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Glucose Sensing in the Hepatic Portal Vein and Its Role in Food Intake and Reward

2023; Elsevier BV; Volume: 16; Issue: 2 Linguagem: Inglês

10.1016/j.jcmgh.2023.03.012

2352-345X

Sam Z. Bacharach, Michael G. Tordoff, Amber L. Alhadeff,

Pancreatic function and diabetes

The detection of nutrients in the gut influences ongoing and future feeding behavior as well as the development of food preferences. In addition to nutrient sensing in the intestine, the hepatic portal vein plays a considerable role in detecting ingested nutrients and conveying this information to brain nuclei involved in metabolism, learning, and reward. Here, we review mechanisms underlying hepatic portal vein sensing of nutrients, particularly glucose, and how this is relayed to the brain to influence feeding behavior and reward. We additionally highlight several gaps where future research can provide new insights into the effects of portal nutrients on neural activity in the brain and feeding behavior. The detection of nutrients in the gut influences ongoing and future feeding behavior as well as the development of food preferences. In addition to nutrient sensing in the intestine, the hepatic portal vein plays a considerable role in detecting ingested nutrients and conveying this information to brain nuclei involved in metabolism, learning, and reward. Here, we review mechanisms underlying hepatic portal vein sensing of nutrients, particularly glucose, and how this is relayed to the brain to influence feeding behavior and reward. We additionally highlight several gaps where future research can provide new insights into the effects of portal nutrients on neural activity in the brain and feeding behavior. SummaryWe review mechanisms underlying hepatic portal vein sensing of nutrients, particularly glucose, and its influence on feeding behavior. We additionally highlight gaps where future research can refine our knowledge of how portal nutrients modulate brain activity and food intake. We review mechanisms underlying hepatic portal vein sensing of nutrients, particularly glucose, and its influence on feeding behavior. We additionally highlight gaps where future research can refine our knowledge of how portal nutrients modulate brain activity and food intake. Food intake is governed by a complex set of biological mechanisms involving the body and brain.1Andermann M.L. Lowell B.B. Toward a wiring diagram understanding of appetite control.Neuron. 2017; 95: 757-778Abstract Full Text Full Text PDF PubMed Scopus (279) Google Scholar, 2Clemmensen C. Müller T.D. Woods S.C. et al.Gut-brain cross-talk in metabolic control.Cell. 2017; 168: 758-774Abstract Full Text Full Text PDF PubMed Scopus (162) Google Scholar, 3Shechter A. Schwartz G.J. Gut-brain nutrient sensing in food reward.Appetite. 2018; 122: 32-35Crossref PubMed Scopus (21) Google Scholar In particular, nutrient sensing in the gastrointestinal tract is fundamental to regulating energy homeostasis and feeding behavior.2Clemmensen C. Müller T.D. Woods S.C. et al.Gut-brain cross-talk in metabolic control.Cell. 2017; 168: 758-774Abstract Full Text Full Text PDF PubMed Scopus (162) Google Scholar The body contains multiple organs with a wide variety of transporters and sensors that detect several nutrients, including but not limited to carbohydrates, proteins, and fats. The detection of glucose, the main source of energy for all cells in the body, is of particular metabolic importance. Circulating blood glucose concentrations are maintained within a tight range, and major fluctuations can cause serious disturbances such as blurred vision, fatigue, and in extreme cases, loss of consciousness or death.4Wasserman D.H. Four grams of glucose.Am J Physiol Endocrinol Metab. 2009; 296: E11-E21Crossref PubMed Scopus (257) Google Scholar To maintain glucose homeostasis, the body has specialized systems for glucose sensing.5Stanley S. Moheet A. Seaquist E.R. Central mechanisms of glucose sensing and counterregulation in defense of hypoglycemia.Endocr Rev. 2019; 40: 768-788Crossref PubMed Scopus (44) Google Scholar, 6Verberne A.J.M. Sabetghadam A. Korim W.S. Neural pathways that control the glucose counterregulatory response.Front Neurosci. 2014; 8: 38Crossref PubMed Scopus (99) Google Scholar, 7Wachsmuth H.R. Weninger S.N. Duca F.A. Role of the gut-brain axis in energy and glucose metabolism.Exp Mol Med. 2022; 54: 377-392Crossref PubMed Scopus (15) Google Scholar To deal with excess glucose, the body prepares for incoming nutrients with metabolic responses and mechanisms to curb additional food intake. Conversely, when energy is low, the body initiates counterregulatory processes to conserve and produce glucose. To this end, levels of glucose (and other nutrients) are sensed in the gastrointestinal tract and hepatic portal area and trigger the initiation of appropriate metabolic, digestive, or counterregulatory processes. In turn, the signals generated by peripheral nutrient detection are communicated to the brain to modulate current and future food intake. After absorption from the gastrointestinal tract, nutrients enter the circulatory system through mesenteric capillary beds that flow into the hepatic portal vein (HPV). The HPV is exposed to the largest range of concentrations of glucose in the body.8Croset M. et al.Rat small intestine is an insulin-sensitive gluconeogenic organ.Diabetes. 2001; 50: 740-746Crossref PubMed Google Scholar, 9Soty M. Gautier-Stein A. Rajas F. et al.Gut-brain glucose signaling in energy homeostasis.Cell Metab. 2017; 25: 1231-1242Abstract Full Text Full Text PDF PubMed Google Scholar, 10Strubbe J.H. Bruggink J.E. Steffens A.B. Hepatic portal vein cannulation for infusion and blood sampling in freely moving rats.Physiol Behav. 1988; 65: 885-887Crossref Scopus (14) Google Scholar Therefore, the HPV may be the most important area in the body to sense glucose levels and trigger appropriate behavioral and physiological changes. Here, we focus on glucose sensing within the HPV and how it influences food intake. After briefly summarizing the anatomy of the HPV, we review literature on the effects of HPV glucose sensing on food intake. We additionally discuss putative gut-brain mechanisms that relay glucose-related information to the brain to influence feeding behavior and reward processing. Last, we discuss current gaps in knowledge and future research directions that will lead to a better mechanistic understanding of both portal glucose sensing and the portal control of feeding behavior. We suggest that HPV glucose sensing, compared with intestinal glucose sensing, is often overlooked and should be revisited to gain a more complete understanding of the gut-brain control of feeding behavior. A portal system describes a venous system where blood passes through 2 capillary beds before returning to the heart. Accordingly, the hepatic portal system comprises a series of veins that carries blood from the capillary beds of the gastrointestinal tract and spleen to the capillary beds of the liver before being returned to the heart.11Pellerito J. Polak J. Anatomy normal doppler signatures of abdominal vessels. In: Introduction to Vascular Ultrasonography. 7th ed. Elsevier, New York, NY2019: 439-449Google Scholar,12Shah V. Kamath P. Portal hypertension and variceal bleeding.in: Sleisenger and Fordtran's Gastrointestinal and Liver Disease. 92. Elsevier, New York, NY2019: 1443-1470Google Scholar The majority of ingested nutrients that are absorbed through the gastrointestinal tract pass through the HPV before being processed and filtered in the liver.11Pellerito J. Polak J. Anatomy normal doppler signatures of abdominal vessels. In: Introduction to Vascular Ultrasonography. 7th ed. Elsevier, New York, NY2019: 439-449Google Scholar,12Shah V. Kamath P. Portal hypertension and variceal bleeding.in: Sleisenger and Fordtran's Gastrointestinal and Liver Disease. 92. Elsevier, New York, NY2019: 1443-1470Google Scholar The HPV receives input from 3 major veins that carry blood from distinct parts of the gastrointestinal tract (Figure 1).12Shah V. Kamath P. Portal hypertension and variceal bleeding.in: Sleisenger and Fordtran's Gastrointestinal and Liver Disease. 92. Elsevier, New York, NY2019: 1443-1470Google Scholar Most proximal to the liver are the gastric and gastro-omental veins, which carry blood from the distal esophagus, stomach, and duodenum to the portal vein. Just ventral to this junction is the splenic vein, which carries blood from the spleen. The inferior mesenteric vein (which carries blood from the transverse, descending, and sigmoid colon, as well as the rectum) joins with the splenic vein just before the HPV junction. Last, the superior mesenteric vein carries blood from the duodenum, jejunum, ileum, cecum, and ascending and transverse colon. All of these veins converge to the HPV before it enters the liver.12Shah V. Kamath P. Portal hypertension and variceal bleeding.in: Sleisenger and Fordtran's Gastrointestinal and Liver Disease. 92. Elsevier, New York, NY2019: 1443-1470Google Scholar Light and electron microscopy have uncovered the structural organization of the HPV, which is composed of 3 distinct layers (Figure 1, insert).13Ts'ao C.H. Glagov S. Kelsey B.F. Special structural features of the rat portal vein.Anat Rec (Hoboken). 1970; 166: 529-539Crossref Scopus (22) Google Scholar,14Dong H.-M. Ichimura K. Sakai T. Structural organization of hepatic portal vein in rat with special reference to musculature, intimal folds, and endothelial cell alignment.Anat Rec (Hoboken). 2010; 293: 1887-1895Crossref PubMed Scopus (11) Google Scholar The external layer (tunica adventitia) is a layer of connective tissue containing collagen and elastic fibrils. The middle layer (tunica media) comprises 2 distinct smooth muscle layers. The outer layer is composed of smooth muscle, which is aligned longitudinally and spans the proximal to distal parts of the vein. Below is a layer of circular smooth muscle which is aligned circumferentially about the vein. The inner layer (tunica interna) comprises a thin layer of endothelial cells that line the lumen of the HPV. Sensory afferents, which convey HPV signals to the central nervous system, innervate the HPV throughout these layers (Figure 1, insert). The nature of this innervation and its influence in regulating food intake are described throughout this review. It is worth noting that the majority of experiments discussed in this review catheterize and infuse glucose in the HPV slightly above or below the junction of the superior mesenteric and portal veins.10Strubbe J.H. Bruggink J.E. Steffens A.B. Hepatic portal vein cannulation for infusion and blood sampling in freely moving rats.Physiol Behav. 1988; 65: 885-887Crossref Scopus (14) Google Scholar Thus, any feeding effects with HPV infusions can be attributed to nutrient sensing that occurs within or downstream of this region of the HPV, though it does not exclude the possibility that nutrient sensing occurs within smaller input veins as well. Russek15Russek M. Demonstration of the influence of an hepatic glucosensitive mechanism on food-intake.Physiol Behav. 1970; 5: 1207-1209Crossref PubMed Scopus (0) Google Scholar was the first to show that infusions of glucose into the HPV in the dog cause termination of an ongoing meal. Subsequent studies have replicated this effect showing that portal glucose infusions decrease food intake across species, including rodents, rabbits, chickens, and dogs.15Russek M. Demonstration of the influence of an hepatic glucosensitive mechanism on food-intake.Physiol Behav. 1970; 5: 1207-1209Crossref PubMed Scopus (0) Google Scholar, 16Campbell C.S. Davis J.D. Licking rate of rats is reduced by intraduodenal and intraportal glucose infusion.Physiol Behav. 1974; 12: 357-365Crossref PubMed Scopus (0) Google Scholar, 17Novin D. Sanderson J.D. Vanderweele D.A. The effect of isotonic glucose on eating as a function of feeding condition and infusion site.Physiol Behav. 1974; 13: 3-7Crossref PubMed Scopus (79) Google Scholar, 18Booth D.A. Jarman S.P. Inhibition of food intake in the rat following complete absorption of glucose delivered into the stomach, intestine or liver.J Physiol. 1976; 259: 501-522Crossref PubMed Scopus (60) Google Scholar, 19VanderWeele D.A. Skoog D.R. Novin D. Glycogen levels and peripheral mechanisms of glucose-induced suppression of feeding.Am J Physiol. 1976; 231: 1655-1659Crossref PubMed Scopus (17) Google Scholar, 20Yin T.H. Tsai W.H. Barone F.C. et al.Effects of continuous intramesenteric infusion of glucose and amino acids on food intake in rats.Physiol Behav. 1979; 22: 1207-1210Crossref PubMed Scopus (0) Google Scholar, 21Russek M. Lora-Vilchis M.C. Islas-Chaires M. Food intake inhibition elicited by intraportal glucose and adrenaline in dogs on a 22 hour-fasting/2 hour feeding schedule.Physiol Behav. 1980; 24: 157-161Crossref PubMed Scopus (27) Google Scholar, 22Shurlock T.G. Forbes J.M. Evidence for hepatic glucostatic regulation of food intake in the domestic chicken and its interaction with gastro-intestinal control.Br Poult Sci. 1981; 22: 333-346Crossref PubMed Scopus (33) Google Scholar, 23Lacy M.P. Van Krey H.P. Skewes P.A. et al.Effect of intrahepatic glucose infusions on feeding in heavy and light breed chicks.Poult Sci. 1985; 64: 751-756Crossref PubMed Scopus (0) Google Scholar, 24Novin D. Robinson K. Culbreth L.A. et al.Is there a role for the liver in the control of food intake?.Am J Clin Nutr. 1985; 42: 1050-1062Abstract Full Text PDF PubMed Scopus (0) Google Scholar, 25Tordoff M.G. Friedman M.I. Hepatic portal glucose infusions decrease food intake and increase food preference.Am J Physiol. 1986; 251: R192-R196PubMed Google Scholar, 26Rusby A.A. Anil M.H. Chatterjee P. et al.Effects of intraportal infusion of glucose and lysine on food intake in intact and hepatic-vagotomized chickens.Appetite. 1987; 9: 65-72Crossref PubMed Scopus (7) Google Scholar, 27Tordoff M.G. Friedman M.I. Hepatic control of feeding: effect of glucose, fructose, and mannitol infusion.Am J Physiol. 1988; 254: R969-R976PubMed Google Scholar, 28Tordoff M.G. Tluczek J.P. Friedman M.I. Effect of hepatic portal glucose concentration on food intake and metabolism.Am J Physiol. 1989; 257: R1474-R1480PubMed Google Scholar, 29Baird J.P. Grill H.J. Kaplan J.M. Intake suppression after hepatic portal glucose infusion: all-or-none effect and its temporal threshold.Am J Physiol. 1997; 272: R1454-R1460PubMed Google Scholar, 30Baird J.P. Grill H.J. Kaplan J.M. Effect of hepatic glucose infusion on glucose intake and licking microstructure in deprived and nondeprived rats.Am J Physiol. 1999; 277: R1136-R1143PubMed Google Scholar, 31Langhans W. Grossmann F. Geary N. Intrameal hepatic-portal infusion of glucose reduces spontaneous meal size in rats.Physiol Behav. 2001; 73: 499-507Crossref PubMed Scopus (0) Google Scholar, 32Mithieux G. Misery P. Magnan C. et al.Portal sensing of intestinal gluconeogenesis is a mechanistic link in the diminution of food intake induced by diet protein.Cell Metab. 2005; 2: 321-329Abstract Full Text Full Text PDF PubMed Scopus (155) Google Scholar, 33Delaere F. Duchampt A. Mounien L. et al.The role of sodium-coupled glucose co-transporter 3 in the satiety effect of portal glucose sensing.Mol Metab. 2012; 2: 47-53Crossref PubMed Scopus (94) Google Scholar This effect on feeding is localized to the portal vein and not the to jugular15Russek M. Demonstration of the influence of an hepatic glucosensitive mechanism on food-intake.Physiol Behav. 1970; 5: 1207-1209Crossref PubMed Scopus (0) Google Scholar,25Tordoff M.G. Friedman M.I. Hepatic portal glucose infusions decrease food intake and increase food preference.Am J Physiol. 1986; 251: R192-R196PubMed Google Scholar,27Tordoff M.G. Friedman M.I. Hepatic control of feeding: effect of glucose, fructose, and mannitol infusion.Am J Physiol. 1988; 254: R969-R976PubMed Google Scholar,29Baird J.P. Grill H.J. Kaplan J.M. Intake suppression after hepatic portal glucose infusion: all-or-none effect and its temporal threshold.Am J Physiol. 1997; 272: R1454-R1460PubMed Google Scholar or caval20Yin T.H. Tsai W.H. Barone F.C. et al.Effects of continuous intramesenteric infusion of glucose and amino acids on food intake in rats.Physiol Behav. 1979; 22: 1207-1210Crossref PubMed Scopus (0) Google Scholar veins, suggesting that the anorectic effects are triggered by local sensing within the HPV or liver, rather than sensing elsewhere in circulation or in the brain. While overwhelming evidence supports a role for HPV glucose sensing for inhibiting food intake, it is worth noting that there are other studies showing no effect, or even increases, in feeding following HPV glucose infusions.17Novin D. Sanderson J.D. Vanderweele D.A. The effect of isotonic glucose on eating as a function of feeding condition and infusion site.Physiol Behav. 1974; 13: 3-7Crossref PubMed Scopus (79) Google Scholar,23Lacy M.P. Van Krey H.P. Skewes P.A. et al.Effect of intrahepatic glucose infusions on feeding in heavy and light breed chicks.Poult Sci. 1985; 64: 751-756Crossref PubMed Scopus (0) Google Scholar,34Baile C.A. Zinn W. Mayer J. Feeding behavior of monkeys: glucose utilization rate and site of glucose entry.Physiol Behav. 1971; 6: 537-541Crossref PubMed Google Scholar, 35Yin T.H. Tsai C.T. Effects of glucose on feeding in relation to routes of entry in rats.J Comp Physiol Psychol. 1973; 85: 258-264Crossref PubMed Scopus (46) Google Scholar, 36Stephens D.B. Baldwin B.A. The lack of effect of intrajugular or intraportal injections of glucose or amino-acids on food intake in pigs.Physiol Behav. 1974; 12: 923-929Crossref PubMed Scopus (0) Google Scholar, 37Vanderweele D.A. Novin D. Rezek M. et al.Duodenal or hepatic-portal glucose perfusion: evidence for duodenally-based satiety.Physiol Behav. 1974; 12: 467-473Crossref PubMed Scopus (0) Google Scholar, 38Rezek M. Havlicek V. Novin D. Satiety and hunger induced by small and large duodenal loads of isotonic glucose.Am J Physiol. 1975; 229: 545-548Crossref PubMed Scopus (20) Google Scholar, 39Bellinger L.L. Trietley G.J. Bernardis L.L. Failure of portal glucose and adrenaline infusions or liver denervation to affect food intake in dogs.Physiol Behav. 1976; 16: 299-304Crossref PubMed Scopus (36) Google Scholar, 40Rezek M. Novin D. Hepatic-portal nutrient infusion: effect on feeding in intact and vagotomized rabbits.Am J Physiol. 1977; 232: E119-E130PubMed Google Scholar, 41Strubbe J.H. Steffens A.B. Blood glucose levels in portal and peripheral circulation and their relation to food intake in the rat.Physiol Behav. 1977; 19: 303-307Crossref PubMed Scopus (100) Google Scholar, 42Rezek M. Havlicek V. Friesen H. Hepatic-portal glucose and insulin levels: relationship to glucose-induced satiety and hunger.J Nutr. 1979; 109: 1665-1672Abstract Full Text PDF PubMed Scopus (0) Google Scholar There are several experimental factors that may have led to contradictory results, including the energy state of the animal, infusion parameters, and food used in intake tests. First, in contrast to experiments where animals were fed ad libitum, experiments in which animals were food restricted overnight prior to portal infusion generally did not observe reductions in food intake.17Novin D. Sanderson J.D. Vanderweele D.A. The effect of isotonic glucose on eating as a function of feeding condition and infusion site.Physiol Behav. 1974; 13: 3-7Crossref PubMed Scopus (79) Google Scholar,23Lacy M.P. Van Krey H.P. Skewes P.A. et al.Effect of intrahepatic glucose infusions on feeding in heavy and light breed chicks.Poult Sci. 1985; 64: 751-756Crossref PubMed Scopus (0) Google Scholar,34Baile C.A. Zinn W. Mayer J. Feeding behavior of monkeys: glucose utilization rate and site of glucose entry.Physiol Behav. 1971; 6: 537-541Crossref PubMed Google Scholar, 35Yin T.H. Tsai C.T. Effects of glucose on feeding in relation to routes of entry in rats.J Comp Physiol Psychol. 1973; 85: 258-264Crossref PubMed Scopus (46) Google Scholar, 36Stephens D.B. Baldwin B.A. The lack of effect of intrajugular or intraportal injections of glucose or amino-acids on food intake in pigs.Physiol Behav. 1974; 12: 923-929Crossref PubMed Scopus (0) Google Scholar,39Bellinger L.L. Trietley G.J. Bernardis L.L. Failure of portal glucose and adrenaline infusions or liver denervation to affect food intake in dogs.Physiol Behav. 1976; 16: 299-304Crossref PubMed Scopus (36) Google Scholar,41Strubbe J.H. Steffens A.B. Blood glucose levels in portal and peripheral circulation and their relation to food intake in the rat.Physiol Behav. 1977; 19: 303-307Crossref PubMed Scopus (100) Google Scholar,43Bellinger L.L. Williams F.E. The effect of portal and jugular infused glucose, mannitol and saline on food intake in dogs.Physiol Behav. 1989; 46: 693-698Crossref PubMed Scopus (11) Google Scholar Long-term (eg, overnight) food restriction impacts mechanisms underlying motivation and metabolism, such as those underlying glycogen storage, that likely interact with portal nutrient sensing, perhaps explaining these results. In contrast, acute food restriction (3–4 hours before food intake tests) does not influence the intake suppression elicited by portal glucose infusions.32Mithieux G. Misery P. Magnan C. et al.Portal sensing of intestinal gluconeogenesis is a mechanistic link in the diminution of food intake induced by diet protein.Cell Metab. 2005; 2: 321-329Abstract Full Text Full Text PDF PubMed Scopus (155) Google Scholar,33Delaere F. Duchampt A. Mounien L. et al.The role of sodium-coupled glucose co-transporter 3 in the satiety effect of portal glucose sensing.Mol Metab. 2012; 2: 47-53Crossref PubMed Scopus (94) Google Scholar Second, the parameters of the portal infusion (eg, rate and concentration) may have consequences on the experimental outcome. In the rat, glucose is absorbed from the gut at a constant rate of 3 mg/min per 100 g body weight for up to 2 hours after a meal.44Niewoehner C.B. Gilboe D.P. Nuttall F.Q. Metabolic effects of oral glucose in the liver of fasted rats.Am J Physiol. 1984; 246: E89-E94PubMed Google Scholar Additionally, portal vein blood flows at ∼10 mL/min and portal glucose levels are between 0.8–2.0 g/L after a meal.25Tordoff M.G. Friedman M.I. Hepatic portal glucose infusions decrease food intake and increase food preference.Am J Physiol. 1986; 251: R192-R196PubMed Google Scholar The experimental parameters that produce the most reliable portal feeding effects use infusion rates of approximately 0.1 mL/min (or less) and infuse over several hours before the feeding tests begin.25Tordoff M.G. Friedman M.I. Hepatic portal glucose infusions decrease food intake and increase food preference.Am J Physiol. 1986; 251: R192-R196PubMed Google Scholar,27Tordoff M.G. Friedman M.I. Hepatic control of feeding: effect of glucose, fructose, and mannitol infusion.Am J Physiol. 1988; 254: R969-R976PubMed Google Scholar, 28Tordoff M.G. Tluczek J.P. Friedman M.I. Effect of hepatic portal glucose concentration on food intake and metabolism.Am J Physiol. 1989; 257: R1474-R1480PubMed Google Scholar, 29Baird J.P. Grill H.J. Kaplan J.M. Intake suppression after hepatic portal glucose infusion: all-or-none effect and its temporal threshold.Am J Physiol. 1997; 272: R1454-R1460PubMed Google Scholar,32Mithieux G. Misery P. Magnan C. et al.Portal sensing of intestinal gluconeogenesis is a mechanistic link in the diminution of food intake induced by diet protein.Cell Metab. 2005; 2: 321-329Abstract Full Text Full Text PDF PubMed Scopus (155) Google Scholar,33Delaere F. Duchampt A. Mounien L. et al.The role of sodium-coupled glucose co-transporter 3 in the satiety effect of portal glucose sensing.Mol Metab. 2012; 2: 47-53Crossref PubMed Scopus (94) Google Scholar These are likely the most consistent parameters, as they mimic physiological rates of glucose absorption. The timing of HPV infusion in relation to the feeding test is a large source of variability in the literature that we will return to when we discuss satiety/satiation subsequently. Third, the quality of the test diet may impact the ability to observe food intake reductions following portal glucose infusion. Several studies failed to report decreases in food intake if the subjects' maintenance diet was used as the test diet, and many (but not all) of those that reported decreases used a novel test diet. Therefore, it has been suggested that the use of novel foods and contexts may improve the ability to observe food intake changes following portal glucose infusions.25Tordoff M.G. Friedman M.I. Hepatic portal glucose infusions decrease food intake and increase food preference.Am J Physiol. 1986; 251: R192-R196PubMed Google Scholar Consistent with this, most failures to obtain effects of portal glucose infusions on food intake use within-subject designs, which often confound sensory and metabolic cues that can be used to learn about the nutrient value of the test food. While these experimental conditions can influence whether HPV glucose infusions inhibit food intake, other considerations do not seem to affect experimental outcome. For example, testing in the light vs dark phase does not have an impact, nor does the consistency of the food (ie, solid vs liquid food).25Tordoff M.G. Friedman M.I. Hepatic portal glucose infusions decrease food intake and increase food preference.Am J Physiol. 1986; 251: R192-R196PubMed Google Scholar,27Tordoff M.G. Friedman M.I. Hepatic control of feeding: effect of glucose, fructose, and mannitol infusion.Am J Physiol. 1988; 254: R969-R976PubMed Google Scholar,29Baird J.P. Grill H.J. Kaplan J.M. Intake suppression after hepatic portal glucose infusion: all-or-none effect and its temporal threshold.Am J Physiol. 1997; 272: R1454-R1460PubMed Google Scholar Food intake can be reduced in several ways, and an examination of meal microstructure can provide insights into the behavioral function of HPV nutrient sensing. Two main processes exist to decrease feeding; those of satiation and satiety.45Bellisle F. Drewnowski A. Anderson G.H. et al.Sweetness, satiation, and satiety.J Nutr. 2012; 142: 1149S-1154SAbstract Full Text Full Text PDF PubMed Scopus (106) Google Scholar,46Blundell J.E. Lawton C.L. Cotton J.R. et al.Control of human appetite: implications for the intake of dietary fat.Annu Rev Nutr. 1996; 16: 285-319Crossref PubMed Google Scholar Satiation is the perception of fullness during a meal that eventually terminates ongoing eating. On the other hand, satiety refers to feelings of fullness between meals which prevent future eating from occurring. Whether portal glucose sensing influences satiation or satiety is debated. Baird et al29Baird J.P. Grill H.J. Kaplan J.M. Intake suppression after hepatic portal glucose infusion: all-or-none effect and its temporal threshold.Am J Physiol. 1997; 272: R1454-R1460PubMed Google Scholar systematically tested temporal parameters for hepatic portal glucose–mediated decreases in feeding and found that portal glucose does not terminate an ongoing meal, but rather decreases the sizes of subsequent meals. This result was interpreted as an effect on satiety, as portal glucose infusion had longer-term, rather than immediate, effects on feeding behavior. In contrast, other studies support the argument that portal nutrient sensing decreases the size of ongoing meals, implying an effect on satiation.31Langhans W. Grossmann F. Geary N. Intrameal hepatic-portal infusion of glucose reduces spontaneous meal size in rats.Physiol Behav. 2001; 73: 499-507Crossref PubMed Scopus (0) Google Scholar,47Rüttimann E.B. Arnold M. Hillebrand J.J. et al.Intrameal hepatic portal and intraperitoneal infusions of glucagon-like peptide-1 reduce spontaneous meal size in the rat via different mechanisms.Endocrinology. 2009; 150: 1174-1181Crossref PubMed Scopus (218) Google Scholar It is worth noting that these studies involved remotely triggered portal infusions in rats consuming an ongoing meal, whereas Baird et al29Baird J.P. Grill H.J. Kaplan J.M. Intake suppression after hepatic portal glucose infusion: all-or-none effect and its temporal threshold.Am J Physiol. 1997; 272: R1454-R1460PubMed Google Scholar measured feeding responses with an intraoral glucose infusion. Although the experimental paradigm in Langhans et al31Langhans W. Grossmann F. Geary N. Intrameal hepatic-portal infusion of glucose reduces spontaneous meal size in rats.Physiol Behav. 2001; 73: 499-507Crossref PubMed Scopus (0) Google Scholar was arguably more naturalistic, the results of HPV glucose infusions on meal size were inconsistent, as only 1 dose of glucose (1 mmol), but not lower or higher doses, elicited feeding effects. Other studies supporting a role for HPV glucose sensing on satiation, or at least on short-term feeding behavior, examined lick microstructure.16Campbell C.S. Davis J.D. Licking rate of rats is reduced by intraduodenal and intraportal glucose infusion.Physiol Behav. 1974; 12: 357-365Crossref PubMed Scopus (0) Google Scholar,24Novin D. Robinson K. Culbreth L.A. et al.Is there a role for the liver in the control of food intake?.Am J Clin Nutr. 1985; 42: 1050-1062Abstract Full Text PDF PubMed Scopus (0) Google Scholar,30Baird J.P. Grill H.J. Kaplan J.M. Effect of hepatic glucose infusion on glucose intake and licking microstructure in deprived and nondeprived rats.Am J Physiol. 1999; 277: R1136-R1143PubMed Google Scholar These studies gave short (1–5 minutes) portal glucose infusions to rats prior to lick spout access. After these brief portal infusions, licking behavior was initially decreased compared with saline infusion controls, but this was a transient effect, persisting for about 10 minutes.16Campbell C.S. Davis J.D. Licking rate of rats is reduced by intraduodenal and intraportal glucose infusion.Physiol Behav. 1974; 12: 357-365Crossref PubMed Scopus (0) Google Scholar,24Novin D. Robinson K. Culbreth L.A. et al.Is there a role for the liver in the control of food intake?.Am J Clin Nutr. 1985; 42: 1050-1062Abstract Full Text PDF PubMed Scopus (0) Google Scho