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Recent Advances in Nutritional Sciences

The Role of Apolipoprotein A-IV in Food Intake Regulation^{1 ,2}

Department of Pathology, University of Cincinnati, OH 45267 and ^* Department of Surgery, Louisiana State University Medical Center, Shreveport, LA 71130

³To whom correspondence should be addressed.

	ABSTRACT

TOP ABSTRACT INTRODUCTION Intravenous Infusion of APO... Inhibition of Food Intake... Is APO A-IV a... Potential Role of APO... APO A-IV Inhibits Gastric... Regulation of Intestinal APO... Effect of Chronic High... Perspectives. REFERENCES

 
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.

KEY WORDS: • apolipoprotein A-IV • chylomicron • intestine • satiety • Sprague-Dawley rats

	INTRODUCTION

TOP ABSTRACT INTRODUCTION Intravenous Infusion of APO... Inhibition of Food Intake... Is APO A-IV a... Potential Role of APO... APO A-IV Inhibits Gastric... Regulation of Intestinal APO... Effect of Chronic High... Perspectives. REFERENCES

 
Apolipoprotein (apo)⁴ A-IV was discovered about 22 y ago (Swaney et al. 1977 ), but its physiologic role was not firmly established until recently. Apo A-IV is a protein secreted only by the small intestine in humans (Apfelbaum et al. 1987 , Green et al. 1980 ). In rodents, both the small intestine and the liver secrete apo A-IV; however, the small intestine is the major organ responsible for the circulating apo A-IV (Fukagawa et al. 1994 ). It has been demonstrated that apo A-IV production by the small intestine is stimulated by active lipid absorption (Apfelbaum et al. 1987 , Hayashi et al. 1990 , Kalogeris et al. 1994 ). Hayashi et al. (1990) demonstrated that the stimulation of apo A-IV production by lipid feeding is associated with the formation of chylomicrons. They further demonstrated that the stimulation of apo A-IV production by fat absorption can be abolished by a Pluronic surfactant called Pluronic L-81 (L-81). Tso et al. (1981 ) demonstrated that the formation of chylomicrons is inhibited by L-81. In vivo studies (Fujimoto et al. 1992, 1993a and 1993b ) have provided evidence that apo A-IV may be involved in the inhibition of food intake after the ingestion of fat.

	Intravenous Infusion of APO A-IV Inhibits Food Intake.

TOP ABSTRACT INTRODUCTION Intravenous Infusion of APO... Inhibition of Food Intake... Is APO A-IV a... Potential Role of APO... APO A-IV Inhibits Gastric... Regulation of Intestinal APO... Effect of Chronic High... Perspectives. REFERENCES

 
Rats were implanted with indwelling intravenous infusion cannulas and allowed to recover for 1 wk before feeding studies. After the rats were food deprived for 24 h, various intestinal lymph samples from donor rats and solutions of apo A-IV and apo A-I were infused intravenously to determine whether food intake was affected when nonpurified diet was provided. Fujimoto et al. (1992) demonstrated that after intravenous infusion of physiological saline through indwelling right atrial catheters rats ate 3.90 ± 0.40 g during the first 30 min after refeeding. Infusion of food-deprived intestinal lymph collected from food-deprived rats had very little effect on food intake compared with saline infusion in the rats deprived of food for 24 h. In contrast, the intestinal lymph collected from a rat that was actively absorbing lipid markedly suppressed food intake during the first 30 min (P < 0.01). This suppression of food intake was not observed in the subsequent 30 min.

The fact that intestinal lymph collected from rats actively absorbing fat inhibits food intake indicates that a change occurs in one or more factors that actually inhibit the absorption of fat. The lipid content of lymph increases as much as 10–15 times during fat absorption, making it possible that the extra lipid present in chylous lymph (in the form of chylomicrons) may actually be responsible for the inhibition of food intake. To test whether the change in the lipid content of lymph is responsible for reducing food intake in rats deprived of food for 24 h, a separate group of rats was infused intravenously with a diluted intralipid solution. When 2 mL of 20 g/L intralipid in saline containing 42 µmol of triglyceride and 3.1 µmol of phospholipid (composition comparable to the lymph collected during active lipid absorption) was infused intravenously, food intake was not suppressed. This result indicated that the effect of chylous lymph on food intake was not caused by its lipid content.

Fujimoto et al. (1992) reasoned that if the lipid component of the chylous lymph is not inhibiting food intake, it must be apo A-IV because it is the only apolipoprotein secreted by the small intestine that is markedly stimulated by lipid feeding (Hayashi et al. 1990 ). Because L-81 blocks the stimulation of apo A-IV production by the small intestine during lipid absorption, Fujimoto et al. (1992) determined whether the lymph from a rat fed lipid plus L-81 had any effect on food intake. Lymph from L-81–treated rats did not inhibit food intake, but the lymph collected during the reversal of L-81 inhibition was very potent in inhibiting food intake. This suggests that apo A-IV is probably the factor in chylous lymph that is responsible.

Fujimoto et al. (1992) further studied the effect of apo A-IV–deficient chylous lymph on feeding. The chylous lymph treated with normal goat serum suppressed food intake significantly in the first 30 min. In contrast, chylous lymph that was treated with apo A-IV antiserum had no effect on food intake—the rat consumed an amount of food similar to that consumed by the saline controls. In contrast, lymph treated with apo A-I antiserum was just as effective as the untreated lymph in inhibiting food intake. Either apo A-IV (200 µg) or apo A-I dissolved in 2 mL physiological saline was infused intravenously in 24-h food deprived rats; 200 µg apo A-IV, an amount comparable to that present in 2 mL of lymph collected from a rat actively absorbing lipid, suppressed food intake significantly and to the same extent as the chylous lymph collected during 6–8 h of lipid infusion. The inhibition of food intake by apo A-IV was dose dependent. In contrast, 200 µg apo A-I did not affect food intake. No nonphysiologic reactions such as sedation, ataxia or hyperthermia were observed after apo A-IV and chylous lymph infusion. These studies led Fujimoto et al. (1992) to first propose that apo A-IV is a circulating signal released by the small intestine in response to fat feeding and is likely the mediator for the anorectic effect of a lipid meal. This function is unique to apo A-IV and is not shared by apo A-I, even though all of the functions that are ascribed to apo A-IV in the in vitro studies can also be performed by apo A-I.

	Inhibition of Food Intake by APO A-IV is Centrally Mediated.

TOP ABSTRACT INTRODUCTION Intravenous Infusion of APO... Inhibition of Food Intake... Is APO A-IV a... Potential Role of APO... APO A-IV Inhibits Gastric... Regulation of Intestinal APO... Effect of Chronic High... Perspectives. REFERENCES

 
One potential site at which apo A-IV can elicit the inhibition of food intake is in the hypothalamus because it is intimately involved in the regulation of food intake and energy metabolism (Woods et al. 1998 ). Fujimoto et al. (1993a) reported that administration of apo A-IV into the third cerebroventricular decreased food intake in a dose-dependent manner and with a potency that was ~50-fold higher than intravenous administration. In contrast, when apo A-I was infused into the third ventricule, it had no effect on food intake. When goat anti-rat apo A-IV serum was administered into the third ventricle at 1100 h (during the light phase when rats usually do not eat), all rats tested began to eat. Fujimoto et al. (1993a) proposed that apo A-IV antiserum removes any present endogenous apo A-IV.

Evidence suggests that de novo synthesis of apo A-IV in the brain is unlikely (Elsbourhagy et al. 1987 ). Fujimoto et al. (1993a and 1993b) proposed that apo A-IV (or perhaps a fragment thereof) released by the small intestine may traverse the blood-brain barrier and act in the central nervous system. They demonstrated by electroimmunoassay that apo A-IV, or a fragment of apo A-IV, is present in the third ventricular cerebrospinal fluid; that apo A-IV concentration in third ventricular cerebrospinal fluid increases as a result of lipid feeding; and by using immunohistochemical technique, that specific staining for apo A-IV in astrocytes and tanycytes appear throughout both white and gray matter. The granular nature and perinuclear distribution of apo A-IV immunoreactivity suggests that apo A-IV may be contained in perinuclear organelles or vesicles. The demonstration of immunoreactive apo A-IV in tanycytes does not necessarily indicate a selective uptake mechanism for apo A-IV because tanycytes take up a variety of neurotransmitters and nonmetabolizable amino acids. The presence of apo A-IV immunostaining in astrocytes indicates uptake of apo A-IV by astrocytes. Whether astrocytes are involved in satiety mechanisms associated with lipid feeding is unknown.

	Is APO A-IV a Short-term Satiety Factor?

TOP ABSTRACT INTRODUCTION Intravenous Infusion of APO... Inhibition of Food Intake... Is APO A-IV a... Potential Role of APO... APO A-IV Inhibits Gastric... Regulation of Intestinal APO... Effect of Chronic High... Perspectives. REFERENCES

 
Although there is compelling evidence that apo A-IV can acutely inhibit food intake during the ingestion of a lipid meal, the temporal relationship between intestinal synthesis and secretion of apo A-IV and satiety has to be considered. The question is whether the increases in plasma levels of apo A-IV in response to lipid feeding are rapid enough and of sufficiently large magnitude to elicit satiety. Rodriguez et al. (1997) demonstrated that when a gastric bolus of 0.5 mL of a 200 g/L intralipid solution (containing 100 mg of triglyceride) was fed to rats, there was a significant increase of plasma apo A-IV within 15 min, with the increment remaining significant until 30 min after the meal. These changes in plasma apo A-IV concentration observed by Rodriguez et al. (1997) were similar to those observed by Fujimoto et al. (1992) in an experiment in which intravenous apo A-IV produced a significant dose-dependent inhibition of food intake. Rodriguez et al. (1997) therefore concluded that the increase in plasma levels of apo A-IV produced in response to lipid meals was sufficiently quick and large enough to produce satiety, thereby supporting a role for apo A-IV in the short-term control of food intake in rats.

	Potential Role of APO A-IV in the Long-term Control of Food Intake.

TOP ABSTRACT INTRODUCTION Intravenous Infusion of APO... Inhibition of Food Intake... Is APO A-IV a... Potential Role of APO... APO A-IV Inhibits Gastric... Regulation of Intestinal APO... Effect of Chronic High... Perspectives. REFERENCES

 
Evidence from a number of experiments suggests that apo A-IV may be involved in the long-term regulation of food intake and body weight gain. First, it has been demonstrated that intravenous administration of apo A-IV decreases food intake in rats given free access to food (Fujimoto et al. 1993b ), suggesting that exogenously administered apo A-IV controls food intake under conditions of food accessibility. In rats with free access to food, central administration of apo A-IV antiserum stimulates feeding during the light cycle (Fujimoto et al. 1993a ). Similar studies done during the dark phase may help clarify the role of apo A-IV in the control of individual meals.

The second finding indicating a potential role of apo A-IV in the long-term regulation of food intake is linked to the circadian rhythm of lymph and serum apo A-IV. Fukagawa et al. (1994) reported that in rats given free access to food, both serum and intestinal lymph apo A-IV exhibited a circadian rhythm, with the level significantly higher during the dark period than the light period. When Fukagawa et al. (1994) examined the serum apo A-IV level in food-deprived rats, they found that serum apo A-IV exhibited the same circadian rhythm as in the fed rats, but that the serum apo A-IV concentrations were significantly higher at all time points in the rats given free access to food than in the food-deprived rats. This result indicated that although free access feeding greatly increased the levels of serum apo A-IV, it did not change the pattern of the inherent circadian rhythm of serum apo A-IV. The fact that serum apo A-IV increased during the dark phase, corresponding to the most active feeding period of rats, is potentially of physiologic importance and suggests a physiologic role of apo A-IV in the regulation of food intake.

The third finding supporting the potential long-term regulation of food intake and body weight by apo A-IV is derived from a recent paper reporting the down-regulation of intestinal apo A-IV mRNA levels by leptin (Morton et al. 1998 ). Preliminary data suggest that leptin decreases apo A-IV synthesis and secretion by the small intestinal epithelial cells. In addition to the effect of leptin on the transcriptional control of apo A-IV mRNA level, it has also been demonstrated that intestinal apo A-IV synthesis and secretion is up-regulated by insulin in both rodents and humans (Attia et al. 1997 , Black and Ellinas 1992 ). Energy homeostasis in the body is accomplished by a highly integrated and redundant neurohumoral system that prevents the effect of short-term fluctuations in energy balance on fat mass (review by Woods et al. 1998 ). Insulin and leptin are both hormones secreted in proportion to the body adiposity, and they play a critical role in this energy homeostasis. Because both leptin and insulin seem to regulate intestinal apo A-IV synthesis, apo A-IV may be involved in the long-term regulation of food intake and body weight.

	APO A-IV Inhibits Gastric Motility as Well as Gastric Secretion.

TOP ABSTRACT INTRODUCTION Intravenous Infusion of APO... Inhibition of Food Intake... Is APO A-IV a... Potential Role of APO... APO A-IV Inhibits Gastric... Regulation of Intestinal APO... Effect of Chronic High... Perspectives. REFERENCES

 
How does apo A-IV inhibit food intake? One possibility is by inhibiting gastric emptying and gastric acid secretion. Intracisternal injections of purified apo A-IV inhibited gastric acid secretion (Okumura et al. 1994 and 1995 ) and gastric motility (Okumura et al. 1996 ) in rats in a dose-dependent manner. Intracisternal infusion of physiologic doses of apo A-IV markedly inhibited gastric motility as well as gastric acid secretion in a dose-dependent manner (Fig. 1 ). The doses of apo A-IV used in these studies were thought to reproduce the levels of apo A-IV measured in cerebrospinal fluid after lipid feeding (Fujimoto et al. 1993a ). Intravenous infusion of similar doses of apo A-I did not elicit gastric responses. As proposed by Okumura et al. (1994) , apo A-IV acts as an enterogastrone, that is, a humoral mediator released by the intestine that mediates the humoral inhibition of gastric acid secretion as well as motility by the ingestion of fat. At present, it is not clear if there is a direct link between the effects of apo A-IV on food intake and its effects on gastric function. Apo A-IV could directly influence central feeding mechanisms; alternatively, it could affect feeding through its effects on gastric function, especially via inhibition of gastric emptying (McHugh and Moran, 1985 ).

View larger version (22K): [in this window] [in a new window]   Figure 1. The effect of intracisternal injection of apolipoprotein (apo) A-IV on gastric secretion in pylorus-ligated conscious rats. Under brief isoflurane anesthesia, rats were fed intracisternal injection of apo A-IV and the pylorus was ligated. Two hours after intracisternal injection, the rats were killed, the stomach was removed and gastric acid output was determined. Each column represents the mean ± SEM, n = 4–9. *P < 0.05 compared with saline control [adapted from Okumura et al. (1995) ].

	Regulation of Intestinal APO A-IV Synthesis and Secretion.

TOP ABSTRACT INTRODUCTION Intravenous Infusion of APO... Inhibition of Food Intake... Is APO A-IV a... Potential Role of APO... APO A-IV Inhibits Gastric... Regulation of Intestinal APO... Effect of Chronic High... Perspectives. REFERENCES

In contrast, delivery of lipid to the ileum stimulated both ileal and jejunal apo A-IV synthesis. Subsequent experiments in rats equipped with jejunal or ileal Thiry-Vella fistulas (segment of intestine isolated luminally from the rest of the gastrointestinal tract) demonstrated that ileally infused lipid elicited an increase in proximal jejunal apo A-IV synthesis independent of the presence of jejunal lipid, and that both ileum and more distal sites may be involved in the stimulation. These results strongly support the existence of a signal arising from the distal gut that is capable of stimulating synthesis of apo A-IV in the proximal gut. These findings have important physiologic implications. The distal intestine plays an important role in the control of gastrointestinal function. Nutrients (especially lipid) delivered to the ileum inhibit gastric emptying (Lin et al. 1990 , MacFarlane et al. 1983 ), decrease intestinal motility and transit (MacFarlane et al. 1983 , Spiller et al. 1984 ) and decrease pancreatic secretion (Harper et al. 1979 ). Nutrients in the ileum also inhibit food intake (Meyer et al. 1994 , Welch et al. 1985 ). The mechanisms for these effects have been collectively termed the "ileal brake" (Spiller et al. 1984 ) and appear to be related to the release of one or more peptide hormones from the distal intestine (Aponte et al. 1985 , Jin et al. 1993 , Pappas et al. 1985 , Savage et al. 1987 ). These effects have traditionally been considered operative only in the event of abnormal delivery of undigested nutrients to the distal gut, such as the malabsorptive state (Spiller et al. 1984 ). However, growing evidence supports the notion that because of the rapid gastric emptying during the early phases of a meal, nutrients reach the distal gut even under normal conditions (Lin et al. 1990 , Meyer et al. 1994 , Rodriguez et al. 1997 ). We recently studied the intraluminal and mucosal distribution of a bolus of ³H-triolein–labeled intralipid (0.5 mL of a 20% emulsion) fed by gavage. By 15–30 min, radiolabeled lipid was distributed evenly throughout the entire gut with 10–15% of the load recovered in the ileum and cecum combined. The presence of substantial amounts of lipids in these distal sites persisted for at least 4 h after the meal. When we examined apo A-IV synthesis by the small intestine, we found rapid stimulation (between 15 and 30 min) of apo A-IV synthesis throughout the intestine, including the ileum. This was associated with significant stimulation of lymphatic output and plasma levels of apo A-IV by 30 min after the gastric lipid load (Rodriguez et al. 1997 ). Consequently, even under normal conditions, a far greater length of the intestine could be involved in the absorption of a lipid meal and in the control of gastric and upper gut function than previously thought. Thus, the "ileal brake" may play an important role in the normal control of gut function.

The most likely peptide to mediate the phenomenon of "ileal brake" is peptide tyrosine-tyrosine (PYY). Kalogeris et al. (1998) recently reported that PYY stimulates jejunal apo A-IV synthesis and secretion. Continuous intravenous infusion of physiologic doses of PYY elicits significant increases in both synthesis and lymphatic transport of apo A-IV in rats. We believe that this is the first demonstration of the involvement of a gastrointestinal hormone in the control of expression and secretion of an intestinal apolipoprotein, thus bringing together two separate areas of research in gastrointestinal physiology.

	Effect of Chronic High Fat Feeding on Intestinal Apo A-IV Synthesis.

TOP ABSTRACT INTRODUCTION Intravenous Infusion of APO... Inhibition of Food Intake... Is APO A-IV a... Potential Role of APO... APO A-IV Inhibits Gastric... Regulation of Intestinal APO... Effect of Chronic High... Perspectives. REFERENCES

 
The effect of chronic feeding of a high fat diet on intestinal apo A-IV synthesis is inconclusive. We know that acute administration of a lipid meal results in marked stimulation of apo A-IV synthesis and levels in both the jejunum and the ileum (Apfelbaum et al. 1987 ). In contrast, the chronic consumption of a high fat diet (30 g/100 g by weight of diet as fat) results in stimulation of apo A-IV synthesis and mRNA levels in the jejunum but not in the ileum. Does the ileum then become less responsive to lipid after chronic feeding of a high fat diet or does the adaptation of the digestive and absorptive processes result in fat no longer reaching the ileum? This question warrants further investigation.

In humans, chronic consumption of a high fat diet significantly elevates plasma apo A-IV levels. This elevation was observed during wk 1 of high fat diet consumption (Weinberg et al. 1990 ) but disappeared during wk 2 thus leading the investigators to conclude that there is autoregulation of intestinal apo A-IV production in response to diets high in fat. Consequently, both rodent and human data seem to suggest that intestinal apo A-IV synthesis and secretion become less responsive to fat after chronic high fat diet consumption. This warrants further investigation because a good understanding of how intestinal apo A-IV synthesis is modified by chronic high fat feeding may provide clues as to why a high fat diet predisposes both animals and humans to obesity.

	Perspectives.

TOP ABSTRACT INTRODUCTION Intravenous Infusion of APO... Inhibition of Food Intake... Is APO A-IV a... Potential Role of APO... APO A-IV Inhibits Gastric... Regulation of Intestinal APO... Effect of Chronic High... Perspectives. REFERENCES

 
Intestinal apo A-IV is a protein stimulated by dietary lipid with a potentially important physiologic role in the integrated control of digestive function and ingestive behavior as well as a presumed role in cholesterol and lipoprotein metabolism. Its role in the regulation of upper gut function and satiety still needs to be addressed. For instance, there is no information about what molecular form of apo A-IV is involved, i.e., free monomer, a homodimeric form (Weinberg and Spector 1985 ), HDL bound apo A-IV or, perhaps, apo A-IV–derived bioactive peptides. This issue will have to be addressed before a comprehensive understanding of the physiology of apo A-IV can be achieved. There is very good evidence that exposure of both the jejunum and ileum to fat results in the stimulation of apo A-IV synthesis and secretion by the respective segments of intestine. Exposure of the ileum to lipid also results in the secretion of PYY, which in turn stimulates further synthesis and release of apo A-IV by the jejunum. It is apparent from a number of studies that the stimulation of apo A-IV biosynthesis by lipid absorption and by PYY is mediated by different molecular mechanisms because the mRNA levels increase markedly during lipid stimulation, but mRNA levels remain the same during PYY stimulation. Preliminary data that seem to indicate that the effect of chylomicron formation and PYY on intestinal apo A-IV synthesis are additive.

	FOOTNOTES

 
¹ Supported by a grant from the National Institutes of Health DK 32288 and DK 53444.

² Manuscript received 13 May 1999. Initial review completed 9 June 1999.

⁴ Abbreviations used: apo, apolipoprotein; L-81, Pluronic L-81; PYY, peptide tyrosine-tyrosine.

	REFERENCES

TOP ABSTRACT INTRODUCTION Intravenous Infusion of APO... Inhibition of Food Intake... Is APO A-IV a... Potential Role of APO... APO A-IV Inhibits Gastric... Regulation of Intestinal APO... Effect of Chronic High... Perspectives. REFERENCES

 

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