👤 Raymond Tso

Apolipoprotein A-IV (apo A-IV) is secreted by the intestine associated with chylomicron. Intestinal apo A-IV synthesis is stimulated by fat absorption, which is probably mediated by chylomicron formation. The stimulation of apo A-IV synthesis in the jejunum and ileum is attenuated by intravenous leptin infusion. Intestinal apo A-IV synthesis is also stimulated by a factor from the ileum, probably peptide tyrosine-tyrosine (PYY), which has been demonstrated to affect satiety. Apo A-IV has been proposed to physiologically control food intake, a function not shared by apo A-I, and this inhibitory effect is centrally mediated. Recently, apo A-IV was demonstrated in the hypothalamus. The hypothalamic apo A-IV level was reduced by food deprivation and restored by lipid feeding. Intracerebroventricular administration of apo A-IV antiserum increased feeding and decreased the hypothalamic apo A-IV mRNA level, implying that feeding is normally limited by endogenous apo A-IV. Central administration of neuropeptide Y (NPY) significantly increased hypothalamic apo A-IV mRNA levels in a dose-dependent manner. The stimulation of intestinal synthesis and secretion of apo A-IV by lipid absorption are rapid; thus, apo A-IV is capable of short-term regulation of food intake. Evidence also suggests apo A-IV's involvement in the long-term regulation of food intake and body weight. Chronic ingestion of high fat blunts the hypothalamic apo A-IV response to lipid feeding and may therefore explain why chronic intake of high fat predisposes animals and humans to obesity. Show less

Apolipoprotein A-IV (apoA-IV) is an exchangeable apolipoprotein that shares many functional similarities with related apolipoproteins such as apoE and apoA-I but has also been implicated as a circulating satiety factor. However, despite the fact that it contains many predicted amphipathic alpha-helical domains, relatively little is known about its tertiary structure. We hypothesized that apoA-IV exhibits a characteristic functional domain organization that has been proposed to define apoE and apoA-I. To test this, we created truncation mutants in a bacterial system that deleted amino acids from either the N- or C-terminal ends of human apoA-IV. We found that apoA-IV was less stable than apoA-I but was more highly organized in terms of its cooperativity of unfolding. Deletion of the extreme N and C termini of apoA-IV did not significantly affect the cooperativity of unfolding, but deletions past amino acid 333 on the C terminus or amino acid 61 on the N terminus had major destabilizing effects. Functionally, apoA-IV was less efficient than apoA-I at clearing multilamellar phospholipid liposomes and promoting ATP-binding cassette transporter A1-mediated cholesterol efflux. However, deletion of a C-terminal region of apoA-IV, which is devoid of predicted amphipathic alpha helices (amino acids 333-376) stimulated both of these activities dramatically. We conclude that the amphipathic alpha helices in apoA-IV form a single, large domain that may be similar to the N-terminal helical bundle domains of apoA-I and apoE but that apoA-IV lacks the C-terminal lipid-binding and cholesterol efflux-promoting domain present in these apolipoproteins. In fact, the C terminus of apoA-IV appears to reduce the ability of apoA-IV to interact with lipids and promote cholesterol efflux. This indicates that, although apoA-IV may have evolved from gene duplication events of ancestral apolipoproteins and shares the basic amphipathic helical building blocks, the overall localization of functional domains within the sequence is quite different from apoA-I and apoE. Show less

The antiatherogenic properties of apoA-IV suggest that this protein may act as an anti-inflammatory agent. We examined this possibility in a mouse model of acute colitis. Mice consumed 3% dextran sulfate sodium (DSS) in their drinking water for 7 days, with or without daily intraperitoneal injections of recombinant human apoA-IV. apoA-IV significantly and specifically delayed the onset, and reduced the severity and extent of, DSS-induced inflammation, as assessed by clinical disease activity score, macroscopic appearance and histology of the colon, and tissue myeloperoxidase activity. Intravital fluorescence microscopy of colonic microvasculature revealed that apoA-IV significantly inhibited DSS-induced leukocyte and platelet adhesive interactions. Furthermore, apoA-IV dramatically reduced the upregulation of P-selectin on colonic endothelium during DSS-colitis. apoA-IV knockout mice exhibited a significantly greater inflammatory response to DSS than did their WT littermates; this greater susceptibility to DSS-induced inflammation was reversed upon exogenous administration of apoA-IV to knockout mice. These results provide the first direct support for the hypothesis that apoA-IV is an endogenous anti-inflammatory protein. This anti-inflammatory effect likely involves the inhibition of P-selectin-mediated leukocyte and platelet adhesive interactions. Show less

Apolipoprotein A-IV (apo A-IV) is secreted by the intestine associated with chylomicron. Intestinal apo A-IV synthesis is stimulated by fat absorption, probably mediated by chylomicron formation. The stimulation of apo A-IV synthesis in the jejunum and ileum is attenuated by intravenous leptin infusion. Intestinal apo A-IV synthesis is also stimulated by a factor from the ileum, probably peptide tyrosine-tyrosine (PYY), which has been demonstrated to affect satiety. Apo A-IV has been proposed to physiologically control food intake, and this inhibitory effect is centrally mediated. Recently, apo A-IV was demonstrated in the hypothalamus. The hypothalamic apo A-IV level was reduced by food deprivation and restored by lipid feeding. Intracerebroventricular administration of apo A-IV antiserum stimulated feeding and decreased the hypothalamic apo A-IV mRNA level, implying that feeding is normally limited by endogenous apo A-IV. Central administration of neuropeptide Y (NPY) significantly increased hypothalamic apo A-IV mRNA levels in a dose-dependent manner. The stimulation of intestinal synthesis and secretion of apo A-IV by lipid absorption are rapid; thus, apo A-IV is capable of short-term regulation of food intake. Evidence also suggests apo A-IV's involvement in long-term regulation of food intake and bodyweight. The chronic ingestion of high fat blunts the intestinal apo A-IV response to lipid feeding and may therefore explain why chronic intake of high fat predisposes animals and humans to obesity. Show less

The focus of this article is to review evidence that apolipoprotein A-IV (apo A-IV) acts as a satiety factor. Additionally, information regarding the general involvement of apo A-IV in the regulation of food intake and body weight is stated. Apo A-IV is a glycoprotein synthesized by the human intestine. In rodents, both the small intestine and liver secrete apo A-IV, but the small intestine is the major organ responsible for circulating apo A-IV. There is now solid evidence that the hypothalamus, especially the arcuate nucleus, is another active site of apo A-IV expression. Intestinal apo A-IV synthesis is markedly stimulated by fat absorption and does not appear to be mediated by the uptake or reesterification of fatty acids to form triglycerides. Rather, the local formation of chylomicrons acts as a signal for the induction of intestinal apo A-IV synthesis. Intestinal apo A-IV synthesis is also enhanced by a factor from the ileum, probably peptide tyrosine-tyrosine (PYY). The inhibition of food intake by apo A-IV is mediated centrally. The stimulation of intestinal synthesis and secretion of apo A-IV by lipid absorption are rapid; thus apo A-IV likely plays a role in the short-term regulation of food intake. Other evidence suggests that apo A-IV may also be involved in the long-term regulation of food intake and body weight, as it is regulated by both leptin and insulin. Chronic ingestion of a high-fat diet blunts the intestinal as well as the hypothalamic apo A-IV response to lipid feeding. It also suppresses apo A-IV gene expression in the hypothalamus. Whereas it is tempting to speculate that apo A-IV may play a role in diet-induced obesity, we believe the confirmation of such a proposal awaits further experimental evidence. Show less

Apolipoprotein A-IV (apo A-IV), a peptide expressed by enterocytes in the mammalian small intestine and released in response to long-chain triglyceride absorption, may be involved in the regulation of gastric acid secretion and gastric motility. The specific aim of the present study was to determine the pathway involved in mediating inhibition of gastric motility produced by apo A-IV. Gastric motility was measured manometrically in response to injections of either recombinant purified apo A-IV (200 microg) or apo A-I, the structurally similar intestinal apolipoprotein not regulated by triglyceride absorption, close to the upper gastrointestinal tract in urethane-anesthetized rats. Injection of apo A-IV significantly inhibited gastric motility compared with apo A-I or vehicle injections. The response to exogenous apo A-IV injections was significantly reduced by 77 and 55%, respectively, in rats treated with the CCK(1) receptor blocker devazepide or after functional vagal deafferentation by perineural capsaicin treatment. In electrophysiological experiments, isolated proximal duodenal vagal afferent fibers were recorded in vitro in response to close-arterial injection of vehicle, apo A-IV (200 microg), or CCK (10 pmol). Apo A-IV stimulated the discharge of duodenal vagal afferent fibers, significantly increasing the discharge in 4/7 CCK-responsive units, and the response was abolished by CCK(1) receptor blockade with devazepide. These data suggest that apo A-IV released from the intestinal mucosa during lipid absorption stimulates the release of endogenous CCK that activates CCK(1) receptors on vagal afferent nerve terminals initiating feedback inhibition of gastric motility. Show less

Apolipoprotein A-IV (apo A-IV) is an anorectic protein produced in the intestine and brain that has been proposed as a satiety signal. To determine whether diet-induced obesity alters apo A-IV gene expression in the intestine and hypothalamus, rats were fed a high-fat (HF), low-fat (LF), or standard chow (CHOW) diet for 2, 4, 6, 8, or 10 wk. Rats fed the HF diet had significantly greater body weights than rats given the LF and CHOW diets. Intestinal and plasma apo A-IV levels were comparable across dietary groups and time. LF and CHOW rats had comparable hypothalamic apo A-IV mRNA across the course of the experiment. However, HF rats had a slow and progressive diminution in hypothalamic apo A-IV mRNA over time that became significantly lower than that of LF or CHOW rats by 10 wk. Intragastric infusion of lipid emulsion to animals that were fasted overnight significantly stimulated hypothalamic apo A-IV mRNA in LF and CHOW rats but had no effect in HF rats. These results demonstrate that chronic consumption of a HF diet significantly reduces apo A-IV mRNA levels and the response of apo A-IV gene expression to dietary lipids in the hypothalamus. This raises the possibility that dysregulation of hypothalamic apo A-IV could contribute to diet-induced obesity. Show less

Apolipoprotein A-IV (apo A-IV) is a satiety protein synthesized in the small intestine and hypothalamus. To further understand the roles of central apo A-IV in the management of daily food intake, we have examined the diurnal patterns of hypothalamic apo A-IV gene and protein expression in freely feeding and food-restricted (food provided 4 h daily between 1000 h and 1400 h) rats. In freely feeding rats, the hypothalamic apo A-IV mRNA and protein levels fluctuated, with high levels during the light phase, peaking at 0900 h (3 h after lights on), and low levels during the dark phase, with a nadir at 2100 h (3 h after lights off). The daily patterns of the fluctuation, however, were altered in food-restricted rats, which had a marked decrease in hypothalamic apo A-IV mRNA and protein levels during the 4 h-feeding period of the light phase. Although corticosterone (CORT) secretion temporally coincided with the decreasing phase of apo A-IV in the hypothalamus, depletion of CORT by adrenalectomy significantly decreased, rather than increased, hypothalamic apo A-IV mRNA and protein levels. These results indicate that the diurnal expression of hypothalamic apo A-IV is regulated by factors other than the circulating CORT, for example, the reduced food intake and body weight in adrenalectomized animals. The fact that hypothalamic apo A-IV level and food intake were inversely related during the normal diurnal cycle as well as in the period of restricted feeding suggests that hypothalamic apo A-IV is involved in the regulation of daily food intake. Show less

This review discusses the regulation of the intestinal and hypothalamic apolipoprotein A-IV (apo A-IV) gene and protein expression. Apo A-IV is a glycoprotein secreted together with triglyceride-rich lipoproteins by the small intestine. Intestinal apo A-IV synthesis is stimulated by fat absorption, probably mediated by chylomicron formation. This stimulation of intestinal apo A-IV synthesis is attenuated by intravenous leptin infusion. Chronic ingestion of a high-fat diet blunts the intestinal apo A-IV in response to dietary lipid. Intestinal apo A-IV synthesis is also stimulated by members of the pancreatic polypeptide family, including peptide YY (PYY), neuropeptide Y (NPY), and pancreatic polypeptide (PP). Recently, apo A-IV was demonstrated to be present in the hypothalamus as well. Hypothalamic apo A-IV level was reduced by food deprivation and restored by lipid feeding. Intracerebroventricular administration of apo A-IV antiserum stimulated feeding and decreased the hypothalamic apo A-IV mRNA level, implying that feeding is intimately regulated by endogenous hypothalamic apo A-IV. Central administration of NPY significantly increased hypothalamic apo A-IV mRNA levels in a dose-dependent manner. Show less

Although many exciting functions of Apolipoprotein A-IV(apo-A IV) have been proposed, this review focuses on its unique role in regulating food intake. Apo-A IV is a glycoprotein produced by human intestine and rodent intestine and liver, but the small intestine is the major organ responsible for the circulating apo-A-IV. Our Laboratory recently demonstrated that apo-A IV protein and apo-A IV mRNA were present in rat hypothalamus. Intestinal apo-A IV synthesis is markedly stimulated by fat absorption and the formation of chylomicrons. Intestinal apo-A IV synthesis is also enhanced by the peptide tyrosine-tyrosine. The inhibition of food intake by apo-A IV is mediated centrally. Apo-A IV likely plays a role in the short-term regulation of food intake. Other evidence suggests that apo-A IV may also be involved in the long-term regulation of food intake and body weight. Reduction of apo-A IV in response to lipid feeding in both animal and humans that chronically consume a high-fat diet may explain in part why the chronic ingestion of a high-fat diet predisposes to obesity. Show less

Apolipoprotein AIV (apo AIV) is a circulating signal released from intestinal cells in response to lipid feeding and contributes to the anorectic effect of a lipid meal. We have demonstrated that apo AIV is also synthesized in the hypothalamus, and that hypothalamic apo AIV gene expression is regulated physiologically. Neuropeptide Y (NPY) is a hypothalamic neuropeptide with broad regulatory actions in the central nervous system. In the present studies, the effects of intracerebroventricular (i.v.t.) administration of NPY and of intraduodenal lipid infusion on hypothalamic apo AIV gene expression were determined using competitive RT-PCR in fasted rats. I.v.t. injection of NPY alone significantly increased apo AIV mRNA levels in the hypothalamus in a dose-dependent manner. Intraduodenal infusion of lipid also stimulated the gene expression of hypothalamic apo AIV, but no further significant increment occurred when i.v.t. injection of NPY was combined with lipid infusion. These results suggest that NPY and lipid may regulate apo AIV gene expression in the rat hypothalamus. Show less

Rat apolipoprotein AIV (apo AIV) is a 43-kDa intestinal apolipoprotein that is important in lipid metabolism and the suppression of food intake. In this study, a full-length rat apo AIV was expressed in Escherichia coli and purified in a bioactive form. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and mass spectrometric analysis revealed that the isolated recombinant protein has a molecular mass of approximately 43 kDa, similar to that of natural rat apo AIV. Immunoblot analysis and N-terminal amino acid sequencing confirmed the identity of the recombinant apo AIV protein as natural rat apo AIV. The recombinant protein was functional in lipoprotein binding assays. Biological activity was assessed behaviorally in that the recombinant protein suppressed food intake of fasted rats comparably to natural rat apo AIV. Neither native nor recombinant apo AIV elicited a conditioned taste aversion (CTA) at doses that suppress feeding. These results indicate that the recombinant apo AIV is structurally and functionally indistinguishable from rat natural apo AIV, making this overexpression and purification scheme a powerful tool for future structure and function studies. Show less

Lipid, particularly long-chain triglyceride, initiates feedback regulation of gastrointestinal function. To determine whether the site of action of lipid is pre- or postabsorptive, we investigated the ability of mesenteric lipid-fed lymph to inhibit gastric motor function. Lymph was collected from awake lymph-fistula rats during intestinal infusion with either a glucose-saline maintenance solution or lipid. Intra-arterial injection of lymph collected during intestinal lipid infusion significantly inhibited gastric motility in anesthetized recipient rats compared with injection of equivalent amounts of triglyceride or lymph collected during intestinal infusion of maintenance solution. Lymph collected from rats during lipid infusion with Pluronic L-81 [an inhibitor of chylomicron formation and apolipoprotein (apo) A-IV secretion] compared with lymph injection from donor animals treated with Pluronic L-63 (a noninhibitory control for Pluronic L-81) was significantly less potent. Injection of purified recombinant apo A-IV significantly inhibited gastric motility. Products of lipid digestion and absorption, other than fatty acids or triglyceride, released by the intestine during lipid digestion likely serve as signals to initiate intestinal feedback regulation of gastrointestinal function. Most likely, apo A-IV is one of the signals involved. Show less

A 61-year-old woman who was a New York City hospital employee developed fatal inhalational anthrax, but with an unknown source of anthrax exposure. The patient presented with shortness of breath, malaise, and cough that had developed 3 days prior to admission. Within hours of presentation, she developed respiratory failure and septic shock and required mechanical ventilation and vasopressor therapy. Spiral contrast-enhanced computed tomography of the chest demonstrated large bilateral pleural effusions and hemorrhagic mediastinitis. Blood cultures, as well as DNA amplification by polymerase chain reaction of the blood, bronchial washings, and pleural fluid specimens, were positive for Bacillus anthracis. The clinical course was complicated by liver failure, renal failure, severe metabolic acidosis, disseminated intravascular coagulopathy, and cardiac tamponade, and the patient died on the fourth hospital day. The cause of death was inhalational anthrax. Despite epidemiologic investigation, including environmental samples from the patient's residence and workplace, no mechanism for anthrax exposure has been identified. Show less

We determined apolipoprotein AIV (apo AIV) content in intestinal epithelial cells using immunohistochemistry when leptin was administered intravenously. Most of the apo AIV immunoreactivity in the untreated intestine was located in the villous cells as opposed to the crypt cells. Regional distribution of apo AIV immunostaining revealed low apo AIV content in the duodenum and high content in the jejunum that gradually decreases caudally toward the ileum. Intraduodenal infusion of lipid (4 h) significantly increased apo AIV immunoreactivity in the jejunum and ileum. Simultaneous intravenous leptin infusion plus duodenal lipid infusion markedly suppressed apo AIV immunoreactivity. Duodenal lipid infusion increased plasma apo AIV significantly (measured by ELISA), whereas simultaneous leptin infusion attenuated the increase. These findings suggest that leptin may regulate circulating apo AIV by suppressing apo AIV synthesis in the small intestine. Show less

Apolipoprotein A-IV (apo A-IV) is a glycoprotein synthesized by the human intestine. In rodents, both the small intestine and liver secrete apo A-IV, but the small intestine is the major organ responsible for the circulating apo A-IV. Intestinal apo A-IV synthesis is markedly stimulated by fat absorption and appears not to be mediated by the uptake or reesterification of fatty acids to form triglycerides. Rather, the formation of chylomicrons acts as a signal for the induction of intestinal apo A-IV synthesis. Intestinal apo A-IV synthesis is also enhanced by a factor from the ileum, probably peptide tyrosine-tyrosine. The inhibition of food intake by apo A-IV is mediated centrally. The stimulation of intestinal synthesis and the secretion of apo A-IV by lipid absorption are rapid; thus, apo A-IV likely plays a role in the short-term regulation of food intake. Other evidence suggests that apo A-IV may also be involved in the long-term regulation of food intake and body weight. Chronic ingestion of a high-fat diet blunts the intestinal apo A-IV response to lipid feeding and may explain why the chronic ingestion of a high-fat diet predisposes both animals and humans to obesity. Show less

Apolipoprotein AIV (apo AIV) is a satiety protein secreted by the small intestine. We demonstrate for the first time that apo AIV protein and apo AIV mRNA are present in rat hypothalamus, a site intimately involved in the integration of signals for regulation of food intake and energy metabolism. We further characterized the regulation of hypothalamic apo AIV mRNA levels. Food-deprived animals showed a pronounced decrease in gene expression of apo AIV in the hypothalamus, with a concomitant decrease in the jejunum. Refeeding fasted rats with standard laboratory chow for 4 h evokes a significant increase of apo AIV mRNA in jejunum but not in hypothalamus. However, lipid refeeding to the fasted animals restored apo AIV mRNA levels both in hypothalamus and jejunum. Intracerebroventricular administration of apo AIV antiserum not only stimulated feeding, but also decreased apo AIV mRNA level in the hypothalamus. These data further confirm the central role of apo AIV in the regulation of food intake. Show less

Procolipase is secreted as a protein consisting of 101 amino acids. In the intestinal lumen, procolipase is activated by trypsin and cleaves to form the active colipase and the pentapeptide from the amino terminus. This pentapeptide is called enterostatin. Pancreatic procolipase synthesis is stimulated by a high-fat diet. A large body of evidence has been gathered in the past decade demonstrating the role of enterostatin in the inhibition of food intake; in particular, fat intake. This aspect of enterostatin will be discussed in this review. Other functions of enterostatin such as the inhibition of insulin secretion, will not. Apolipoprotein AIV is a protein synthesized by the human intestine. Similar to procolipase, the synthesis and secretion of apo AIV are also stimulated by fat absorption. In 1992, Fujimoto et al. first demonstrated that apo AIV is a satiety signal secreted by the small intestine following the ingestion of a lipid meal. Subsequently, this initial observation was followed by a number of studies supporting apo AIV's role in the inhibition of food intake. This review will discuss the role of apo AIV in inhibiting food intake. Show less

We examined the role of vagal innervation in lipid-stimulated increases in expression and synthesis of intestinal apolipoprotein A-IV (apoA-IV). In rats with duodenal cannulas and superior mesenteric lymph fistulas given duodenal infusions of lipid emulsion, vagotomy had no effect on either intestinal lipid transport, lymphatic apoA-IV output, or jejunal mucosal apoA-IV synthesis. In rats with jejunal Thiry-Vella fistulas, ileal lipid infusion elicited a twofold stimulation of apoA-IV synthesis without affecting apoA-IV mRNA levels; vagotomy blocked this increase in apoA-IV synthesis. Direct perfusion of jejunal Thiry-Vella fistulas produced 2- to 2.5-fold increases in both apoA-IV synthesis and mRNA levels in the Thiry-Vella segment; these effects were not influenced by vagal denervation. These results suggest two mechanisms whereby lipid stimulates intestinal apoA-IV production: 1) a vagal-dependent stimulation of jejunal apoA-IV synthesis by distal gut lipid that is independent of changes in apoA-IV mRNA levels and 2) a direct stimulatory effect of proximal gut lipid on both synthesis and mRNA levels of jejunal apoA-IV that is independent of vagal innervation. Show less

Apolipoprotein (apo) A-IV is a glycoprotein synthesized by the human intestine. In rodents, both the small intestine and the liver secrete apo A-IV; the small intestine, however, is by far the major organ responsible for the circulating apo A-IV. Intestinal apo A-IV synthesis is markedly stimulated by fat absorption and appears not to be mediated by the uptake or reesterification of fatty acids to form triglycerides. Rather, it is the formation of chylomicrons that acts as a signal for the induction of intestinal apo A-IV synthesis. Intestinal apo A-IV synthesis is also enhanced by a factor from the ileum and that factor is probably peptide tyrosine-tyrosine (PYY). The inhibition of food intake by apo A-IV is probably mediated centrally. The stimulation of intestinal synthesis and secretion of apo A-IV by lipid absorption are rapid; thus, apo A-IV likely plays a role in the short-term regulation of food intake. Other evidence suggests that apo A-IV may also be involved in the long-term regulation of food intake and body weight. Chronic ingestion of a high fat diet blunts the intestinal apo A-IV response to lipid feeding and may explain why the chronic ingestion of a high fat diet predisposes both animals and humans to obesity. Show less

We tested whether secretion of apolipoprotein (apo) A-IV depends upon intestinal triglyceride (TG) transport by comparing output kinetics of TG and apo A-IV during and after duodenal lipid infusion in lymph-fistula rats. Lipid infusion (triolein, 40 mumol/h, 8 h) produced increases in lymphatic TG and apo A-IV output. After 8 h, triolein infusate was replaced with glucose-saline; TG output returned to basal levels 4-5 h later. However, apo A-IV output continued at significantly elevated levels until 20 h after the start of the experiment. Bile diversion blocked this continued output of A-IV during the post-lipid period, and resulted in basal TG output that was 75% lower than in bile-intact rats. Return of bile or low-dose triolein infusion (5 mumol/h) into the intestine reversed these effects. There were no differences in hepatic synthesis or filtration of plasma A-IV into lymph between bile-intact and bile-diverted groups. Intestinal A-IV synthesis was elevated in both groups even during the post-lipid period. The results support the hypothesis that intestinal triglyceride transport drives apo A-IV secretion, and suggest the existence of a bile-dependent, post-translational mechanism for the control of lymphatic apo A-IV output. Show less

Apolipoprotein (apo) A-IV is a protein synthesized, in humans, only by the small intestine. It has a molecular weight of 46 000 Da. This paper summarizes the evidence supporting its role as a satiety factor following the ingestion of fat. This function of apo A-IV is unique and not shared by other apolipoproteins, including apo A-I. The satiety effect of apo A-IV is centrally mediated. The mechanism of how apo A-IV inhibits food intake is not clear but it probably acts by inhibiting both gastric acid secretion as well as gastric motility. Lipid absorption stimulates apo A-IV synthesis and secretion by the jejunum. In addition to lipid feeding, there is evidence that a factor which is released as a result of lipid absorption in the distal small intestine also stimulates the synthesis and release of apo A-IV by the jejunum. This factor is probably PYY. Show less

We postulated that dose-responsive satiety after oil premeals varies with the number of gut sensors stimulated by lipolytic products along intestine. These experiments in fasted rats on satiety after oil premeals were performed to 1) determine whether satiety was induced by lipolytic products but not triglycerides; 2) confirm that oil empties from the stomach at rates that vary with oil loads; 3) ascertain that increasing rates of oil entry into duodenum extend the length of gut contacted by lipolytic products; and 4) judge whether length of gut contacted correlated with dose-responsive satieties to dietary oils. 5) Using specific antagonists, we attempted to define how satiety was signalled by gut sensors. Timing and degrees of satiety did not correlate with timing and extent of gastric distensions but, rather, with the timing and extent of spread of lipolytic products along small bowel. Satiety after the highest premeal load of oil was blocked by Pluronic L-81, an inhibitor of intestinal secretion of apolipoprotein A-IV, but was unaffected by MK-329 (a specific antagonist of cholecystokinin) or by capsaicin blockade of chemosensory nerves. Show less

We tested whether exogenous peptide YY (PYY) can stimulate synthesis and lymphatic secretion of intestinal apolipoprotein AIV (apo AIV). Rats with mesenteric lymph fistulas and right atrial cannulas were given continuous intravenous infusions of control vehicle or PYY at 25, 50, 75, 100, or 200 pmol . kg-1 . h-1. PYY (75-200 pmol . kg-1 . h-1) stimulated lymphatic apo AIV output from 1.5- to 3.5-fold higher than basal output. In separate experiments, PYY (100 pmol . kg-1 . h-1) produced a 60% increase in jejunal mucosal apo AIV synthesis but had no effect on mucosal apo AIV mRNA levels at doses up to 200 pmol . kg-1 . h-1. Finally, exogenous PYY infusion (100 pmol . kg-1 . h-1) produced a plasma PYY increment of 30 pM compared with an increment of 18.7 pM in response to ileal infusion of lipid. These results support the hypothesis that PYY may be an endocrine mediator of the effects of distal gut lipid on production and release of intestinal apo AIV, likely via a posttranscriptional mechanism of action. Show less