Thylakoids Promote Satiety in Healthy Humans. Metabolic Effects and

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Thylakoids Promote Satiety in Healthy Humans. Metabolic Effects and Mechanisms Charlotte Erlanson-Albertsson,*,1 Per-Åke Albertsson,2 Karolina Gustafsson,1 Caroline Montelius,1 Sinan C. Emek, 2 Rickard Köhnke,1 and Mona Landin-Olsson3 1Department

of Experimental Medical Science, Appetite Control Unit, Lund University, BMC B11, Lund, Sweden 2Department of Biochemistry, Lund University, Lund, Sweden 3Department of Clinical Medicine, Lund University, Lund, Sweden *E-mail: [email protected]. Tel: 46-46-222 85 89, 46-46-70 288 1782. Fax: 46-46-222 40 22

Thylakoids are the photosynthetic membranes of the chloroplasts in green leaves. Thylakoids have been found to promote satiety when added to food, both in animal experimental models and in human. The thylakoids act through inhibition of lipase-colipase catalysed hydrolysis of triacylglycerol, which is the main dietary fat component. The mechanism for inhibition is either a binding of thylakoids to lipase-colipase, which thereby prevents to act as a lipolytic enzyme complex or binding of thylakoids to the triacylglycerol droplet, thereby hindering the access of lipase-colipase to its substrate. Thylakoids consist of proteins and lipids in a membrane structure containing various protein-bound pigments. The thylakoid membranes are fairly resistant to gastrointestinal breakdown, which may be an important property to explain the satiety promoting effect. Satiety is promoted through the release of cholecystokinin, a gastrointestinal hormone that causes an inhibition of gastric emptying and stimulation of satiety mechanism in the brain. The hunger hormone ghrelin is suppressed as well as insulin. In human short-term experiments thylakoids added to food promote satiety signalling. In long-term a reduced body fat mass was observed. © 2012 American Chemical Society In Emerging Trends in Dietary Components for Preventing and Combating Disease; Patil, B., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2012.

Keywords: Food intake; insulin; ghrelin; leptin; abdominal fat; body fat; CCK; blood lipids; blood glucose

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Introduction The greatest Cultural Revolution in modern time occurred around 1970. At that time fast food was introduced being highly palatable and available at low cost on many places. At the same time obesity started to increase. The obesity started in USA, then spread to Western Europe and is now increasing in Asia. The incidence of obesity correlates with introduction of modern Western fast food, being energydense and containing fat and sucrose (1). Globally one billion of persons are overweight (BMI > 26) and 300 millions obese (BMI >30). According to the National Health and Nutrition Examination Survey around 40 % of the population in US is obese (2, 3). In Sweden around 2,5 million people are overweight and 400 000 obese. In Sweden around 40 000 obese patients are treated with medical preparations to reduce their body weight, thus only a small percentage in relation to the number of obese subjects. Obesity induces various diseases like diabetes, hypertension, cardiovascular disease, cancer and depression. There are great social costs for loss of work among the obese subjects as well as for the treatment, which is often life-long. There are therefore strong arguments to combat obesity (4).

Cause of Obesity Obesity is an imbalance in energy intake in proportion to energy expenditure. Energy expenditure has not changed during the same period, indicating that overeating is the main cause for obesity. Under normal conditions food intake is normally balanced with energy expenditure (5). This occurs through the action of appetite regulating signals, acting to regulate food intake in proportion to energy needs. Appetite control occurs through the action of hunger and satiety signals (6, 7). Obesity has been linked to either an over expression of hunger signals, a low expression of satiety signals, or an inadequate regulation of these. A reduced satiety signalling leads to overeating and to suppressed cellular nutrient uptake and oxidation. Such a reduced satiety signalling is found in obese subjects, particularly in relation to palatable food (8, 9). Palatable food is highly concentrated on energy content. Volume of food is an important factor in regulating satiety. With highly energy-dense food, the satiety component is further reduced (7). Adding volume through liquids does not produce satiety; the volume must instead be included in the food eaten (10). The highly palatable food eaten today hence does not produce satiety and therefore overeating leads to an expanded fat mass and obesity.

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Hunger Signals During energy deficiency hunger signals are released that trigger food intake (11). A low blood sugar level is the most obvious sign of energy deficiency of the body. A low blood sugar level releases several hunger signals, acting to restore energy balance. Hunger involves three processes: 1) food seeking 2) food intake and 3) food storage. One important hunger signal is ghrelin, released from the stomach when the stomach is empty (12). Ghrelin levels are raised during fasting and suppressed within 30 minutes after the start of a meal. Obese subjects often have a blunted response to food; the ghrelin levels are not adequately suppressed. Obese children with Prader-Willis disease have significantly elevated levels of ghrelin levels, which may explain their overeating. Carbohydrate is more efficient to suppress ghrelin levels after feeding, whereas fat is least effective and protein in between (13). This could explain why fat easily promotes overeating.

Satiety Signals The satiety signals act to promote satiety. Their function could be summarised in three processes: 1) termination of eating 2) stimulation of uptake of nutrients into the cell and 3) stimulation of utilization of body energy stores during fasting. Following ingestion of food satiety signals are released. These are released in the intestine and serve to induce an early satiety during a meal. Satiety signals from adipose tissue serve the function to act satiety between two meals, thus regulating inter-meal satiety. Termination of eating occurs through the action of gastrointestinal satiety hormones, such as cholecystokinin (14), glucagon-like peptide1 (15) and enterostatin (16). These are released when food enters the intestine and produce satiety through activation of reward molecules such as serotonin, which brings the body into a state of rest. A stimulated uptake of nutrients is particularly important for liver cells, where fuel sensing occurs and where inter-meal satiety is regulated (17). A stimulation of energy expenditure during fasting is important to keep the energy levels of the cell at a level sufficient for basal function (18). This occurs through activation of glucose and fat oxidation. A strengthening of satiety will act both to promote a decreased food intake and to stimulate energy expenditure.

Satiety with Green Leave Components (Thylakoids) We have in our experiments identified certain components from the green leave spinach, so called thylakoids that produce satiety. The satiating response has been documented in experimental animal models as well as in human studies. Thylakoids are those cell structures within the plant cell that is responsible for the light reaction of photosynthesis (19) (Figure 1). Thylakoids consist of proteins and lipids, 50 % of each. In addition they contain chlorophyll and various antioxidants like carotenoids and vitamin E (20). The lipids are mainly polyunsaturated of omega-3-type and most of these in the form of galactolipids. Thylakoids are the most common type of biological membrane and therefore have a great potential as source for functional food components. The thylakoids have 523 In Emerging Trends in Dietary Components for Preventing and Combating Disease; Patil, B., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2012.

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no taste when harvested and can be rapidly isolated. A large-scale procedure for the preparation of purified thylakoids have been described where the thylakoids are precipitated at pH 4.7 , the iso-electric pH of thylakoids, to increase the yield of material (21).

Figure 1. Thylakoids are membranes responsible for the light reaction of photosynthesis in the chloroplasts of green plants. They contain membrane lipids, hydrophobic intrinsic membrane proteins and pigments necessary for the photosynthetic process.

Animal Studies Starting with animal studies in rat we demonstrated that thylakoids when added to high-fat food at a concentration of 2 mg chlorophyll per gram food significantly suppressed food intake and caused a reduced body weight by 18,5 % (22). The reduction of food intake started a few days after the thylakoids were given into the food, suggesting that the thylakoids did not have any aversive effect, which otherwise would have acted immediately. Instead there was a gradual inhibition of food intake with thylakoids, revealing that the satiety signals were gradually upregulated. The promotion of satiety was explained by raised levels of the satiety hormone cholecystokinin, being significantly elevated from 0,086 ± 0,12 pmol /l to 0,675 ± 0,08 pmol /l in the thylakoid group compared to the control group. Cholecystokinin (CCK) is a gastrointestinal hormone that ensures proper digestion and absorption of food through stimulation of pancreatic juice and bile and through inhibition of gastric emptying. CCK is released by fatty acids and amino acids as long as food digestion is going on and ceases after the aborption of the food products by the intestine (23). CCK in addition to peripheral effects in the intestine also has central effects in the brain, with a 524 In Emerging Trends in Dietary Components for Preventing and Combating Disease; Patil, B., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2012.

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stimulated release of serotonin, a reward molecule that is important for central satiety (24). A stimulated release of CCK suggests that the food processing in the intestine is slowed down by thylakoids and that brain satiety is induced. In addition to a reduced body weight we observed reduced levels of circulating triacylglycerol levels from 1,02 ± 0,13 mmol /l in control animals to 0,62 ± 0,04 mmol /l in the animals receiving thylakoids in the food. An elevated level of triacylglycerol is a common phenomenon in obese subjects with a great fat mass. The elevation suggest that the blood lipids are either not taken up by the peripheral cells or that they are not utilized. We cannot at present time explain the reduced triacylglycerol levels, but this is a phenomenon that we have observed in other experiments both in animals and in humans following addition of thylakoids in the food. The satiety signals released by thylakoids probably stimulate the uptake and utilization of triacylglycerol. The reduction of triacylglycerol levels is important to prevent any aberrant accumulation of lipids in other tissues, including the arterial wall where it causes atherosclerosis, in pancreas, where it causes diabetes or in liver, where it causes deregulation of the liver. In further animal experimental studies we gave mice a thylakoid-enriched high-fat diet during 100 days, and control mice were given a high-fat diet (25). During this feeding paradigm the mice receiving thylakoids had a significantly reduced food intake and reduced weight gain by 17 % compared to control mice. The effect started not until 30 days of feeding, suggesting that the weight reducing effect was gradually set up in the animals. The animals also had a significantly reduced body fat mass by 33 % and reduced triacylglycerol levels by 25 %. The reduction of triacylglycerol levels correlates with a reduced body fat mass in the animals receiving thylakoids. The thylakoid-treated animals also had reduced serum glucose levels by 19 % and reduced fatty acid levels by 17 % compared to control animals, suggesting a better metabolic control. High-fat feeding often leads to hyperglycaemia, hyperlipidemia and an increased fat mass, effects that thus were prevented with thylakoids. Also in the mice treated with thylakoids the fasting levels of the satiety hormone CCK was elevated at the end of the experiment by 65 % (25). CCK is a satiety hormone released as long as intestinal digestion is going on; the elevated levels suggest that the animals had a prolonged time for food digestion. The release of CCK seemed specific, since another gastrointestinal hormone, PYY, was not released. PYY is produced in the lower part of the gut, whereas CCK is produced in the upper part (26). This suggests that the delayed fat digestion occurs in the upper small intestine and is not as severe as should be expected when digestive enzymes are lacking, where digestion could continue all along the intestine, even at distal ileum (27). Thus thylakoids act to slow down fat processing temporarily, the main effect being in the upper small intestine.

Thylakoid Effect in Man We also examined if human was affected by thylakoids added to food (28). After an overnight fasting healthy humans were served a breakfast containing various doses of thylakoids (between 5 and 50 grams of thylakoid powder) added 525 In Emerging Trends in Dietary Components for Preventing and Combating Disease; Patil, B., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2012.

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as a pesto sauce on a sandwich, eaten together with tomatoes and basil. Blood samples were taken during six hours and then analyzed for various hormones. It was found that thylakoids promoted the release of CCK in a dose dependent way, the optimal dose being 25 gram of thylakoid, which gave an increased CCK level from 0, 5 ± 0,15 pmol /l to 1,3 ± 0,20 pmol /l at time point 6 hours. Whereas control breakfast gave a CCK release that raised within one hour after start of feeding and was at fasting level after four hours, the thylakoid enriched breakfast gave a release of CCK after one hour, and stayed elevated for six hours, being significantly elevated compared to the control. This suggests that thylakoids promote satiety also in man. The prolonged satiety was also obvious from the appearance of free fatty acids in the circulation. During the control meal free fatty acids appeared in the circulation after three hours, whereas in the thylakoid meal the free fatty acids had not appeared in the circulation after six hours. Free fatty acids emerge in the circulation when energy is needed and in a state of hunger. With thylakoids the satiety was still acting after three hours and remained at this state after six hours. The hunger hormone ghrelin was significantly suppressed by thylakoids by 25 % compared to control feeding in man (28). Ghrelin is elevated during fasting and suppressed by feeding. A suppression of ghrelin levels means less hunger and could be an effect of raised CCK levels, CCK being known to reduce ghrelin levels (29). Normally ghrelin is most efficiently suppressed by carbohydrate in the food and least by fat. It may be that not only fat is more slowly processed by thylakoids but also carbohydrate, the carbohydrates remaining in the intestine acting to suppress the ghrelin response. Suppressed ghrelin levels mean less hunger and less craving for reward, ghrelin being an important hormone for reward seeking (30). The satiety hormone leptin was significantly elevated by thylakoids, when measured six hours after feeding compared to control feeding in man, by around 40 % (28). Leptin is normally involved in prolonged fasting such as over-night fasting where it promotes satiety and fat oxidation (31). An elevation of serum leptin levels following a meal has been observed after six-hours, suggesting leptin to act also during inter-meal satiety, providing this reaches a six-hour interval (12). Raised leptin levels by thylakoids suggest that either satiety is promoted or that fat oxidation is promoted prior to next meal (32). To our surprise also insulin levels were reduced by thylakoids compared to control in the human feeding experiment by around 37 % (28). This suggests that thylakoids also affect glucose uptake and glucose metabolism. Glucose levels in the blood were not different during the thylakoid meal compared to the control meal. The observation of reduced insulin levels hence suggests increased insulin sensitivity. This could be due to the suppressed secretion of ghrelin, since ghrelin is known to reduce insulin sensitivity (33). It appears that thylakoids influence both lipid- and carbohydrate metabolism.

The Mechanism of Action of Thylakoids The mechanism of the thylakoid action is that they reduce the rate of fat digestion as demonstrated in vitro (22). The enzyme mainly responsible for 526 In Emerging Trends in Dietary Components for Preventing and Combating Disease; Patil, B., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2012.

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intestinal fat digestion is pancreatic lipase and its cofactor, pancreatic co-lipase. Pancreatic lipase is inactive and unable to bind to its triglyceride substrate under the conditions of the gastrointestinal tract, i.e. in the presence of bile salt and phospholipids. However in the presence of colipase lipase is active (34). This occurs through the binding of colipase to the triglyceride interface and a simultaneous binding of lipase (34). Colipase hence anchors lipase to its triglyceride substrate, which is subsequently hydrolysed. The tertiary structure of the lipase-colipase complex has been determined and it is clear that the complex exposes a hydrophobic surface that fits to the hydrophobic triglyceride substrate (35). Both colipase and lipase contribute to the hydrophobic surface, which is necessary for the subsequent hydrolysis of fat. Colipase deficiency has been identified in humans demonstrating steatorrhea and also in knockout animals, which suffered from a severely impaired fat digestion (27, 36). The binding of thylakoids to the lipase/colipase complex could cause the inhibition of lipolysis.

Inhibition of Lipolysis Thylakoid membranes were found to inhibit pancreatic lipase-colipase activity in a dose-dependent way (22). Other biological membranes like mitochondria, plasma membranes and bacterial membranes also inhibited lipolysis. Thus this inhibiting effect of thylakoids seems to be a general effect of biological membranes. We also separated the proteins from the lipids in the thylakoid membranes (22). This demonstrated that the protein fraction had the most important inhibiting property. After trypsin treatment the external protein loops of thylakoid membranes were removed; the remaining fragments still had the property to inhibit lipolysis, suggesting that the membrane spanning regions of the intrinsic proteins of thylakoids possessed the inhibitory effect. One of the major membrane proteins, LHCII, light harvesting complex II, of thylakoids was isolated and found to inhibit lipolysis. LHCII contains four hydrophobic membrane-spanning loops and a synthetic peptide identical with one of these also inhibited lipolysis although not as efficient as the whole protein. Other hydrophobic proteins, like the cytochrome bf complex and transhydrogenase of thylakoids were also able to inhibit lipolysis (22). In contrast the water-soluble protein serum albumin had no inhibiting capacity on the lipase-colipase catalysed hydrolysis of fat, confirming previous studies (37).

Binding of Thylakoids To understand the mechanism for inhibition of lipolysis the binding of thylakoids to lipase-colipase and the oil droplet was investigated. It was found that the thylakoids strongly bound to the lipase-colipase complex (22). The binding probably occurs at the hydrophobic surface, normally responsible for the binding to the triglyceride substrate. In this way lipolysis thus could be inhibited. However, thylakoids also bound to the triacylglycerol surface, the thylakoids having a strong affinity for the oil phase (22). Calculation of the surface of thylakoids in comparison with the surface of the oil droplets in our in vitro 527 In Emerging Trends in Dietary Components for Preventing and Combating Disease; Patil, B., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2012.

assay demonstrated that the thylakoids actually covered the surface of the oil droplet/triglycerides. With such a mechanism the thylakoids would hinder access of the lipase-colipase complex to the interface. There is probably a complex interaction between the lipase, colipase, bile salt, oil droplet and thylakoids and it is at present time not possible to determine whether the binding of thylakoids to lipase-colipase is the most important property to explain the inhibited lipolysis or the binding of thylakoids to the oil droplet.

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Satiety Following Inhibition of Lipolysis We have in previous studies demonstrated that inhibition of the lipase-colipase mediated hydrolysis of fat leads to a promoted satiety and a reduced body weight gain in experimental animal models (38). The inhibition lead to reduced food intake, raised CCK-levels and reduced triacylglycerol levels. In those studies we also compared with the lipase inhibitor Xenical, which is clinically used for treatment of obesity. Xenical induces steatorrhea but does not promote satiety signalling (39). The explanation is the rapid passage of the fatty intestinal content during production of fatty stools. With thylakoids the food digestive products remain in the intestine until they are digested; this means that satiety signalling is promoted, at least from the upper small intestine. The absorption of the food products has probably occurred in the proximal intestine, since distal hormones were not affected.

Thylakoids in the Gastro-Intestinal Tract The thylakoids are eventually broken down by gastro-intestinal enzymes and absorbed as nutrient products (40). The breakdown of thylakoids is however remarkably slow. In an experiment thylakoid membranes as well as plasma membranes were treated with gastrointestinal proteases, and the breakdown products analysed by gel electrophoresis and mass spectrophotometer. It was found that thylakoids remained resistant for two hours at 37 °C, whereas the plasma membranes were degraded within 10 minutes. Also delipidated thylakoid membranes were rapidly degraded, suggesting that the pigments contained in the thylakoids membrane proteins were responsible for the resistance toward proteolysis. Addition of oil into the incubation further enhanced the protease resistance of thylakoids. There are quite a few proteins that inhibit pancreatic lipase-colipase activity in vitro. Unpublished studies have demonstrated that these proteins (casomorphin or lactoglobulin) does not promote satiety or reduced body weight gain in vivo during feeding experiments. The explanation is probably that these proteins are rapidly hydrolysed in the gastrointestinal tract. With such proteins added to food the inhibition of lipase-colipase is only transient and does not affect fat digestion, food processing and satiety. Mitochondria strongly inhibit lipase-colipase in vitro (22) and when added to food failed to reduce body weight gain in growing mice. This suggests that mitochondria are not resistant to gastrointestinal hydrolysis, probably because they contain much less pigments than thylakoids. Mitochondria-rich food such as red 528 In Emerging Trends in Dietary Components for Preventing and Combating Disease; Patil, B., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2012.

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meat has however been found helpful to control energy balance, reduce abdominal fat mass and waist circumference in human epidemiological studies, suggesting that there may be some reduction of fat digestion and promotion of satiety in man (41).

Figure 2. Mechanism of action of thylakoids in regulating appetite. Thylakoids are added to food (1), causing a delayed fat digestion in the intestine (2). The delayed process of digestion causes an increased release of the satiety hormone cholecystokinin (CCK) (3). CCK causes a peripheral inhibition of gastric emptying, hence casing a distension of the stomach (4). CCK also causes the release of rewarding satiety molecules like serotonin, in this way establishing a central reward/satiety (5).

Future Experiments Obesity results from a prolonged small positive energy imbalance, and treatment needs to reverse this imbalance. Many different diets have been tried to treat obesity, and weight loss occurs with all of them. There is currently no evidence that supports the superiority of one macronutrient composition for diets over any other. The principal effect seems to be the degree of adherence to the prescribed calorie reduction. Obesity drugs have been developed that tap brain mechanisms for controlling feeding and the gastrointestinal tract and its peptides. Future experiments will be performed where overweight and obese subjects will be given thylakoids to the daily food or as capsulas served with each meal. The dose of thylakoids will be tested, but should be around 5 gram of thylakoids each day. 529 In Emerging Trends in Dietary Components for Preventing and Combating Disease; Patil, B., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2012.

Conclusions

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Appetite regulation with palatable food is a difficult issue, mainly since such type of food is rapidly digested and easily absorbed by the intestine. Through the addition of thylakoids from green leaves the food digestion is delayed enabling gastrointestinal satiety mechanism to work, both peripherally and centrally, as summarized in Figure 2. Future experiments will tell whether the addition of thylakoids to the daily food is an efficient treatment for overweight or obesity.

Acknowledgments This work has been possible through grants from Swedish Medical Research Council, Vinnova, Formas, Carl Trygger Foundation and Royal Physiographic Society of Lund, Sweden.

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