Would Free Fatty Acids Enhance Treatment of Obesity?

Abstract

See “Free fatty acids have more potent effects on gastric emptying, gut hormones, and appetite than triacylglycerides” by Little TJ, Russo A, Meyer JH, et al, on page 1124. See “Free fatty acids have more potent effects on gastric emptying, gut hormones, and appetite than triacylglycerides” by Little TJ, Russo A, Meyer JH, et al, on page 1124. The regulation of satiation, gut hormone signaling, and gastric emptying are increasingly relevant to developing therapies to combat obesity. A significant component of satiation results from altered gastric emptying in response to the mechanical and chemical properties of ingested food. In this issue of Gastroenterology, Little et al1Little T.J. Russo A. Meyer J.H. et al.Free fatty acids have more potent effects on gastric emptying, gut hormones, and appetite than triacylglycerides.Gastroenterology. 2007; 133: 1124-1131Google Scholar contribute to the understanding of gut hormone signaling in response to different forms of fat and their potential application in obesity treatment. They examine how fatty acids (FA), in comparison to triacylglycerides (TGs), affect gastric emptying, gut hormone secretion, appetite, and energy intake in humans. Their analysis yields provocative results and raises several important questions. Satiation, the process that promotes meal termination and thereby limits meal size, is modulated by several hormones (including gastrin, cholecystokinin [CCK], peptide YY [PYY], GLP-1, and insulin) and reflex responses that arise from the small intestine.2Camilleri M. Review: Integrated upper gastrointestinal response to food intake.Gastroenterology. 2006; 131: 640-658Abstract Full Text Full Text PDF Scopus (168) Google Scholar These hormones are secreted in a coordinated manner with the arrival of food, or chyme, in different areas of the gastrointestinal tract; they facilitate transit through the gut at a rate that facilitates mixing and digestion. The nutrient content of a meal influences the rate of its emptying from the stomach through osmotic and calcium-binding properties of the products of digestion in the duodenum, with calcium saponifying partially hydrolyzed TGs.3Hunt J.N. Pathiak J.D. The osmotic effects of some simple molecules and ions on gastric emptying.J Physiol (Lond). 1960; 154: 254-269Google Scholar, 4Hunt J.N. Mechanisms and disorders of gastric emptying.Annu Rev Med. 1983; 34: 219-229Google Scholar FA with ≥12 carbon chains retard gastric emptying through a CCK-mediated reflex which involves inhibition of the antrum, stimulation of the pylorus, and relaxation of the fundus.5Heddle R. Dent J. Read N.W. et al.Antropyloroduodenal motor responses to intraduodenal lipid infusion in healthy volunteers.Am J Physiol. 1988; 254: G671-G679Google Scholar Therefore, gastric emptying and satiation are influenced by the hydrolysis of TG to free FAs (FFA): This principle is central to the study designed by Little et al. The study directly compares in humans the effects of FFAs and TG on gastrointestinal hormone secretion, food intake, and gastric emptying of the FFA and TG components of the meal by radiolabeling the fat moieties and quantifying their emptying by an external gamma camera. Nine healthy young men with a normal body mass index were evaluated on 3 different occasions with intragastric administration of FFA, TG, and control (milk protein, 4%). As predicted from comparisons of effects of hydrolyzed versus nonhydrolyzed fats in animal species, CCK release occurred earlier with the FFAs than with TG. In humans, hydrolyzed fats are more likely to release CCK, fat hydrolysis is essential in the regulation of gastric emptying, and FA of ≥12 carbon chains are required to induce the physiologic effects of fats.6Degen L. Matzinger D. Drewe J. et al.Role of free fatty acids in regulating gastric emptying and gallbladder contraction.Digestion. 2006; 74: 131-139Google Scholar, 7Lal S. McLaughlin J. Barlow J. et al.Cholecystokinin pathways modulate sensations induced by gastric distension in humans.Am J Physiol. 2004; 287: G72-G79Crossref PubMed Scopus (79) Google Scholar Little et al also confirmed that CCK release was associated with increased postprandial fullness, retardation of gastric emptying, and somewhat reduced calorie ingestion at a buffet meal 4 hours later. These results were expected because CCK is a negative feedback signal that limits the amount of food consumed during an individual meal.8Beglinger C. Degen L. Fat in the intestine as a regulator of appetite—role of CCK.Physiol Behav. 2004; 83: 617-621Google Scholar It might be argued that understanding the different effects of FFA and TG on gastric emptying, hormone secretion, and satiation or appetite is not clinically relevant because most fat in the human diet comes in the form of TG. However, the results reported in this issue of Gastroenterology raise 2 questions regarding potential application of FFA to increase satiation and retard gastric emptying in the management of obesity: Is the difference in effects of the 2 different macronutrients—FFA and TG—clinically relevant? If so, are the effects of FFA sustained? Prior studies have shown that gastric motor function adapts to the effects of diet. For instance, after consuming a high-fat diet, there is acceleration, rather than slowing, of the post-lag gastric emptying of a high-fat test meal.9Castiglione K.E. Read N.W. French S.J. Adaptation to high-fat diet accelerates emptying of fat but not carbohydrate test meals in humans.Am J Physiol. 2002; 282: R366-R371Google Scholar By contrast, supplementation of the diet for 2 weeks with excess calories as fat in the form of TGs did not alter significantly gastric motor functions or satiation.10Park M.I. Camilleri M. O’Connor H. et al.Effect of different macronutrients in excess on gastric sensory and motor functions and appetite in normal-weight, overweight or obese humans.Am J Clin Nutr. 2007; 85: 411-418Google Scholar Similarly, feeding rats a high-fat diet diminishes the enterogastric inhibition of gastric emptying by intestinal oleate (a C18 chain fatty acid) and diminishes the ability of CCK to inhibit gastric emptying.11Covasa M. Ritter R.C. Adaptation to high-fat diet reduces inhibition of gastric emptying by CCK and intestinal oleate.Am J Physiol. 2000; 278: R166-R170Google Scholar Thus, the gut hormonal and motor response to dietary fats or FFA may attenuate with time and “dietary FFA substitution” may not be a viable medium-term approach to decrease caloric intake in humans. Furthermore, the recent identification of CD36 as a specific lingual taste receptor for FFA also argues against “dietary FFA substitution” therapy for obesity.12Laugerette F. Passilly-Degrace P. Patris B. et al.CD36 involvement in orosensory detection of dietary lipids, spontaneous fat preference, and digestive secretions.J Clin Invest. 2005; 115: 2965-2967Google Scholar CD36 is located in many tissues including the tongue, fats cells, digestive tract, heart, and skeletal muscle; it recognizes and facilitates the transfer of FA into cells12Laugerette F. Passilly-Degrace P. Patris B. et al.CD36 involvement in orosensory detection of dietary lipids, spontaneous fat preference, and digestive secretions.J Clin Invest. 2005; 115: 2965-2967Google Scholar and the formation of chylomicrons.13Nauli A.M. Nassir F. Zheng S. et al.CD36 is important for chylomicron formation and secretion and may mediate cholesterol uptake in the proximal intestine.Gastroenterology. 2006; 131: 1197-1207Google Scholar In rats, a high-fat diet has a “hyperphagic effect” with increased meal size and decreased time intervals between meals.14Warwick Z.S. Dietary fat dose dependently increases spontaneous caloric intake in rat.Obes Res. 2003; 11: 859-864Google Scholar CD36 may be responsible for this “hyperphagic effect” of dietary fat by contributing to the cephalic phase of digestion, increasing fat intake, and optimizing dietary lipid digestion and absorption by the small intestine, particularly the proximal regions.15Nassir F. Wilson B. Han X. et al.CD36 is important for fatty acid and cholesterol uptake by the proximal but not distal intestine.J Biol Chem. 2007; 282: 19493-19501Google Scholar “Dietary FFA substitution” delivered by mouth may conceivably potentiate the intake and absorption of dietary fat and counteract the potential benefit of intragastric administration of FFA on gastric emptying and gut hormone release (as in the study of Little et al), which may theoretically result in weight loss. In addition to the question regarding relevance, other results of the study by Little et al merit consideration. The results suggest that only ∼25% (average) of FFA emptied 4 hours after installation into the stomach. Non-nutrient liquids empty from the stomach exponentially.16Camilleri M. Malagelada J.-R. Brown M.L. et al.Relation between antral motility and gastric emptying of solids and liquids in humans.Am J Physiol. 1985; 249: G580-G585Google Scholar With increase in the nutrient and calorie content of the liquid, there is a deceleration from an exponential rate toward a linear (and therefore slower) rate of emptying.17Collins P.J. Houghton L.A. Read N.W. et al.Role of the proximal and distal stomach in mixed solid and liquid meal emptying.Gut. 1991; 32: 615-619Google Scholar Gastric emptying of liquid foods is controlled so that approximately 200 kcal/h is delivered to the duodenum.3Hunt J.N. Pathiak J.D. The osmotic effects of some simple molecules and ions on gastric emptying.J Physiol (Lond). 1960; 154: 254-269Google Scholar, 4Hunt J.N. Mechanisms and disorders of gastric emptying.Annu Rev Med. 1983; 34: 219-229Google Scholar However, even with solid food, the stomach empties >90% of a meal of ∼400 kcal (similar to the FFA meal administered in the study of Little et al) over 4 hours. What could account for the significant gastric retention of FFA at 4 hours found in the Little et al study? There are 3 main considerations. First, intubating the gastrointestinal tract may profoundly affect gastric function and retard emptying of a meal,18Read N.W. Al Janabi M.N. Bates T.E. et al.Effect of gastrointestinal intubation on the passage of a solid meal through the stomach and small intestine in humans.Gastroenterology. 1983; 84: 1568-1572Google Scholar most likely from stimulation of the mucosal mechanoreceptors in the stomach by the tube. However, Little et al removed the nasogastric feeding tube immediately after instillation of the test meal. Therefore, it is unlikely that gastric intubation would explain the significant gastric retention of FFA. Second, marked delay in the gastric emptying of FFA may represent an “order effect,” wherein the sequence of administration of the 3 different study emulsions affected the results. This is also unlikely given that the order of the fat emulsions was randomized. Because the intraindividual coefficient of variation in gastric emptying is 12%–15%,19Choi M.-G. Camilleri M. Burton D.D. et al.13C-octanoic acid breath test for gastric emptying of solids: accuracy, reproducibility and comparison with scintigraphy.Gastroenterology. 1997; 112: 1155-1162Google Scholar such an order effect could not account for the dramatic retardation in gastric emptying (∼75% average retention at 4 h). Third, extraneous circumstances might be considered. For example, one might postulate that the 123I radiolabel become dissociated from the fat moiety (FFA) and adhered to, or was taken up by, the gastric mucosa, so that it appeared not to empty. The prior literature does not support the observation that a relatively small molecule, such as a fatty acid, in a liquid meal would be retained in the stomach for 4 hours in the absence of underlying pathology. In fact, when 123I-labeled corn oil was mixed in liquid oil (melted Crisco or Olestra) and allowed to resolidify before administration, >90% of the fat emptied from the stomach at 4 hours.20Meyer J.H. Elashoff J.D. Lake R. Gastric emptying of indigestible versus digestible oils and solid fats in normal humans.Dig Dis Sci. 1999; 44: 1076-1082Google Scholar Interestingly, Little et al observed that the initial emptying of FFA was sufficient to stimulate a greater CCK response than with TG; their data suggest that, after the first hour, FFAs were then retained presumably as a result of the negative feedback from the intestine. A second intriguing result of the study is the early increase of PYY release (in the first hour) in response to FFA relative to TG. PYY is a gut hormone released postprandially by the direct contact of fat with the ileocolonic region,21Greely Jr, G.H. Hashimoto T. Izukura M. et al.A comparison of intraduodenally and intracolonically administered nutrients on the release of peptide-YY in the dog.Endocrinology. 1989; 125: 1761-1765Google Scholar typically 2–3 hours after food ingestion. The increase in PYY release in the first postprandial hour in response to FFA is consistent with an alternative neural or humoral pathway regulating PYY release22Onaga T. Zabielski R. Kato S. Multiple regulation of peptide YY secretion in the digestive tract.Peptides. 2002; 23: 279-290Google Scholar and with the report that intraduodenal infusion of lipids in humans caused a rise in PYY before the nutrients reached the distal gastrointestinal tract.23Pilichiewicz A.N. Little T.J. Brennan I.M. et al.Effects of load and duration, of duodenal lipid on antropyloroduodenal motility, plasma CCK and PYY, and energy intake in healthy men.Am J Physiol. 2006; 290: R668-R677Google Scholar Release of PYY by fat in the proximal but not distal gut depends on an atropine-sensitive cholinergic pathway suggesting vagally mediated release.24Lin H.C. Taylor I.L. Release of peptide YY by fat in the proximal but not distal gut depends on an atropine-sensitive cholinergic pathway.Regul Pept. 2004; 117: 73-76Google Scholar Postprandially released CCK may be responsible for this vagally mediated PYY release by activating CCKA receptors on vagal afferent nerve terminals.25Holzer H.H. Turkelson C.M. Solomon T.E. et al.Intestinal lipid inhibits gastric emptying via CCK and a vagal capsaicin-sensitive afferent pathway in rats.Am J Physiol. 1994; 267: G625-G629Google Scholar, 26Lloyd K.C. Holzer H.H. Zittel T.T. et al.Duodenal lipid inhibits gastric acid secretion by vagal, capsaicin-sensitive afferent pathways in rats.Am J Physiol. 1993; 264: G659-G663Google Scholar Inhibition of this early postprandial PYY release with a CCKA antagonist in response to the gastric infusion of FFA would support the hypothesis that a CCK-stimulated vagal pathway mediates the early PYY release. A third observation is that intragastric FFA administration was associated with a higher PYY response than with TG beyond 2 hours postinfusion. Because FFAs were not emptying from the stomach during this period, this higher PYY response would not be expected; very little of the FFA would reach the distal small bowel. These observations suggest either the presence of a hitherto unexplored effect of intragastric FA on PYY release or the dissociation of the radiolabel and its retention in stomach while the FFA were delivered to the distal small bowel to release the PYY. In summary, the results from Little et al indicate that FFAs are more potent stimuli for gut hormone release than TGs (Figure 1). Specifically, FFAs cause an earlier and more dramatic increase in CCK and PYY after a meal. The clinical potential of this finding is considerable; CCK and PYY are regarded as major players in induction of satiation. However, much remains to be learned about the complex processes of gastric emptying of fat moieties and gut hormone signaling in response to the ingestion of food, as well as the molecular basis for preference for fat in the diet. The processes involved in appetite and satiation and the responses to different nutrients are critical to the pathophysiology of many gastrointestinal diseases, including obesity. Greater understanding of the neurohormonal control and the gastric emptying and uptake of fat moieties may lead to novel applications for obesity management. Free Fatty Acids Have More Potent Effects on Gastric Emptying, Gut Hormones, and Appetite Than TriacylglyceridesGastroenterologyVol. 133Issue 4PreviewBackground & Aims: The effects of fat on gastric emptying (GE), gut hormones, and energy intake are dependent on digestion to free fatty acids (FFAs). In animals, small intestinal oleic acid inhibits energy intake more potently than the triacylglyceride (TG) triolein, but there is limited information about the comparative effects of FFA and TG in human beings. We compared the effects of FFA and TG on GE, gut hormone secretion, appetite, and energy intake in healthy males. Methods: Nine men (age, 23 ± 2 y; body mass index, 22 ± 1 kg/m2) were studied on 3 occasions to evaluate the effects of (1) 40 g oleic acid (FFA, 1830 kJ), (2) 40 g macadamia oil (TG, 1856 kJ; both 600-mL oil-in-water emulsions stabilized with 4% milk protein and labeled with 15 MBq 123I), or (3) 600 mL 4% milk protein (control, 352 kJ), administered intragastrically, on GE, plasma cholecystokinin (CCK) and peptide-YY (PYY) levels, appetite perceptions, and subsequent energy intake. Full-Text PDF