small intestine,
but is absorbed within the proximal parts; therefore the physiological
relevance of these direct effects remains unclear.
Two further proteins that are thought to be involved in lipid
sensing include the fatty acid transport protein (FATP4) and the fatty
acid translocase (FAT CD36). Both are membrane proteins that
facilitate long-chain FFA uptake into mammalian cells [78]. CD36 is
Fig. 3. mRNA expression of GPR120 in different gut segments normalized to 18S
expression. Data represent means SEM of biopsies from 9 healthy subjects. Signi-
cant differences compared to duodenum are indicated by *, p b 0.05; **, p b 0.01;
***, p b 0.001.
important for the production of OEA; in addition, it is thought to
function as specic lipid-taste receptor in lingual epithelium [7981].
To what extend FATP4 is involved in GI chemosensitivity, however, is
not clear [23]. Finally, the formation of chylomicron components such
as apo A-IV in response to long chain FFA uptake appear to be critical
for the secretion of intestinal CCK suggesting an alternative lipid
sensing pathway [81].
4.3. Proteins
Although the products of protein hydrolysis, i.e. peptones and
amino acids also stimulate secretion of GI peptides from EEC, the exact
mechanisms by which these molecules are detected remain elusive
[82]. Like for glucose- and lipid-sensing, several mechanisms have
been proposed. Choi et al. [83] demonstrated a role for GPR93:
increasing the expression of GPR93 in STC-1 cells increased CCK
mRNA expression and CCK secretion. In addition, it is thought that
glutamine, a potent stimulus for GLP-1 release in GLUTag cells, may
act in part via the sodium-dependent amino-acid transporter SLC38A2
[38,84]. It is proposed that electrogenic nutrient transporters trigger
cell excitability by small inward currents and that this depolarizing
effect contributes to peptide release from EEC. This may also include
the oligopeptide transporting systems PEPT1 and PEPT2 [38,84].
Matsumura et al. [85] showed that transfection of PEPT1 in STC-1 cells
evokes membrane depolarization and di-peptide-stimulated hor-
mone secretion in a pH-dependent manner. Finally, there is evidence
that the extracellular Ca2+ sensing receptor (CaR) may account for
sensing mechanisms in the gut. Several studies show CaR expression
along the small and large intestine and suggest potential roles in
signaling protein availability [86].
 R.E. Steinert, C. Beglinger / Physiology & Behavior 105 (2011) 6270
5. Interactions between entero-endocrine cells and
visceral afferents
The secretory products of EEC are released upon stimulation (e.g.
food ingestion) by exocytosis at the basolateral membrane into the
interstitial space of the lamina propria. They either interact locally in a
paracrine fashion on primary afferent neurons and other cells, or they
enter the systemic circulation via capillaries draining into the hepatic
portal vein or more slowly via the lymph to act in an endocrine
fashion [23,87]. Because many of the gut peptides are subject to a high
liver extraction and a rapid breakdown by proteolytic enzymes,
largest concentrations are found very near the site of secretion, i.e. in
the lamina propria of the mucosa, the submucosa and in the hepatic
portal vein rather than in the systemic circulation [8891]. This is an
important consideration when evaluating their physiological actions.
In this regard, it has been suggested that gut peptides such as GLP-
1 or PYY3-36 exert their anorectic effects mainly via receptors close to
the site of secretion on receptors on vagal afferent bers innervating
the lamina propria. It has been demonstrated that the anorectic effect
of intraperitoneal administration of GLP-1 or PYY3-36 in rodents is
blocked by total abdominal vagotomy or subdiaphragmatic vagal
deafferentiation (SDA) [92,93]. In addition, there is solid evidence that
GLP-1 receptors in the hepatic portal region contribute to the effect of
GLP-1 on peripheral glucose handling in rodents [94]. Very recently,
also intestinal CCK has been implicated in the regulation of glucose
homeostasis via a gut-brain-liver neuronal axis independently of
changes in circulating insulin levels [95]. The authors propose that in
response to gut lipid sensing, intestinal CCK activates CCK-1 receptors
on visceral vagal afferents which relay a signal via the brain to the
liver to directly inhibit glucose production [95]. In line with these
ndings, a recent study using functional magnetic resonance imaging
conducted in humans showed that C12 FFAs increase brainstem- and
hypothalamic-activity within 24 min following infusion, and that
this effect is dependent on CCK-1 receptors [96].
Finally, a role of the lymphatic transport of gut peptides has been
suggested as mechanism to protect GI peptides such as GLP-1 from
degradation. Tso and coworkers [97,98] demonstrated that postpran-
dially GLP-1 concentrations in intestinal lymph are up to 10-fold
higher than in portal blood. In contrast to insulin that enters the
lymph mainly by ltration from capillaries, it appears that GLP-1 is
partly secreted directly into visceral lacteals [97]. Also, the volume in
which GLP-1 is diluted is less in lymph and the concentration of
dipeptidylpeptidase IV (DPP-IV), a protease that leads to the rapid
inactivation of GLP-1, is considerably lower in lymph. The physiolog-
ical relevance of the lymphatic transport of gut peptides, however,
awaits further investigation.
6. Chemosensory mechanisms and secretion patterns of
gut peptides
Gut hormone secretion by nutrients provide an example of
different mechanisms of luminal chemosensory mechanisms.
For example GLP-1 shows a biphasic secretion pattern, with an
early-phase secretion within 1530 min after meal onset and a
prolonged second phase from 60 min up to 2 or 3 hours [89,99103].
The time course of glucose-stimulated GLP-1 secretion is more rapid
and shorter lived, whereas the effects of lipids are stronger, slower in
onset but last longer [28,100,101,104106]. Different mechanisms
have been proposed to account for the different secretory responses.
A neurohumoral proximal to distal loop is proposed to account for
the early-phase secretion because nutrients do not reach the distal
intestine, where the majority of L-cells is present, within 30 min after
ingestion [100,101]. CCK or GIP secreted from the proximal small
intestine are possible candidates for mediating the stimulation of
distal L-cells [64,100]. Other studies have also suggested the in-
volvement of vagal sensory neurons and neural pathways with M1
67
muscarinic or nicotinic receptors to stimulate the secretion of GLP-1
[100,105,107].
An alternative explanation for the early-phase secretion of GLP-1
(and here in particular for the more rapid and shorter lived glucose-
stimulated GLP-1 release) is that luminal glucose in the proximal gut
directly stimulates GLP-1 secretion [50,108,109]. 1) The time course of
glucose-triggered secretion of GLP-1 in humans is consistent with
glucose reaching the proximal intestine [101]. 2) In vitro studies using
GLUTag, STC-1 or NCIH716 cell culture models demonstrate that EEC
are themselves glucose sensitive [26,27], and 3) proximal entero-
endocrine L-cells have been shown to express different chemosensory
proteins such as sweet-taste receptors and -gustducin to sense
glucose [50]. Thus, the limited number of L-cells present in duodenum
and proximal jejunum could account for the early phase of
postprandial GLP-1 in particular in response to carbohydrate meals.
In contrast, direct contact of nutrients in the distal small intestine
may account for the second-phase of GLP-1 secretion and here
for the effects of lipids which are stronger, slower in onset but last
longer. As mentioned earlier, GPR120, a fatty acid GPCR has been
implicated in the later phase of gut peptide secretion [68], however,
the physiological relevance of these direct effects remains unclear
because the majority of ingested food does not transit to distal
intestinal segments.
Alternatively, the second phase secretion may depend on the
production of metabolites from non-absorbable food by the gut
microora, most importantly short chain free fatty acids such as
acetate, propionate or butyrate [80]. In addition, bile acids have
recently been suggested to function as complex metabolic regulators
and not just simple lipid solubilizers [110]. Katsuma et al. [111]
showed that bile acids promote GLP-1 secretion through TGR5 in
entero-endocrine STC-1 cells implicating that bile acids may function
as mediators of lipid-stimulated secretion of GLP-1 within the
enterohepatic recirculation.
7. Summary and conclusions
Nutrient sensing in the gut represents a complex interplay
between EEC and visceral afferents. Digestive processes such as
pancreatic secretion, gastric emptying or even meal termination are
regulated by chemical components of ingested food that either
(i) trigger the secretion of peripheral humoral factors such as CCK,
GLP-1 or PYY or (ii) activate independently (or as downstream target
of EEC products) primary afferent neurons. The chemosensory signals
are initiated by a complex machinery that mediates different taste
modalities with specic chemosensory receptors in the stomach,
duodenum and the small and large intestine. Recent examples of the
specic receptor systems include the sweet-taste receptor hetero-
dimer T1R2/T1R3 or receptors for medium and long-chain FFA such as
GPR120.
Despite the increasing scientic interest and endeavor in this
research area, one of the major problems in studying nutrient sensing,
however, remains that EEC are extremely difcult to study in
particular in humans. 1) EEC are sparse and irregular localized along
the gut and it is not possible to obtain direct access in humans.
2) Measurements of hormone plasma level are only an indirect
measure of EEC function and their secretory responses to specic
nutrients 3) Local paracrine interaction between EEC and vagal
afferents are not reected in hormone plasma level. Therefore, most
evidence for the mechanisms underlying GI nutrient sensing comes
from in vitro or animal studies using specic knockout strains. In
evaluating these ndings, it is, however, important to recall that these
data are obtained mainly from transformed cells or transgenic mice
and it is not clear whether all ndings represent normal in vivo
functions of EEC. The recent discrepancies on the effects of articial
sweetener-stimulated GLP-1 secretion between humans and in vitro
studies are only one example emphasizing this issue.
68 R.E. Steinert, C. Beglinger / Physiology & Behavior 105 (2011) 6270
Why is it important to have a particular focus on studies conducted
in humans? Considering the epidemic proportions of obesity and its
co-morbidities such as diabetes and cardiovascular disease, the
pharmacological features of some of the gut peptides including CCK,
GLP-1 or PYY3-36 are of considerable interest in the development of
effective clinical treatment: 1) CCK, GLP-1 or PYY3-36 are anorexi-
genic (satiating) and this effect is seen not only in healthy subjects,
but is preserved in obese or diabetic persons [28,87,112114]. 2) Data
show that fasting and postprandial plasma levels of these peptides are
much lower in obese than in lean subjects suggesting that a deciency
in circulating levels is associated with the pathogenesis of obesity
[114116]. Moreover, GLP-1 functions as a physiological incretin
hormone that enhances postprandial insulin release, suppresses
glucagon secretion, delays gastric emptying and thereby improves
the postprandial glucose prole [89].
The question is whether it is possible to directly increase the
secretion of these peptides from endogenous stores using specic
stimuli. For example, the development of specic secretagogues to
increase plasma levels of GLP-1, analogous to the use of sulfonylureas,
could induce an increase in insulin secretion for the treatment of type
2 diabetes.
In addition, the benecial effects of Roux-en-Y bypass surgery on
postprandial satiation, weight loss and diabetes are thought to be due,
at least in part, to the increased GLP-1, PYY and CCK secretions seen
after such surgery [112,116]. If endogenous secretion of these
peptides could be modulated without serious anatomic and irrevers-
ible interventions such as Roux-en-Y bypass, it would be a major
break-through in diabetes and obesity treatment. At present,
however, the exact chemosensory mechanisms and their functional
involvements in the secretion of gut peptides remain poorly
understood and more research will be required in humans.
8. Funding
The work was supported in part by a grant of the Swiss National
Science Foundation (Grant No. 320000118330) and an unrestricted
grant of Hoffmann-La Roche.
Acknowledgements
We thank the team of the Clinical Research Center and Department
of Biomedicine Mrs. Claudia Blsi, Mrs. Sylvia Ketterer and Mrs.
Gerdien Gamboni for expert technical assistance.
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