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Taste transduction, central signaling, and reward
Regardless of the taste detected, TRCs directly or indirectly release various neurotransmitters [107-112] or peptide hormones [113-117] that activate the CT and GP nerve fibers. The specific mechanism is not completely understood; however, this may involve direct TRC to nerve connections, in which Type II cells generate ATP that interacts via connexins to nerve fibers [65, 66]. A second mechanism is that indirect signaling from TRC Type II cells that sense tastants, release ATP, which then stimulates Type III TRCs to release neurotransmitters that activate afferent nerves. Support of this latter hypothesis comes from the finding that Type III cells are the only TRCs that express voltage gated calcium channels and neurotransmitters, such as serotonin [108, 109]. Additionally, the release of ATP from Type II cells can bind to P2X receptors [64], which are ion channels that open in response to extracellular ATP and expressed by Type III TRCs (Figure 5). While this intriguing and yet unestablished transduction mechanism is currently under investigation, the afferent CT and GP fibers indeed receive input from taste bud complexes and signal upstream to the nucleus of the solitary tract (NTS) of the caudal brainstem.
Endocrine function
In addition to the stomach serving as an endocrine organ secreting gastrin and somatostatin, which influence gastric acid secretion, the stomach releases at least two signals, leptin and ghrelin, which may be integral for intestinal sensing and absorption of nutrients, as well as the control of energy intake. Furthermore, while the stomach lacks chemosensory properties, more recent evidence suggests a role of gastric nutrients in altering endocrine secretions although this is still debated.
Gastric Leptin
Leptin, a 16 kDa protein that is normally secreted from adipose tissue and reflective of energy status, also is secreted by epithelial cells of the stomach [185-188] and thought to play a role in gastrointestinal signaling [189]. Gastric leptin secretion is influenced by feeding [190], neurotransmitter release [191], as well as other gastrointestinal hormones [189]. Furthermore, the identification of leptin receptors (LepR) on the cell bodies of vagal afferents [192, 193] and application of leptin increases activation of neurons in the vagus [194], which implies that gastric leptin may play a role in feeding behavior. Indeed, leptin and CCK synergistically activate vagal neurons [195-197], and produce synergistic reductions in food intake [198, 199]. It is thought that gastric leptin, rather than circulating leptin is responsible for leptin activation of the vagal afferents. Evidence of this comes from the finding that gastric, but not circulating leptin quickly rises after ingestion of a meal [190] and circulating hormones typically do not utilize a vagally mediated pathway [200]. Also, despite the acidic pH of the stomach, leptin remains stable, and enters the intestinal lumen [189]. This, together with the identification of leptin receptors on the brush border of the intestinal lumen denotes the possibility of gastric leptin influencing intestinal function [201]. Interestingly, application of leptin to an enterocyte cell model or intestinal infusion of leptin increases enterocyte absorption of amino acids [202]. The effects of intestinal luminal leptin on sugar transport are less clear. For example, luminal leptin has an adverse effect on glucose absorption, decreasing expression of the active glucose transporter SGLT1 [201, 203]. However, in vitro and in vivo, luminal leptin increases expression of the passive sugar transporters GLUT2 and GLUT5 [204]. Additionally, luminal leptin may inhibit secretion of intestinal triglyceride processing via inhibition of apolipoprotein A-IV [205, 206]. In addition to its effects on nutrient transport, leptin activates enteroendocrine cells of the duodenum evoking the release of CCK. Interestingly, luminal leptin alone sufficiently increases plasma CCK concentrations similar to that of a meal [189]. This mediation of CCK secretion by gastric leptin is thought to be a positive regulatory loop as intestinally released CCK stimulates secretion of gastric leptin as well [189]. Despite these findings, the relative contribution of gastric leptin to food intake has yet to be elucidated, but the finding that vagal afferents contain leptin receptors [193] denotes a possible role in this gastric peptide in the regulation of food intake.
Ghrelin
Of all the hormones and peptides secreted from the gastrointestinal tract, only one discovered thus far has been shown to promote food consumption. Discovered in nearly 15 years ago, ghrelin, the potent orexigen, is a 28 amino acid peptide released mainly from specialized endocrine X/A-type cells [207] of the stomach. It exerts its physiological effects on stimulating eating and growth hormone (GH) secretion by binding to the growth hormone (GH) secretagogue receptor-1a (GHS-R1a). Compared to other peptides released from the GI tract, ghrelin is unique due to its increased circulating levels during fasting, which together with its ability to increase food intake, indicates the possibility of a role in initiating a meal. In addition to its direct effects in stimulating food intake, ghrelin also decreases energy expenditure and promotes the storage of fatty acids in adipocytes, denoting its potential importance in pathological conditions, such as obesity.
Ghrelin is the endogenous ligand for the GHS-R1a receptor or recently renamed, “ghrelin receptor.” Both ghrelin and its receptor are located in peripheral and central tissues. Within the central nervous system (CNS), ghrelin is localized in hypothalamic and pituitary nuclei of the forebrain that are heavily implicated in the control of food intake or growth hormone secretion. Despite the initial finding that ghrelin stimulates GH secretion [208], the most potent biological function of the peptide is stimulation of food intake through a GH-independent mechanism [209]. The arcuate nucleus (ARC) of the hypothalamus, which is involved in controlling food intake, expresses the highest concentration of centrally distributed ghrelin [210]. Although ghrelin is distributed throughout the central nervous system, peripheral ghrelin from the GI tract, most notably the stomach, is thought to be the primary site for ghrelin secretion and circulating ghrelin [211]. In support of this, partial or complete, gastrectomy (removal of the stomach) markedly reduces circulating ghrelin levels by approximately 70% [212]. Ghrelin is produced in the mucosal layer of the stomach by the endocrine X/A-type cells [207], which are distributed throughout the stomach, but are highly concentrated in the gastric fundus [213]. Gastric X/A-type cells increase in number throughout the fetal period, reaching a maximum during infancy. Likewise, ghrelin levels in the stomach are low during development. One month following birth, however, ghrelin concentrations reach a peak and show no further increase. While the stomach is the main site of ghrelin secretion, ghrelin is detected throughout all layers of the GI tract, salivary glands and alimentary organs, such as the pancreas [214], all of which contribute to the remaining 30% of circulating ghrelin. In the circulation, ghrelin is represented by two forms: des-acyl ghrelin and acyl ghrelin (n-octanoyl-modified ghrelin) [215]. The former version is 5 to 10 times more abundant in plasma than the latter; however, the less common acyl-peptide is thought to be the active form in nearly all physiological, behavioral, and endocrine processes, including food intake. To yield the biologically active acyl-ghrelin, the enzyme, gastric O-acyl transferase (GOAT), cleaves the pre-proghrelin peptide [216]. While the finding of two forms or ghrelin as well as the enzyme responsible for yielding the active form of ghrelin have been recent in respect to the discovery of ghrelin, both total ghrelin and active ghrelin plasma concentrations have been shown to be highly correlative following experimental manipulations [217]. A variety of factors control ghrelin secretion from the stomach into the peripheral circulation with energy and macronutrient content of a meal the main contributors.
Intestinal nutrients and satiation
The small intestine of the GI tract serves as a portal for digesting, sensing, and absorbing nutrients, which all contribute to intestinal nutrient satiation. Infusion of a liquid diet into the intestine results in inhibition of food intake [234-237]. While the effects of intestinal nutrient infusions on the suppression of food intake may be long-lasting and extend to multiple hours, termination of the meal begins rapidly, normally seconds after commencing of a nutrient infusion [235, 238]. Thus, it is hypothesized that the sensing, rather than absorption of nutrients is of importance in intestinal nutrients reducing food intake. Furthermore, while intestinal nutrient infusions inhibit feeding in animals, intestinal nutrients surely reduce the rate of gastric emptying, thus increasing distention of the stomach, which could be one way by which nutrients reduce food intake [239]. However, intestinal nutrient infusions also inhibit feeding in animals with gastric fistulas, where gastric distention is absent [235, 240] denoting the importance of intestinal factors in autonomously controlling meal size. Ingesta entering the intestine from the gastric cavity are typically hyperosmotic, and contain a variety of nutrients, all of which influence feeding responses. In animals, the infusion of hyperosmotic loads indeed decreases food intake in freely feeding animals [241]. Despite this, the hyperosmotic and complete nutritive nature of chyme is not the main contributor to intestinal satiation. For example, intestinal infusion of specific macronutrients, such as oligosaccharides [242] or long-chain fatty acids [243] reduces food intake, even in hypotonic or isotonic concentrations.
Intestinal carbohydrates and feeding behavior
Intestinal carbohydrates and sugars have been reported to reduce food intake in both sham- and real-feeding animals [243, 244], and increasing the length of the oligosaccharide used for an intestinal infusion results in a greater reduction of food intake than a simple sugar [245]. Additionally, the digestion of oligosaccharides to simple sugars is nearly essential in reducing food intake as administration of the oligosaccharidase inhibitor, acarbose, results in attenuation of oligosaccharide-induced reduction in food intake [246]. Specifically, the ability of carbohydrates to reduce food intake may require glucose, at least when low concentrations are present as glucose infusions will significantly reduce food intake, but low concentrations of fructose has no effect on feeding [247]. Collectively, these data implicate carbohydrate-induced satiation, and most likely, the detection of glucose in influencing food intake.
The specific intestinal mechanism responsible for glucose-induced satiation is still not completely understood. It is well known that hydrolysis of oligosaccharides produces monosaccharides, which are predominantly absorbed via active transport on the apical membrane of the intestinal epithelium. For example, luminal glucose is largely transported by the active glucose transporter SGLT1 while other monosaccharides, such as fructose, require the passive transporter, GLUT5, for absorption. Interestingly, intestinal infusions of glucose isomers, which are substrates for SGLT1 reduce food intake [248] while the aforementioned fructose does not. However, the findings that intravenous glucose is mostly ineffective at reducing food intake compared to intestinal infusions of glucose, and that glucose in the lumen is inversely related to blood glucose levels exemplifies that a pre-absorptive mechanism is responsible for glucose-induced satiation [245]. This is probably independent of SGLT1 as well because inhibition of SGLT1 activity does not attenuate intestinal glucose-induced satiation [249]. Therefore, the hydrolysis of oligosaccharides to glucose is at least somewhat necessary for carbohydrate-induced reductions in food intake, but the absorption of glucose is not. Recent evidence suggests that luminal intestinal epithelial receptors, similar to those located in the lingual epithelium, may a possible pathway in detecting intestinal glucose, and subsequently regulating dietary absorption of carbohydrates.
Mechanisms of intestinal carbohydrate detection
The transport of luminal glucose in the intestine is carried out by the active glucose transporter SGLT1. To facilitate this process, SGLT1 localized on the apical epithelium of enterocytes transports both glucose and sodium, which is driven by the increased glucose concentration in the intestinal lumen and decreased intracellular Na+ levels due to the basolateral Na+-ATPase [250] (Figure 6). The other major dietary monosaccharide, fructose, is transported into the enterocyte via the passive GLUT5 transporter. Once localized in the enterocyte, glucose exits the cell and enters the hepatic portal circulation via the basolaterally expressed passive transporter, GLUT2 [250]. The general expression pattern for SGLT1 is greatest in the proximal intestine, and more specifically, the duodenum [251]. While the basolaterally expressed GLUT2 may also be expressed on the apical membrane of enterocytes, and has been hypothesized to play a role in post-prandial glucose transport [252-254], an animal model displaying a GLUT2 mutation does not exhibit defects in intestinal glucose absorption [255]. As such, it is hypothesized that SGLT1 is the principal mediator of intestinal glucose absorption.
Intestinal nutrients, conditioned preferences, and reward
In addition to intestinal nutrients playing a profound role in terminating a meal, the exposure of nutrients to the intestine is vital in establish learned food preferences, a term coined “post-oral conditioning.” The evidence of post-oral conditioning influencing feeding behavior comes from studies where intake of a flavored nonnutritive solution is paired with gastric or intestinal infusion of a specific macronutrient, typically carbohydrates that are strong enforcers of post-oral conditioning. For example, rats that are trained alternating days to drink a specific flavor (e.g. grape) paired with a gastric infusion of glucose or another flavor (e.g. cherry) paired with a gastric infusion of water display a profound preference for the grape flavored solution over the cherry solution when given concomitant access to both flavors and in the absence of gastric infusion [320]. In these studies, animals typically “self-infuse” the infusate by starting to drink the flavored solution and the infusion beginning almost simultaneously [321]. However, post-oral infusions of glucose also can also stimulate consumption of a flavored solution when paired 1-h post consumption [322]. The effects of post-oral glucose conditioning flavor preferences also is long lasting, denoting a probable reward pathway controlling this behavior [323-325]. As well as increases in flavor preference, post-oral conditioning with intestinal carbohydrates increases overall intake of the flavored solution [326-328]. The site of action for this phenomenon is the proximal intestine as occluding the stomach prevents gastric infusions from conditioning flavor preferences [329] and duodenal or jejunal, but not ileal [329, 330], or intravascular infusions of sugars [331] results in post-oral flavor conditioning . However, changes in the feeding paradigm, such as water and food deprivation, coupled with a flavored nutritive solution can result in intravascular glucose to condition flavor preferences [332].
While glucose is an extremely strong enforcer of conditioned flavor preferences, other nutritive sweet substances, such as sucrose and fructose can have the same effect [333-336]. However, for the latter, animals require long infusions (>20-h) in conditioning flavor preferences paired with gastric infusions [336]. In contrast to this, nutritive sweet lactose and galactose [320, 337, 338] as well as nonnutritive sweet stimuli, such as sacharrin or sucralose [339, 340] do not condition flavor preferences. The former two may be explained by the inability of an animal to fully digest these nutrients while the latter two are explained by the nonnutritive value. In addition to these findings, research demonstrating that T1R3 KO mice maintain normal post-oral conditioned flavor preferences [340] lends notion that a mechanism other than sweet receptors, such as SGLT1 or SGLT3 activity [341], may be responsible for these findings. Furthermore, in the absence of post-intestinal signaling, such as vagal deafferentation via mechanical [342, 343] or chemical [344] means, animals continue to display conditioned flavor preferences with glucose infusions. Additionally, intestinal satiety peptides, which are released in response to intestinal nutrients, control nutrient-induced satiation, but do not control glucose-induced conditioned flavor preferences [335, 345, 346]. Collectively these findings demonstrate that a pre-absorptive mechanism, localized in the intestine, is responsible for post-oral conditioned flavor preferences induced by glucose.
Table of contents :
1 Introduction
1.1 Obesity and healthcare costs
1.2 The digestive system
1.2.1 Oral cavity
1.2.1.1 Taste
1.2.1.2 Sweet taste
1.2.1.2.1 Sweet taste and feeding behavior
1.2.1.2.2 Mechanisms of oral sweet detection
1.2.1.3 Fat taste
1.2.1.3.1 Fat taste and feeding behavior
1.2.1.3.2 Mechanisms of oral fat detection
1.2.1.4 Taste transduction, central signaling, and reward
1.2.1.5 Obesity and taste
1.2.2 Stomach
1.2.2.1 Gastric distention
1.2.2.2 Endocrine function
1.2.2.2.1 Gastric leptin
1.2.2.2.2 Ghrelin
1.2.3 Intestine
1.2.3.1 Intestinal nutrient satiation
1.2.3.2 Intestinal carbohydrates
1.2.3.2.1 Intestinal carbohydrates and feeding behavior
1.2.3.2.2 Mechanisms of intestinal carbohydrate detection
1.2.3.3 Intestinal fats
1.2.3.3.1 Intestinal fats and feeding behavior
1.2.3.3.2 Mechanisms of intestinal fat detection
1.2.3.4 Intestinal nutrients, conditioned preferences, and reward
1.2.3.5 Obesity and intestinal nutrient satiation
1.2.3.6 Vagal afferents and intstinal nutrient satiation
1.2.3.7 Intestinal satiety peptides
1.2.3.7.1 Cholecystokinin (CCK)
1.2.3.7.2 Glucagon-like Peptide-1 (GLP-1)
1.2.3.7.2 Peptide YY (PYY)
1.2.4 Liver
1.2.4.1 Hepatic nutrients and feeding behavior
1.2.4.2 Hepatic metabolism and feeding behavior
1.2.4.3 Obesity and hepatic metabolism
1.3 Microbiota
1.3.1 Microbiota and energy harvest
1.3.2 Microbiota and intestinal morphology
1.3.3 Microbiota and intestinal endocrine function
1.3.4 Microbiota and inflammation
1.3.5 Microbiota and obesity
1.4 Overall significance and experimental outline
1.4.1 Specific Aim 1
1.4.2 Specific Aim 2
1.4.3 Specific Aim 3
2 Specific Aim 1: How the absence of gut microbiota affects oral and postoral detection of sweet nutrients as well as intestinal sugar transporters
2.1 Introduction
2.2 Up-regulation of intestinal type 1 taste receptor 3 and sodium glucose luminal transporter 1 expression and increased sucrose intake in mice lacking gut microbiota
2.3 Summary of results and conclusions
3 Specific Aim 2: How gut microbiota affects oral and post-oral detection of lipids and associated changes in nutrient-responsive g-protein coupled receptors (GPRs) and intestinal satiety peptides
3.1 Introduction
3.2 Increased oral detection, but decreased intestinal signaling for fats in mice lacking gut microbiota
3.3 Summary of results and conclusions
4 Specific Aim 3: How gut microbiota affects host liver, intestinal, and adipose metabolic parameters in a GF rat model
4.1 Introduction
4.2 Absence of gut microbiota is not protective of fat deposition in the GF F344 rat model
4.3 Specific Aim 3: Summary of results and conclusions
5 General summary
5.1 General results
5.2 General discussion
5.3 General conclusions
6 Index
6.1 Figures
6.1.1 Chapter 1
6.1.2 Chapter 3
6.1.3 Chapter 4
6.1.4 Chapter 5
6.2 Tables
6.2.1 Chapter 4
6.3 Abbreviations
7 References
