TY - JOUR
AU - Liou, A. P.
AB - ABSTRACT The gastrointestinal tract is a highly effective and efficient organ system that digests and absorbs nutrients, contributes to the regulation of glucose homeostasis, and signals postprandial satiety. A network of enteroendocrine cells orchestrates these events through the release of neuropeptide hormones secreted in response to the specific nutrient components within the intraluminal milieu. Nutrient chemosensing by these cells is mediated by cell membrane proteins that have been localized to hormone-producing cells. However, functional studies of the nutrient detection abilities of the endocrine cell population have been limited due to its rare and singly distributed cell type. Recent technological advances have enabled investigations with primary endocrine cells that promise to enhance our current understanding of enteroendocrine cell biology. This review focuses on a particular subset of chemosensing receptors, the G protein-coupled receptors (GPCR), that have been identified as putative nutrient sensors of the major macronutrients, lipids, proteins, and carbohydrates by enteroendocrine cells. The contributions of these receptors in directly activating and stimulating hormone secretion in several subsets of enteroendocrine cells will be discussed, based on evidence gathered by functional studies in animal models, in vitro studies in endocrine cell lines, and newly described findings in primary endocrine cells. Key insights in chemosensory detection and hormone secretion from enteroendocrine cells may help further the studies in larger animal models and guide the formulation of feed or supplements to influence the gastrointestinal signals regulating optimal food intake, absorptive capacity, and growth. INTRODUCTION Growth, development, and overall maintenance of life require the ability to obtain and extract the necessary building blocks from food, of which the gastrointestinal tract reigns in its primary role of digestion and absorption of dietary nutrients. Orchestrating such events in an efficient manner requires an extensive communication system between the gut and the brain, between the gut and the exocrine pancreas, and within the gut itself. Similar to the taste buds of the tongue, whose role is to sense flavors of food, a diffuse network of hormone-secreting enteroendocrine cells are present to “taste” the nutrients delivered during a meal to regulate digestion and nutrient absorption. Enteroendocrine cells are specialized secretory epithelial cells derived from the same crypt-stem cell that produces the 4 primary epithelial cell types of the mucosal lining: absorptive enterocytes, goblet cells, Paneth cells, and enteroendocrine cells (Cheng and Leblond, 1974). Although these cells make up less than 1% of the epithelial cell population, the entirety of the intestinal endocrine cell population makes up 1 of the largest endocrine organs in the body. It serves an important role as a communicating bridge between the luminal environment and the rest of the gastrointestinal tract to regulate gastrointestinal and metabolic functions. There are at least 20 known enteroendocrine cell subtypes categorized by location and the hormone produced (Rindi et al., 2004), and each is involved in particular aspects of gastrointestinal function (Table 1). Table 1. List of the major gastrointestinal hormones, the cell types, location in the gastrointestinal tract, and their various functions Name  Abbreviation  Cell name  Location1  Function  Ghrelin  Ghr  X/A  Stom  Appetite stimulating  Gastrin  Gas  G  Stom  Acid secretion  Histamine  His  ECL  Stom  Acid Secretion  Secretin  Sec  S  D  Bicarbonate secretion  Serotonin  5HT  EC  D, J  Motility and transit, intestinal secretions  Cholecystokinin  CCK  Il  D > J > Il  Satiety, gastric motility, pancreatic secretion, gall bladder contraction, acid secretion  Glucose insulinotropic peptide  GIP  K  D > J  Insulinotropic, bone metabolism, adipose storage  Glucagon-like peptide 1  GLP-1  L  Il  Satiety, insulinotropic, gastric emptying  Peptide YY  PYY  L  Il  Satiety, intestinal motility and transit  Oxyntomodulin  Oxm  L  Il  Satiety  Glucagon-like peptide 2  GLP-2  L  Il  Motility, intestinal integrity, trophic effects, intestinal permeability, satiety  Somatostatin  Sst  D  Stom, D, J, Il  Negative feedback regulation  Name  Abbreviation  Cell name  Location1  Function  Ghrelin  Ghr  X/A  Stom  Appetite stimulating  Gastrin  Gas  G  Stom  Acid secretion  Histamine  His  ECL  Stom  Acid Secretion  Secretin  Sec  S  D  Bicarbonate secretion  Serotonin  5HT  EC  D, J  Motility and transit, intestinal secretions  Cholecystokinin  CCK  Il  D > J > Il  Satiety, gastric motility, pancreatic secretion, gall bladder contraction, acid secretion  Glucose insulinotropic peptide  GIP  K  D > J  Insulinotropic, bone metabolism, adipose storage  Glucagon-like peptide 1  GLP-1  L  Il  Satiety, insulinotropic, gastric emptying  Peptide YY  PYY  L  Il  Satiety, intestinal motility and transit  Oxyntomodulin  Oxm  L  Il  Satiety  Glucagon-like peptide 2  GLP-2  L  Il  Motility, intestinal integrity, trophic effects, intestinal permeability, satiety  Somatostatin  Sst  D  Stom, D, J, Il  Negative feedback regulation  1Stom = stomach, D = duodenum, J = jejunum, Il = ileum. View Large Table 1. List of the major gastrointestinal hormones, the cell types, location in the gastrointestinal tract, and their various functions Name  Abbreviation  Cell name  Location1  Function  Ghrelin  Ghr  X/A  Stom  Appetite stimulating  Gastrin  Gas  G  Stom  Acid secretion  Histamine  His  ECL  Stom  Acid Secretion  Secretin  Sec  S  D  Bicarbonate secretion  Serotonin  5HT  EC  D, J  Motility and transit, intestinal secretions  Cholecystokinin  CCK  Il  D > J > Il  Satiety, gastric motility, pancreatic secretion, gall bladder contraction, acid secretion  Glucose insulinotropic peptide  GIP  K  D > J  Insulinotropic, bone metabolism, adipose storage  Glucagon-like peptide 1  GLP-1  L  Il  Satiety, insulinotropic, gastric emptying  Peptide YY  PYY  L  Il  Satiety, intestinal motility and transit  Oxyntomodulin  Oxm  L  Il  Satiety  Glucagon-like peptide 2  GLP-2  L  Il  Motility, intestinal integrity, trophic effects, intestinal permeability, satiety  Somatostatin  Sst  D  Stom, D, J, Il  Negative feedback regulation  Name  Abbreviation  Cell name  Location1  Function  Ghrelin  Ghr  X/A  Stom  Appetite stimulating  Gastrin  Gas  G  Stom  Acid secretion  Histamine  His  ECL  Stom  Acid Secretion  Secretin  Sec  S  D  Bicarbonate secretion  Serotonin  5HT  EC  D, J  Motility and transit, intestinal secretions  Cholecystokinin  CCK  Il  D > J > Il  Satiety, gastric motility, pancreatic secretion, gall bladder contraction, acid secretion  Glucose insulinotropic peptide  GIP  K  D > J  Insulinotropic, bone metabolism, adipose storage  Glucagon-like peptide 1  GLP-1  L  Il  Satiety, insulinotropic, gastric emptying  Peptide YY  PYY  L  Il  Satiety, intestinal motility and transit  Oxyntomodulin  Oxm  L  Il  Satiety  Glucagon-like peptide 2  GLP-2  L  Il  Motility, intestinal integrity, trophic effects, intestinal permeability, satiety  Somatostatin  Sst  D  Stom, D, J, Il  Negative feedback regulation  1Stom = stomach, D = duodenum, J = jejunum, Il = ileum. View Large Much of the stimuli initiating hormone secretion are in response to the nutrient components of a meal: lipids, carbohydrates, and proteins. Enteroendocrine cells respond either through 2 pathways of chemosensing, either by receiving signals from other cells that sense nutrients (i.e., indirect sensing) or through direct sensing by the endocrine cell itself. Upon stimulation of the enteroendocrine cell, be it by indirect or direct activation, a rise in intracellular calcium initiates release of peptide hormones from basolaterally oriented secretory vesicles. These hormones, in turn, travel in a paracrine or endocrine fashion to affect their target cells. Additionally, these hormones bind specific receptors on vagal afferent neurons to relay postprandial satiety signals to the brain and to relay reflexive efferent signals that affect gastrointestinal secretomotor functions (Raybould, 2010). Most enteroendocrine cells possess an apical surface that is in direct contact with the gastrointestinal lumen and its various nutritional constituents, thus giving pretense for these cells to directly sense luminal nutrients. This review will focus on various studies that have led to the contribution of the G protein-coupled receptors (GPCR) identified as putative chemosensors involved in direct macronutrient sensing by the enteroendocrine cell that results in gut peptide hormone secretion. APPROACHES TO STUDYING ENTEROENDOCRINE CELL BIOLOGY The scarcity and dispersed nature of enteroendocrine cells has previously provided several challenges to studying their biology; therefore, several approaches have been used to facilitate our understanding of their chemosensory abilities that leads to hormone secretion. It is well known from in vivo studies in humans and animals that plasma concentrations of several gut peptide hormones are altered in response to a meal or a specific nutrient challenge. Candidate receptors can be identified by intestinal gene expression profiling or immunohistochemical localization of receptors to hormone-immunoreactive cells. Additionally, pharmacological interventions or targeted gene knockouts facilitate the assessment of the contribution of a candidate nutrient receptor to regulating gut peptide hormone secretion. Many of these studies, however, cannot directly differentiate whether an enteroendocrine cell population is activated to secrete hormones through direct or indirect nutrient sensing, particularly if nonendocrine cells also express these receptors. In vitro studies in endocrine cell lines allow us to study the direct sensing capabilities of these cells and the signaling pathways activated in response to nutrient stimuli (e.g., an influx in intracellular calcium) leading to hormone secretion. However, these cellular responses may or may not emulate the true behavior of the native endocrine cells these cell lines are meant to represent. Indeed, cell lines may differ in the signaling pathways in response to the same luminal stimuli (Iakoubov et al., 2007), making extrapolation between cell lines and native cells challenging. The study of specific native enteroendocrine cell populations has been enhanced by the use of hormone-specific promoter driven green fluorescent protein (GFP) reporter mice, which enables isolation of these rare cell populations by fluorescence activated cell sorting. Both receptor expression profiling and functional activation and secretion assays of enriched populations of native enteroendocrine cell populations have advanced our ability to specifically study the enteroendocrine cell and its direct sensing capabilities (Reimann et al., 2008; Parker et al., 2009; Liou et al., 2011b; Wang et al., 2011). Although the isolation of native cells gives the advantage of interrogating their direct vs. indirect chemosensory abilities, it is unknown how removal of these cells from their micro-environment could affect their behavior. Also, more focus is given to receptor genes that are highly expressed in an isolated cell population relative to a nonendocrine cell population. This bias may underestimate the potential contributions of receptors that are equally present on both enteroendocrine and nonendocrine cells. While each of these approaches has its advantages and limitations, integration of the findings from these studies has facilitated our understanding of enteroendocrine cell biology and its role in regulating gastrointestinal physiology and metabolism. LIPID SENSING Long Chain Fatty Acids The majority of dietary fat is eaten in the form of long chain triacylglycerides, which are broken down into monoglycerides and long-chain fatty acids (LCFA). The presence of LCFA, particularly those of at least 12 carbon chain length, enhances lipid digestion by stimulating the secretion of cholecystokinin (CCK), a neuropeptide hormone produced by duodenal I cells that mediates gallbladder contraction and pancreatic enzyme secretion (Guimbaud et al., 1997; Hildebrand et al., 1998; Degen et al., 2006), inhibits gastric motor function (Lal et al., 2001), and induces postprandial satiety (Lewis and Williams, 1990; McLaughlin et al., 1998, 1999; Feltrin et al., 2004). Aside from regulating their own digestion, LCFA may also serve an additional insulinotropic role by way of stimulating incretin secretion from glucose insulinotropic peptide (GIP)-secreting K cells and glucagon-like peptide (GLP) 1-secreting L cells (Edfalk et al., 2008). Alternatively, LCFA may serve to downregulate ghrelin secretion by oxyntic X/A cells (Lu et al., 2012). The receptors for LCFA are G protein-coupled receptors GPR40 and GPR120. The recently de-orphanized receptor, also known as free fatty acid receptor (FFAR) 1 (Stoddart et al., 2008), is activated by medium- to long-chain saturated and unsaturated fatty acids of greater than 6 carbon chain lengths (Briscoe et al., 2003) whereas GPR120 (also known as the omega-3 fatty acid receptor) more specifically binds LCFA of C14 to C22 carbon chain length (Wellendorph et al., 2009). Transcripts for both of these receptors have been found in the intestine (Itoh et al., 2003; Hirasawa et al., 2005), endocrine cell lines (Hirasawa et al., 2005; Tanaka et al., 2008), and sorted primary enteroendocrine cells expressing CCK, GLP-1, GIP, and ghrelin (Edfalk et al., 2008; Reimann et al., 2008; Parker et al., 2009; Liou et al., 2011b; Lu et al., 2012). Investigations in cell lines demonstrated the first direct chemosensory potential of endocrine cells. The murine enteroendocrine cell line, STC-1, is the lone surrogate model for CCK secretion and also a model for secretion of other hormones including secretin, peptide YY (PYY), pancreatic polypeptide, neurotensin, and proglucagon-derived peptides GLP-1, GLP-2, and GIP (Rindi et al., 1990; Geraedts et al., 2009). Both GPR40 and GPR120 are expressed in these cells. Silencing the expresson of GPR120, and not GPR40, by small interfering RNA (siRNA) prevented both fatty acid-induced CCK (Tanaka et al., 2008) and GLP-1 secretion (Hirasawa et al., 2005). These studies identified GPR120 as the primary GPCR involved in regulating hormone secretion in response to dietary lipid. Indeed, the presence of GPR120 on both a gene and protein level in GLP-1 immunoreactive cells (Hirasawa et al., 2005; Reimann et al., 2008; Miyauchi et al., 2009), primary crypt cultures, and sorted primary L cells (Reimann et al., 2008) supported a role for GPR120 for fatty acid-induced GLP-1 secretion. However, GPR40 is also expressed by these cells, and deletion of this receptor resulted in attenuated incretin secretion in mice (Edfalk et al., 2008). Therefore, the role of GPR40 on incretin secretion, and particularly GLP-1 secretion, remains unclear. The evidence pointing towards GPR120 as a lipid sensor in the duodenal I cell is also not fully clarified. Knockdown of GPR120, and not GPR40, gene expression attenuated CCK secretion in STC-1 cells (Tanaka et al., 2008). However, although primary I cells express both GPR40 and GPR120, direct stimulation of CCK secretion appears to be dependent on GPR40; I cells lacking GPR40 had no secretory response to linolenic acid (Liou et al., 2011b). Whether or not GPR120 is required for fatty acid sensing by these primary I cells has not been tested. An interesting putative counter-regulatory role of GPR120 is the suppression of ghrelin secretion by gastric X/A cells. Ghrelin is the only known gut-derived hormone that stimulates hunger. In humans, plasma ghrelin concentrations consistently peak immediately before a meal and decrease postprandially (Cummings et al., 2001). How this secretory response is regulated, however, is unclear. It is feasible that the presence of digested nutrients in the gastric lumen yields an inhibitory effect on these cells. Recently, GPR120 and GPR40 were found to be expressed in isolated ghrelin-GFP cells; basal ghrelin secretion was suppressed by LCFA in acute cell culture (Lu et al., 2012). Therefore, it is possible that ghrelin secretion can be regulated by both conventional regulatory hormones (e.g., somatostatin) and luminal nutrients through a GPCR mechanism. The GPCR GPR119 is a more recently recognized receptor that is highly expressed in the colon and intestine (Chu et al., 2008), several L cell lines (Chu et al., 2008), and primary L (Reimann et al., 2008), K (Parker et al., 2009), and I cells (Sykaras et al., 2012). Endogenous ligands for this receptor include the oleoylethanolamides (OEA), a satiety factor produced by the small intestine in response to dietary fat (Fu et al., 2007; Schwartz et al., 2008), and 2-oleoylglycerol (2-OG; Hansen et al., 2011), a natural triglyceride breakdown product that shares structural similarities to OEA. The GPCR GPR119 has been implicated in GLP-1 secretion in enteroendocrine cell lines (Chu et al., 2008; Lauffer et al., 2009; Hansen et al., 2011). However, there has not been any evidence to date of the effect of OEA or other GPR119 agonists on hormone secretion by primary L cells. There is limited evidence for GPR119-dependent activation and hormone secretion by K cells. Plasma GIP concentrations increase in response to 2-OG (Hansen et al., 2011), but primary murine K cells do not respond to OEA (Parker et al., 2009). There is also no evidence to date investigating the contribution of GPR119 on primary I cell secretion. Short Chain Fatty Acids Short chain fatty acids (SCFA) are produced by microbial fermentation of plant polysaccharides within the colon. They serve as additional sources of energy, substrates for lipogenesis, and potent signaling molecules. In most monogastric species, bacterial fermentation primarily occurs in the colon, where the majority of PYY and GLP-1-secreting L cells reside. Gene and protein expression of SCFA receptors GPR41 (also known as FFAR3) and GPR43 (also known as FFAR2) in the human colon, particularly in subpopulations of PYY-immunoreactive cells (Karaki et al., 2008; Tazoe et al., 2009) and primary ileal endocrine cells (Reimann et al., 2008; Samuel et al., 2008; Tolhurst et al., 2012), indicate that these SCFA receptors may be involved in PYY or GLP-1 secretion and their downstream effects. Peptide YY decreases food intake and modulates motility and transit time in both the colon and the proximal intestine via a humoral “ileal brake” mechanism (Cuche et al., 2000; Ballantyne, 2006). Intracolonic infusions of SCFA have been shown to inhibit colonic motility, which was believed to be mediated by colonic PYY (Cherbut et al., 1998; Cuche et al., 2000). Immuno-colocalization studies demonstrated that PYY-immunoreactive cells express GPR41 and not GPR43 (Tazoe et al., 2009). Furthermore, SCFA did not affect intestinal motility in GPR43 knockout mice (Dass et al., 2007) whereas plasma PYY concentrations were reduced and intestinal transit time was increased in GPR41 knockout mice (Samuel et al., 2008). Therefore, the current evidence supports a role of GPR41 in driving SCFA-induced PYY secretion from colonic L cells. On the other hand, GPR43 may play a larger role in GLP-1 secretion. Using primary L cell cultures extracted from either GPR41 or GPR43 knockout mice, the absence of GPR43 and not GPR41 significantly reduced SCFA-induced GLP-1 secretion (Tolhurst et al., 2012). Why the discrepancy exists between GLP-1 and PYY secretion, in what is considered to be the same L cell type, is unknown. How these 2 receptors and their signaling pathways interact to result in net secretion of one or the other peptide hormone is subject to further investigation. This phenomenon, however, is not unprecedented and has been observed in vivo (Anini et al., 1999). Compared with studies investigating L cell secretion, there is relatively little data on the contribution of GPR41 and GPR43 on SCFA-induced hormone secretion by other endocrine cells. Given that intraluminal SCFA are more highly concentrated in the distal intestine, it would be assumed that there is little role in these nutrients for chemosensation by more proximal enteroendocrine cells. However, both of these receptors have been found to be expressed on a gene level in I cells (Sykaras et al., 2012) and in X/A cells (Lu et al., 2012), and yet neither of these cell types functionally respond to SCFA (McLaughlin et al., 1998, 1999; Lu et al., 2012). Why these cells have transcript potential to express GPR41 and GPR43 is unclear. A functional role may exist that has not been fully described. PROTEIN SENSING Digestion of dietary protein involves mechanical disruption and enzymatic breakdown by the stomach followed by further enzymatic breakdown by pancreatic proteases in the duodenum, resulting in a hydrolysated protein mixture of oligopeptides and free AA (Silk, 1980). These events are regulated, in part, by the secretion of the gastrointestinal hormones gastrin and CCK in response to oligopeptides and free AA (Taylor et al., 1982; Cuber et al., 1990; Nishi et al., 2001). Gastrin, secreted by G-cells, enhances hydrochloric acid secretion from parietal cells and activates pepsinogen secreted from chief cells. Cholecystokinin, secreted by intestinal I cells, regulates gastric emptying and pancreatic enzyme secretion. The putative chemosensors implicated in gastrin and CCK secretion include the peptone receptor GPR92/93 and several of the C family of G protein-coupled receptors [(GPRC; the extracellular calcium sensing receptor (CaSR), GPRC6A, the umami heterodimeric receptor T1R1+T1R3, and metabotropic glutamate receptors (mGluR)] that bind various subsets of L-AA. The aromatic AA L-phenylalanine and l-tryptophan bind more potently to CaSR than other AA (Conigrave et al., 2000), and aliphatic and basic L-AA are more potent to GPRC6A (Wellendorph et al., 2009). The umami taste receptor, made up of T1R subunits T1R1+T1R3, binds several L-AA but not to aromatic AA (Nelson et al., 2002). The identification of these receptors or their signaling elements in the stomach and intestinal mucosa indicate that these receptors may have roles in chemosensation and, potentially, hormone secretion. Protein Sensing in the Stomach In the stomach, the most well described chemosensor for AA-induced gastrin secretion by the G cell is CaSR. Originally identified in the bovine parathyroid gland as a regulator of parathyroid hormone secretion and plasma calcium homeostasis (Conigrave and Brown, 2006), the CaSR has now been found in multiple other tissues, including the gastrointestinal tract (Ray et al., 1997; Chattopadhyay et al., 1998; Cheng et al., 1999). Therefore, it has been stipulated that CaSR influences several functions in the gastrointestinal tract, including gastrin and gastric acid secretion, colonic motility and fluid absorption, and epithelial cell growth and differentiation as well as in reducing the risk of colon cancer (Hebert et al., 2004). Although calcium is a primary agonist for CaSR, aromatic AA L-phenylalanine and l-tryptophan are potent allosteric activators that dose-dependently decrease the threshold for extracellular calcium and increases the mobilization of intracellular calcium (Conigrave et al., 2000), a necessary step preceding hormone secretion. Both CaSR agonists and L-AA have been shown to directly increase acid secretion by the parietal cell (Busque et al., 2005; Dufner et al., 2005). In addition, not only is CaSR expressed in G-cells (Ray et al., 1997), but administration of allosteric agonist Cinacalcet (Amgen, Thousand Oaks, CA) has been shown to increase serum gastrin and basal gastric acid secretion in humans (Ceglia et al., 2009). Furthermore, the effect of peptone, L-phenylalanine, and calcium on gastrin secretion was completely blocked in CaSR knockout mice (Feng et al., 2010), providing the strongest evidence in support of CaSR as an AA sensor stimulating gastrin secretion. Other putative chemosensors have been immunohistochemically co-localized to the G cell, including GPR92 and GPRC6A but not T1R3 in the mouse, human, and pig (Haid et al., 2011, 2012). Although there is little evidence of a functional contribution of these receptors in peptone and AA-induced gastrin secretion, it is plausible that these other receptors would permit secretory responses to a broader array of substrates. Somatostatin, a neuropeptide secreted by D cells found throughout the length of the gastrointestinal tract, acts as the primary negative feedback signal that modulates the secretory activity of other endocrine cells. Not much is known about the chemodetection sensibilities of D cells, but CaSR, GPRC6A, and GPR92 have been identified in these cells (Haid et al., 2012). Additionally, mGluR and the taste receptor signaling components transient receptor potential cation channel subfamily M member 5 (TRPM5) and phospholipase C (PLC) β 2 have been identified in subsets of somatostatin-secreting gastric D cells (Nakamura et al., 2011). The presence of these receptors and signaling components implies that one or all of these receptors are involved in sensing a broad range of protein breakdown products to regulate protein digestion. Protein Sensing in the Intestine The primary cell type that is responsive to peptides and free AA in the intestine is the CCK-secreting I cell, located primarily in the duodenum and jejunum. Duodenal peptone perfusions in rats activate CCK-sensitive vagal afferents resulting in the inhibition of gastric motility (Raybould, 1991) and a reduction in food intake (Woltman and Reidelberger, 1999) in addition to stimulating exocrine pancreatic secretion of digestive enzymes. Protein hydrolysates are more potent than intact proteins or AA mixtures to stimulate CCK secretion in vivo (Cuber et al., 1990) and in vitro (Nishi et al., 2001). A direct chemosensory role by the I cell has been implicated based on in vitro cellular activation and CCK secretion by STC-1 cells (Cordier-Bussat, 1997; Nemoz-Gaillard, 1998), potentially through GPR92/93-mediated activation of PLC-dependent signaling pathways (Lee et al., 2006; Choi et al., 2007). However, this peptone receptor was not found to be enriched in primary I cells (Liou et al., 2011a), indicating that other mechanisms, be it a non-G protein-coupled receptor or an indirect signal, may be involved in peptone-induced CCK secretion. Although peptone is the more potent secretagogue for I cell secretion, simple aromatic AA, such as L-phenylalanine and l-tryptophan, are also potent stimulants of CCK secretion and CCK-mediated physiological functions. The effects of L-phenylalanine and l-tryptophan include increased pancreatic output in dogs (Meyer and Grossman, 1972) and a reduction of food intake and increased satiety in humans and rhesus macaques (Gibbs et al., 1976; Ballinger and Clark, 1994). The STC-1 cell line is responsive to L-phenylalanine (Mangel et al., 1995), which indicates that a direct chemosensory role for aromatic AA exists. Given the potency of aromatic AA on CCK secretion and the known preference of CaSR for aromatic AA, it was speculated that the CaSR may also provide a direct trigger for dietary protein-induced CCK secretion in the intestinal I cell (Conigrave et al., 2000). Although STC-1 cells weakly express genes for the CaSR, the specific CaSR antagonist NPS2143 (Nemeth et al., 2001) reduced the functional effects of phenylalanine in this cell line (Mangel et al., 1995; Hira et al., 2008). In native I cells, CaSR is highly expressed and detectable on both a gene and protein level relative to non-I cells (Liou et al., 2011c; Wang et al., 2011). Studies using CaSR antagonists and CaSR knockout mice further demonstrated a functional requirement for CaSR for mobilization of intracellular calcium and CCK secretion that is specific to L-aromatic AA and CaSR ligands (Liou et al., 2011c; Wang et al., 2011). Whether or not other AA sensing GPCR may be linked to I-cell chemosensation and CCK secretion is unknown. Certainly, STC-1 cells secrete CCK in response to bitter tastants through the T2R taste receptor complex (Wu et al., 2002; Chen et al., 2006). However, in regards to AA and the umami T1R1+T1R3 heterodimer complex, neither subunit was enriched or detected in primary sorted I cells (Liou et al., 2011c). This does not completely exclude a contribution of the umami taste receptor on CCK secretion in response to direct detection of AA, but it is less likely to be a primary player. It is unknown whether other C family receptors, such as GPRC6A, are expressed by these cells. GLUCOSE SENSING The endocrine cells known to be responsive to luminal glucose are the GIP-secreting K cell, the GLP-1/2 and PYY-secreting L cell, and the serotonin (5HT)-secreting enterochromaffin cell. Both GIP and GLP-1 are incretin hormones that enhance insulin secretion in response to oral glucose, but both have other influences on regulating digestive physiology and metabolism (Baggio and Drucker, 2007). Glucagon-like peptide-2, which is derived from the same proglucagon peptide as GLP-1, has typically been associated with intestinotropic effects and barrier functions (Dube and Brubaker, 2007) but has also been implicated in suppression of food intake and gastric motility (Guan et al., 2012). Serotonin also has secretomotor reflexes responses to luminal and pathological stimuli (Hansen and Witte, 2008). Several non-GPCR mechanisms have been implicated in direct glucose sensing by these enteroendocrine cells, including the sodium-glucose transporter 1 (SGLT1), GLUT2, and ATP-sensitive potassium (KATP) channels. More extensive description of their contribution to glucose sensing leading to gut peptide hormone secretion are discussed elsewhere (Kellett et al., 2008; Reimann et al., 2008; Raybould, 2010; Mace et al., 2012). The most studied GPCR mechanism for glucose sensing has been the sweet taste receptor, of which its heterodimeric GPCR subunits T1R2+T1R3 and its downstream signaling components α-gustducin and the calcium channel TRPM5 have been initially identified and characterized in taste receptor cells of the tongue (Wong et al., 1996; Zhang et al., 2003; Chandrashekar et al., 2006). The sweet taste receptor subunits and signaling proteins have been localized by immunohistochemistry to solitary cells in the gastrointestinal tract of humans (Rozengurt, 2006; Bezencon et al., 2007; Steinert et al., 2011), rats (Hofer et al., 1996; Dyer et al., 2005), mice (Bezencon et al., 2007; Margolskee et al., 2007; Sutherland et al., 2007), dogs (Batchelor et al., 2011), horses (Daly et al., 2012), and pigs (Moran et al., 2010). In particular, α-gustducin has been co-localized to 5HT immunoreactive cells (Sutherland et al., 2007) and both GLP-1 and GIP immunoreactive cells (Jang et al., 2007; Moran et al., 2010; Daly et al., 2012). The presence of sweet taste receptors to hormone secreting cells thus provided an anatomical likelihood for glucose chemosensing by taste receptors in the intestine. In vivo functional studies have further supported the idea that glucose sensed by taste receptors contributes to gut peptide hormone secretion, particularly incretin secretion. Indeed, the effect of glucose-stimulated GLP-1 secretion is attenuated in mice harboring genetic deletions of either α-gustducin or T1R3 (Jang et al., 2007; Kokrashvili et al., 2009). Co-administration of the sweet taste receptor inhibitor lactisole in humans also reduced the effect of intragastric administration of glucose on GLP-1 and PYY secretion (Steinert et al., 2011). Interestingly, the involvement of taste receptors on this observation was specific to glucose, given that lactisole had no effect on hormone secretion in response to mixed liquid meal; the effect of lactisole could not be replicated when glucose was administered intraduodenally (Gerspach et al., 2011). These findings indicate that taste receptors specifically contribute to regionally specific glucose-stimulated gut peptide hormone secretion. The effect of sweeteners themselves, which activate sweet taste receptors directly, on gut peptide hormone secretion has led to inconsistent findings. Incubation of mouse small intestinal tissue in either glucose- or sucralose-enriched media stimulated gurmarin-sensitive GLP-1 secretion (Daly et al., 2012) whereas administration of various artificial sweeteners failed to see an increase in incretin secretion in a rat study (Fujita et al., 2009) and in other human clinical studies (Ma et al., 2009; Wu et al., 2012). Findings from experiments in isolated loops of rat intestine indicate that the effect of sucralose on GIP, GLP-1, and PYY secretion is glucose dependent and may be facilitated by nutrient transporter mechanisms (Mace et al., 2012). Therefore, the mechanisms of how taste receptors are involved in glucose and sweetener-stimulated gut peptide hormone secretion and their relative contributions compared with non-GPCR based glucose sensors still require additional clarification. In vivo studies cannot differentiate whether gut peptide hormone secretion is a result of direct chemosensation by the enteroendocrine cell or indirect activation by signals derived from other glucose-sensing cells. In vitro interrogation of GLP-1 secreting cell lines have supported a role for direct glucose sensing by enteroendocrine cells. The murine-derived L-cell line (GluTag) secretes GIP and GLP-1 in response to both glucose and artificial sweeteners, which is reduced in the presence of gurmarin (Margolskee et al., 2007). Furthermore, in the human-derived L-cell line (NCI-H716) gene silencing of α-gustducin reduced the effect glucose on GLP-1 secretion and the addition of lactisole abolished the dose-dependent effect of GLP-1 secretion in response to sucralose (Jang et al., 2007). However, functional studies in primary L cells do not share the same behavior in response to sweeteners. Although primary L cells demonstrate an increase in intracellular calcium and GLP-1 secretion in response to glucose, α-methyl glucose, and tolbutamide, these cell show little responsiveness to low concentrations of sweeteners that bind to taste receptors (Reimann et al., 2008). This indicates that other glucose sensing mechanisms, and not sweet taste receptors, are involved in direct glucose chemosensing and hormone secretion by the L cell. Similar investigations indicate that primary K cells, which express barely detectable levels of taste receptors, also are not responsive to sucralose (Parker et al., 2009), implicating that taste receptors are not involved in direct glucose-stimulated GIP secretion. As native enteroendocrine cells, isolated primary cells provide better insight to enteroendocrine cell biology than enteroendocrine cell lines. However, primary cell studies cannot completely rule out a role of glucose chemosensation by taste receptors on other cells that could be communicating with and indirectly activating enteroendocrine cells through yet to be defined paracrine, neuronal, or other signals. Although most laboratories have localized taste receptors to hormone-producing cells with immunohistochemical staining, T1R gene expression is detectable along the entirety of the gastrointestinal tract (Dyer et al., 2005). Additionally, protein-level expression of T1R2, T1R3, and taste receptor signaling proteins has been reported within apical membranes vesicles of rat intestine (Mace et al., 2007, 2009) and on the membranes of the intestinal epithelial cell line Caco-2/TC-7 (Le Gall et al., 2007). These findings indicate that taste receptors are not solely expressed on enteroendocrine cells but also potentially on intestinal epithelial cells. Certainly, the lack of enrichment of T1R3 components in I cells (Liou et al., 2011c), L cells (Reimann et al., 2008), and K cells (Parker et al., 2009) relative to nonendocrine cells could be interpreted as both endocrine and nonendocrine cells sharing the same relative expression for T1R transcripts. There are a plethora of studies demonstrating a role of artificial sweeteners on the regulation of nutrient uptake, likely through chemosensation by taste receptors (Mace et al., 2007, 2009; Margolskee et al., 2007; Moran et al., 2010). What contribution the sweet taste receptor has on 1) direct sensing of glucose by enterocytes, 2) indirect activation of enteroendocrine L cells, or 3) a combination of the two is still unclear. It is interesting to note that an even rarer population of chemosensory cells, the brush cell, also expresses α-gustducin and TRPM5 (Hofer et al., 1996). Currently, we know very little regarding the physiology of brush cells and their influence on gastrointestinal function. For now, we can only speculate how glucose chemosensing by brush cells interact with enteroendocrine cells to influence hormone secretion. SUMMARY AND CONCLUSIONS The gastrointestinal peptide hormones secreted by enteroendocrine cells regulate several key digestive and metabolic functions, including gastrointestinal motility and intestinal transit, intra-intestinal digestive and absorptive capacity, extraintestinal uptake of glucose, intestinal adaptation, and the control of appetite. It is clear that enteroendocrine cells are responsive to dietary nutrients, likely through both direct and indirect nutrient chemosensation. Therefore, the macronutrient composition of the diet can affect the way in which these gut hormones are secreted, which can affect the gastrointestinal physiological mechanisms that influence nutrient uptake, growth, and development. This review has discussed several studies from a variety of sources and approaches to understand the mechanisms by which these cells directly detect macronutrients. Particularly, we focus on the GPCR mechanisms involved in the direct chemosensation of proteins, lipids, and carbohydrates that result in hormone secretion. With the exception of potential species-specific differences, the general endocrine cell chemosensory machinery appears to be conserved, particularly with glucose sensing. Intestinal glucose sensing has been a subject of much interest research, as it pertains to both hormone secretion and nutrient absorption, and is likely to involve both endocrine and nonendocrine cell sensing mechanisms. Less attention has been paid to the chemosensors involved in direct activation of hormone secretion in response to dietary lipid and protein, but it would not be surprising if there is also parallel mechanism contributing to the gastrointestinal physiological processes that are of interest in livestock production. With the addition of studies involving GFP-labeled sorted cells that provide insight on the behavior of native endocrine cells, we are getting closer to understanding the nutrient detection capabilities of enteroendocrine cells, particularly that of L, K, and I cells, and it is with much anticipation what further information can be garnered by investigations in these cells as well as other enteroendocrine cell types. What is interesting about the primary cell studies to date is the overlap of gene expression for several peptide hormones and nutrient chemosensing GPCR (Samuel et al., 2008; Egerod et al., 2012; Habib et al., 2012), which incites questions of whether or how macronutrients selectively activate particular subpopulations of enteroendocrine cells. Understanding of intestinal nutrient chemosensory abilities may help guide decisions surrounding the optimization of diets and supplements used in animals to maximize nutrient digestibility, growth, and health. Footnotes 1 Based on a presentation at the preconference symposium titled “Gut Chemosensing: Integrating nutrition, gut function and metabolism in pigs” preceding the 12th International Symposium on Digestive Physiology of Pigs in Keystone, Colorado, May 29 to June 1, 2012, with publication sponsored by Lucta S. A. (Barcelona, Spain), the American Society of Animal Science, and the Journal of Animal Science. LITERATURE CITED Anini Y. 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TI - DIGESTIVE PHYSIOLOGY OF THE PIG SYMPOSIUM: G protein-coupled receptors in nutrient chemosensation and gastrointestinal hormone secretion
JO - Journal of Animal Science
DO - 10.2527/jas.2012-5910
DA - 2013-05-01
UR - https://www.deepdyve.com/lp/oxford-university-press/digestive-physiology-of-the-pig-symposium-g-protein-coupled-receptors-U582ZPAwu9
SP - 1946
EP - 1956
VL - 91
IS - 5
DP - DeepDyve
ER -