Gut fat signaling and appetite control with special emphasis on the effect of thylakoids from spinach on eating behavior

Abstract

The metabolic controls of eating are embedded in a neural system that permits an interaction with the environment. The result is an integrated adaptive response that coordinates the internal milieu with the prevailing environment. Securing adequate amounts of fat and optimizing its storage and use has an evolutionary basis. By generating neuronal and endocrine feedback signals, behavior and metabolism could then adapt to fluctuations in food availability. However, in modern society, foods that appeal to the palate are neither in shortage nor are they difficult to procure. These foods can activate brain reward circuitry beyond their evolved ‘survival advantage’ limits. Many foods high in fat invoke an undeniably pleasurable sensation and could excessively stimulate the brain’s reward pathways leading to overeating. However, the high appeal and potential for being eaten in excess notwithstanding, fat has the added distinction of inducing powerful signals in the gut that are transduced to the brain and result in the regulation of appetite. Fatty acids are sensed by G-protein-coupled receptors on enteroendocrine cells which trigger the release of peptides involved in appetite regulation. Lipid sensing may also occur through the fatty acid translocase, CD-36, on enterocytes. Additionally, fat can activate dopaminergic systems affecting reward, to promote an inhibition over eating. Prolonging the presence of fats in the gastrointestinal lumen permits the activation of signaling mechanisms. Thylakoids, found within the chloroplasts of plants, are flattened disc-like membranous vesicles in which the light-dependent reactions of photosynthesis occur. By interacting with lipids and delaying fat digestion, thylakoid membranes promote the release of peptides involved in appetite regulation and may influence the reward system. This review explores gut lipid sensing and signaling in the context of appetite regulation. The effects of thylakoid membranes on eating behavior are also reviewed.

Introduction

Human appetite is controlled by a complex sequence of events among elements that form the psychobiological system. This system broadly encompasses psychological experiences, peripheral physiologic signals and brain mechanisms.1 Eating when energy stores are depleted and refraining from eating when replete reflects a homeostatic model of eating, or metabolically driven eating which is controlled by neural circuits primarily in the hypothalamus and brainstem. Eating in the absence of such metabolic feedback, termed non-homeostatic eating, involves cognition, reward and emotion. Non-homeostatic eating is controlled by neural circuits principally located in the cortico-limbic structures and has parallels to drug addiction. The metabolic and non-homeostatic controls of eating interact to determine eating behavior.2

The metabolic controls of eating are entrenched in a neural system that permits an interaction with the environment to produce an integrated adaptive response that coordinates metabolic need with the prevailing environment.3 The procurement of energy and essential nutrients is defended by complex redundant pathways, which are different from the neural circuitry involved in fulfilling the metabolic needs of the body. In the modern world, procuring food is not difficult or dangerous. However, this system was designed to cope with evolutionary pressures arising from times of feasting and famine and is therefore predisposed to neural circuits that facilitate the ease of securing and storing energy.4

Emotions evolved as a mechanism to initiate advantageous and preempt potentially harmful stimuli or behavior.3 To elucidate, satiation represents meal termination and satiety prolongs the interval between meals. The pleasurable taste of certain foods and the perceptions of satiation or satiety they invoke are integrated by the brain to build a complex representation of the food and provide an evaluation of its reward value.5, 6 These representations are associated with positive emotions that prompt a motivational drive to find the food and engage in eating.3 The associated pleasing of the senses that indulging in the food brings on is stored by the brain and results in a keen motivation to renew these pleasurable sensations. The reward value of a food and the positive emotions it induces is learned and thereby sought at a future time. The metabolic need is translated into behavioral action by a cognitive and emotional brain that operates on factors such as past experiences, cost and availability.3 Thus, the neural circuits regulating energy homeostasis are intertwined with the cortico-limbic mechanisms involved in learning and memory, reward, and emotions.3 However, the cortico-limbic systems can override the homeostatic systems controlling energy balance as they both act to synchronize the internal milieu with the external world3 (Figure 1).

Figure 1
figure1

Flow diagram depicting the major factors and mechanisms determining the control of ingestive behavior and energy balance. Berthoud HR et al.4

In the prevailing food environment where shortages for the most part are conspicuous by their absence, the 27.5% rise in the global prevalence of obesity as assessed over the past 33 years7 suggests that the non-homeostatic drive is prevailing over metabolic feedback control.2 Activating the mental representation of a behavior outside of awareness prepares a person to rapidly initiate the corresponding behavior.8 Thus, reward evaluation can occur outside of awareness and the corresponding action taken without conscious control.2 Interventions that target this subliminal priming have tremendous potential to reduce the asymmetry between metabolic and non-homeostatic regulation of food intake.

Fat is a concentrated source of energy that can contribute to increased energy intake. Foods high in fat especially those containing added sugars induce an undeniably pleasurable sensation that may increase their selection over other alternatives at the point of choice.9 However, the presence of fats in the gastrointestinal (GI) tract reduces the drive for food.10 Thus, fat contributes to increasing the energy density of the diet but fat can also influence the appetite by inducing the release of hormones involved in regulating eating behavior.11 However, the prolonged presence of fat in the GI tract is necessary for fat to exert its physiologic effects on appetite regulation. Delaying fat digestion is therefore crucial.12

Thylakoids are compartments inside the chloroplasts and are composed of membranes that form the internal photosynthetic membrane system of chloroplasts. By interacting with lipids and delaying fat digestion, thylakoid membranes from spinach promote the release of satiety hormones and may influence the reward system.13, 14, 15, 16 This review will explore gut lipid sensing and GI signaling in the context of appetite regulation. Further, the effects of thylakoid membranes on eating behavior will be reviewed.

Gut lipid sensing and appetite regulation

The GI tract initiates a wide range of responses that result in digestion, absorption and metabolism of a meal. As a highly specialized chemosensory organ, with the capacity to sense ingested nutrients, the primary function of the gut is to optimize these processes. The ingestion of a meal precipitates neural and hormonal signaling from the GI tract in response to gastric distension and the chemical presence of nutrients. Interaction between the enteroendocrine cells located throughout the GI tract and nutrients stimulates the release of peptides that act locally, centrally or peripherally to influence appetite regulation.17

Oral fat exposure acting through a number of receptors and molecules including G-protein-coupled receptors, potassium channels and cluster of differentiation 36 (CD36) may have a role in mediating dietary fat preference and intake.10, 18 However, it is oral exposure to fatty acids rather than triacylglycerides that elicit this response and lipolytic activity in the saliva is sufficient to produce the range of fatty acid concentration that produces the signals.19, 20 The mechanisms involved in intestinal detection of lipids involve molecular sensing elements that largely coincide with those implicated in oral signaling. Luminal contents activate several G-protein-coupled receptors in the enteroendocrine cell membranes. These receptors are activated by fatty acids of more than 12 carbons or their derivatives such as oleoylethanolamine (OEA). Fatty acid-induced activation of these receptors results in the secretion of gut peptides such as cholecystokinin (CCK), glucagon-like peptide-1 (GLP-1) and peptide YY (PYY), that precipitate appetite-suppressant responses.21, 22, 23

The biochemical basis for gut lipid sensing and the induction of signaling to regulate GI function and energy intake are not well understood, but it may be inferred through the identification of locally released or expressed factors potentially important in the gut-brain feedback axis.24 Expression of markers of neuronal activity such as c-Fos, in the caudal brainstem nucleus of the solitary tract, the central nervous system terminus of gut vagal afferents has been demonstrated with intestinal lipid infusions at doses that inhibit feeding, but the effect is blocked by the administration of the serotonin (5-HT) receptor antagonist ondansetron.25, 26, 27 Duodenal 5-HT release acting via vagal 5-HT inotropic receptors to increase gut vagal afferent neurophysiological activity is therefore a possible mechanism by which food intake is regulated. However, evidence points to fat-induced CCK release mediating the activation of duodenal 5-HT receptors.24

In enteroendocrine cells, another possible candidate is CD36, a receptor-like membrane protein, which may act as a lipid sensor to promote peptide release.24 CD36 is also expressed in the ventromedial hypothalmic neurons where it mediates oleic acid signaling. Binding of oleic acid to CD36 alters neuronal activity in the same manner as fat perception by taste receptor cells modulates neuronal action.28 Oleic acid is generated in the gut during digestive hydrolysis of complex dietary lipids. The interaction of CD36 with oleic acid is necessary for the production of OEA, which suppresses energy intake. The precise mechanisms by which OEA exerts its inhibitory effect on feeding are unknown; however, the activation of the nuclear receptor, peroxisome-proliferator-activated receptor-α, an OEA agonist, has been implicated.29, 30, 31, 32 Further, the activation of peroxisome-proliferator-activated receptor-α triggers the production of apolipoprotein IV whose presence is critical for induction of gut to brain signaling conveying information about the presence of fatty acids in the small intestine. The feedback responses initiated include the inhibition of gastric motility.33

Dopamine is a key neurotransmitter that modulates reward. The role of dopamine signaling in reward in highly debated.34, 35 There are two prevalent hypotheses that explain dopamine signaling. The first hypothesis states that overindulgence in pleasurable stimuli occurs when there is a positive correlation between the amount of dopamine signaling and the pleasure derived from the hedonic experience.2 The other hypothesis is that diminished responses within brain reward dopaminergic circuits leads to overeating as a compensatory response.36, 37 High-fat fed GI dysfunction has an important role in dopamine deficiency. Reduced synthesis of the appetite-suppressant OEA may be the link between GI dysfunction and high-fat induced dopamine deficiency. Administration of OEA to high-fat-fed mice has been shown to correct the signaling deficiencies and reduce oral intake of a high-fat emulsion.32, 38

To summarize, fatty acids are sensed by G-protein-coupled receptors on enteroendocrine cells which trigger the release of GI peptides. Other mediators include CD36, which contributes to mobilization of OEA and apolipoprotein IV. These lipid mediators precipitate the activation of receptors on vagal afferents to induce signaling to the central nervous system. Additionally, fats in the gut may activate dopaminergic systems affecting reward, to promote an inhibition over eating.

Gastrointestinal signaling and appetite control

The GI tract is the largest endocrine organ with multiple peptides being produced and released as secretory granules from a single cell type and single peptides having several effects. The brain senses and responds to external cues relating to the availability of foods and coordinates it with internal signals conveying information about the presence and composition of nutrients in the gut, the circulating nutrients and the energy stored as fat.4 The GI signals released as a result of ingestion may be classified as: (i) short-term signals, which are synchronized with episodes of eating; (ii) long-term signals, which reflect the metabolic state of adipose tissue. Both the episodic and long-term or tonic signals interact to determine eating behavior39 (Figure 2).

Figure 2
figure2

Schematic representation of the levels of homeostatic and non-homeostatic controls over the regulation of energy balance: Following ingestion of food, signals from the GI tract, including hormones such as ghrelin, CCK, GLP-1, PYY and insulin as well as glucose, fatty acids and enterostatin, act through vagal stimuli, directly, or both to inform the central nervous system of the nutritional and energy status of the body. Leptin and insulin released in proportion to adipose stores are involved in long-term signaling reflecting the metabolic state of adipose tissue. Long- and short-term signaling interact to determine eating behavior. Although the hypothalamus is a key player in the control of food intake, the integration of signals involves important areas in the limbic system, cortex, midbrain and brainstem to produce coordinated endocrine, autonomic and behavioral responses that regulate appetite and energy balance. Adapted from Schneeberger et al.117 (Bioscientifica Ltd.).

Short-term or episodic signals

Ghrelin is a peptide hormone released into circulation from the stomach. Ghrelin acts via the growth hormone secretagogue receptor-1α. Acylation of ghrelin is necessary for it to bind to the receptor and for ghrelin to cross the blood–brain barrier.40 Circulating levels of ghrelin are elevated during fasting and fall after eating suggesting that ghrelin exerts an orexigenic effect, to stimulate hunger. However, acylated ghrelin as well as the enzyme responsible of activating ghrelin are reduced by high-fat feeding and may inform the central nervous system about the availability rather than the absence of energy.41, 42 Further, evidence suggests that ghrelin may influence the mesolimbic dopamine circuitry to enhance the reward value or motivational wanting for highly desirable foods.43, 44

CCK is released postprandially from the I cells in the proximal GI tract primarily in response to fat and protein hydrolysates.45 CCK appears to act by binding to CCK1 receptors on the vagal nerve,46 causing early meal termination and reducing food intake in animals and humans.47, 48, 49 Evidence suggests that CCK may not wholly rely on this pathway. Selective vagotomy does not fully attenuate the response, and the presence of CCK1 receptors in the hypothalamus suggests that a direct communication without vagal mediation is likely.50, 51 In vagal afferent neurons, the absence of CCK1 receptors has been linked to an elevated ghrelin-mediated drive to eat.52 Also, GLP-1 release is affected by CCK1 receptor antagonism.53 Thus, CCK may at least in part regulate the capacity of vagal afferents to respond to other appetite-related signals.54

Co-secretion of PYY along with GLP-1 occurs in response to a meal from the L cells located throughout the gut, but present in highest concentrations in the distal regions. Peripheral administration of PYY3-36 reduces food intake in rodents and humans.55, 56, 57 The secretion of PYY is stimulated by various macronutrients; but fat appears to be the most potent stimulator of PYY release in humans.58, 59 Using functional magnetic resonance imaging it has been shown that in humans, PYY modulates neural activity in brain areas associated with homeostatic appetite control as well as the higher cortical areas involved in reward and hedonic control. Under conditions of low PYY, hypothalamic activation correlated with energy intake; however, under conditions of high PYY mimicking the prandial state, brain activity predicting energy intake switched from a homeostatic area (hypothalamus) to the orbito-frontal cortex, a brain region implicated in reward processing.60 Thus, PYY may diminish the rewarding value of food by modulation of the orbito-frontal cortex.

GLP-1 is endogenously released by the L cells following nutrient entry, and by neurons of the nucleus of the solitary tract in the hindbrain.61 GLP-1 receptors in the nucleus acumbens and in the ventral tegmental area appear to be responsible for an inhibitory effect of GLP-1 on the rewarding value of food in rats, as evaluated by a progressive ratio test.62 With the identification of strong projections from GLP-1 neurons in the nucleus of the solitary tract to the nucleus acumbens core, it was shown that injections of GLP-1 into the nucleus acumbens reduced food intake.63 Thus, this projection may link signals of satiety in the hindbrain with the forebrain signals of food reward. In the periphery, satiety-inducing effects of GLP-1 are likely mediated by vagal afferents originating in the intestine in combination with other mechanisms that may involve circumventricular organs (lacking the blood-brain barrier).64 Carbohydrate and fat appear to be more potent stimulators of GLP-1 than protein.65 Oxyntomodulin is processed from the same precursor as GLP-1 and is released postprandially. Although oxyntomodulin acts by binding to the GLP-1 receptors, the binding affinity is far lower. When administered centrally or peripherally, oxyntomodulin has been shown to reduce weight gain in rats,66, 67 and food intake in humans;68 however, it has a short circulating half-life, which limits the use of exogenous oxyntomodulin as a means of appetite regulation.69

Pancreatic polypeptide is released from F cells of the pancreatic islets in response to food intake. Pancreatic polypeptide has a high affinity for the Y4 receptor, which is thought to reduce food intake by downregulating the orexigenic neuropeptide orexin and increasing the anorexigenic brain-derived neurotrophic factor.70 Intravenous administration of pancreatic polypeptide reduces food intake in humans.71 However, pancreatic polypeptide too has a short half-life in vivo, which limits its potential as a treatment for obesity.69

In response to the ingestion of fat, procolipase is secreted from the exocrine pancreas. Following secretion, it is converted to colipase by cleavage of the N-terminal pentapeptide enterostatin. Colipase facilitates the action of pancreatic lipase in the digestion of fat; whereas, enterostatin acts as a negative feedback signal regulating fat intake and inducing satiety.72, 73, 74, 75 Studies using immunohistochemistry have shown that procolipase and enterostatin are present in the gastric mucosa and certain brain areas such as the amygdala and hypothalamus. 76, 77 The effect of enterostatin on the regulation of energy intake involves both central and peripheral sites of action. The peripheral mechanisms involve vagal afferent signaling to hypothalamic pathways.78

It has been suggested that enterostatin may also influence the reward system by its actions on the opioidergic systems; but, clear evidence of the binding to opioid receptors has yet to be demonstrated.79 Enterostatin’s effects on appetite acting through the reward system may also be influenced by changes in dopamine activity.80 After an adaptive period of fat consumption, enterostatin has been shown to block dopamine reuptake transport to increase striatal dopamine release measured in rat striatal slices.81 Acting via uncoupling proteins, enterostatin may also raise thermogenesis to increase energy expenditure.79 In humans, oral or intravenous enterostatin administration did not have an effect on subjective satiety ratings, hedonic scores or energy intake;82, 83 however, the effects of endogenously produced enterostatin on appetite have not been investigated.

Long-term or tonic signals

Insulin and leptin represent long-lasting or chronic hormonal regulation of food intake. They are released into circulation proportional to body fat content and their plasma levels determine the rate at which they enter into the central nervous system.84 However, insulin is secreted into the blood in response to changes in blood glucose concentrations. Incretin hormones such as GLP-1 can also stimulate its release. Thus, the relationship between insulin secretion and appetite regulation may not be completely straightforward. 85 Similarly, leptin secretion can become dissociated from body fat content. A decrease in leptin secretion during food deprivation is far greater than what may be expected by a decrease in body fat. The excessive response is designed to provoke the activation of compensatory mechanisms and prevent drastic depletion of body stores.84 Thus, leptin and insulin are not useful as short-term biomarkers of satiety.85 However, leptin signaling in the hippocampus, a brain structure involved in memory and learning, may contribute to inhibiting the formation of associations between a rewarding event and the context in which the rewarding effects of the stimulus were experienced. In rats, it has been shown that leptin suppresses the expression and consolidation of learned appetitive behaviors.86 Further, leptin may have a role in dopamine signaling, but it is not clear as to whether leptin decreases reward-driven energy intake by inhibition of dopamine transmission or by making it more efficient.2

Thylakoid membranes

Thylakoids, found within the chloroplasts of plants, are flattened disc-like membranous vesicles in which the light-dependent reactions of photosynthesis occur.87 Thylakoid membranes consist of a system of paired membranes encasing the lumen and separating it from the surrounding stroma of the chloroplast.88 The grana are the cylindrical stacks of approximately 10–20 tightly appressed (where the membranes are held together by stacking forces) thylakoids that are interconnected by single unstacked stroma lamellae. Granum and stroma membranes differ in their protein composition; yet, the thylakoid membrane system is a continuous membrane and it encloses one inner luminal aqueous phase. The cylindrical granum of stacked membranes is surrounded by stroma lamellae that are interconnected through slits or junctions at the margins of the grana. This structure ensures contiguity of the membrane system across the entire grana-stroma network87 (Figure 3).

Figure 3
figure3

(a) Cross section of a grana. (b) A grana disc viewed from above: Appressed domains, where the membranes are held together by stacking forces, are distinguishable from stroma-exposed domains (i.e., margins), end membrane and stroma lamellae. The appressed domains and the end membranes of grana are essentially flat, whereas the grana margins are curved. Several stroma lamellae are connected to one cylindrical granum of stacked membranes. Reproduced with permission from Elsevier, Albertsson P.118

The thylakoid membrane proteins are both intrinsic or membrane spanning, and extrinsic or attached to the surface of the membrane. The thylakoid membrane proteins and their bound pigments, chlorophyll and carotenoids contribute to 70% of the thylakoid mass.89, 90 The proteins are found in large complexes spaced by lipids to maintain a tight molecular packing. The lipid–protein interface is comprised of solvation shell lipids around the integral membrane proteins that are weakly associated with the hydrophobic surface of the proteins, and lipids that are strongly bound to membrane proteins. The major lipids are the glycerolipids, such as galactolipids and phospholipids.91 The photosynthetic thylakoid membrane system is the location of numerous biochemical reactions requiring regulation in response to light and temperature conditions. Moreover, this system has to constantly battle and recoup from light and oxygen stress. It is of little wonder then that the thylakoid membrane system is a complex, yet, remarkable structure capable of accomplishing myriad functions.88

Inhibition of fat digestion

Lipolysis requires that lipase and the lipid substrate are in close proximity at the oil–water interface. Therefore, both lipase and the lipid droplet must partition from the aqueous and oil phases to the oil–water interface. However, the presence of various surface-active substances released from food, its digestion products and GI secretions complicate the interfacial composition and influence the reaction.92 For instance, the accumulation of bile salts containing highly surface-active bile acids at the interface has been shown to inhibit the adsorption of pancreatic lipase to its lipid substrate.93 The inhibitory effect of bile salts can be subverted by the presence of colipase which forms a complex with lipase in the ratio of 1:1, and binds to the bile salt-dominated interface to firmly anchor pancreatic lipase to the interface. Bile salts promote disruption in the packing of the originally bound substances from food and GI secretions, and form their own clusters. The presence of bile salts as well as that of the lipase-colipase complex is required for hydrolysis to occur.94 Thus, it is possible to regulate fat digestion by interfering with the oil–water emulsion interface or the interaction between the lipase-colipase complex and the lipid substrate.

Thylakoid membranes from spinach have been shown to suppress lipolysis by pancreatic lipase-colipase in a dose-dependent manner, using in vitro mechanisms. Using electron microscopy, it was shown that thylakoid membranes cover the entire interface of an oil droplet in water. Moreover, at a sufficient concentration, thylakoid membranes bind to the lipase-colipase complex in the presence of bile salts. Therefore, it has been suggested that thylakoid membranes inhibit lipolysis by binding to the active site of the lipase-colipase complex and by adsorption to the oil–water interface, thereby preventing interaction between the enzyme complex and its lipid substrate.95 The inhibition of lipolysis following removal of the lipids from the membranes suggests that the inhibiting component may be the membrane-spanning region of the intrinsic proteins.95 However, removal of the lipids reduced the binding 10-fold in strength suggesting that the membrane lipids may also have a role in the inhibition of lipolysis.96

Studies conducted in vitro show that galactolipids from thylakoids of spinach inhibit lipase activity, at the interface of the oil–water emulsion.92, 94 The major galactolipids are monogalactosyldiacylglycerol and digalactosyldiacylglycerol, which comprise 50% and 20%, respectively, of the total lipid content of the membranes. In vitro studies show that galactolipids derived from the thylakoids of spinach delay lipid digestion. Unlike monogalactosyldiacylglycerol, digalactosyldiacylglycerol has a large polar group which may sterically hinder the formation of the lipase-colipase complex or prevent the adsorption of the lipase-colipase complex to the lipid droplet. Thus, digalactosyldiacylglycerol may alter the properties of the interface to inhibit pancreatic lipase activity.

The galactolipids are resistant to displacement by surfactants such as bile salts, which is crucial for their inhibitory action. Galactolipids are not easily digested by pancreatic lipase but are slowly hydrolyzed by pancreatic lipase-related protein 2.92 Therefore, regardless of whether the inhibiting component is protein or lipid, fat digestion is delayed rather than completely inhibited because both components are ultimately digested in the GI tract, to relinquish their hold on fat digestion. Thus, unlike the lipase inhibitor orlistat, the unpleasant effects of fat malabsorption such as oily discharge and anal leakage are avoided.97, 98, 99

The term thylakoids was paired with satiety, appetite, obesity, fat and food intake using the operator ‘AND’. The paired terms were used to perform a literature search on PubMed and Google Scholar. Six human trials were identified for the period ending 30 June 2015. These trials are reviewed against a backdrop of a selection of animal studies, and a summary of the human trials is presented in Table 1.

Table 1 Summary of the effect of thylakoid supplementation in humans, on obesity and metabolic parameters

Animal studies

In rats fed a high-fat diet, supplementation with thylakoids from spinach for 13 days as well as 100 days reduced food intake and body weight, reduced circulating levels of triacylglycerol and increased plasma concentrations of CCK compared with high-fat-fed controls. Further, there was an increase in lipase and colipase secretion in thylakoid-treated animals compared with controls following binding of the membranes to the lipase-colipase complex.95, 100 Additionally, at the end of 100 days, there was a reduction in body fat, serum glucose and free fatty acids; however, there was no change in PYY concentrations. There was a reduction in serum leptin, which was consistent with the reduction in adipose tissue.100

In another study, rats were fed a high-fat, low-fat or thylakoid-supplemented high-fat diet for 32 days. Although there was no change in energy intake, the rats in the thylakoid-supplemented group lost significantly more weight and percent body fat than the rats in the other groups. Increased binding to pancreatic lipase-colipase by thylakoids was also demonstrated.13 In rats fed a standard chow diet, supplementation with thylakoids from spinach for 10 days reduced food intake, with no effects on blood glucose, but a reduction in the insulin response compared with the controls.98 Following a 4-week high-fat diet, thylakoids fed to pigs increased plasma CCK concentrations over a period of 6 h, whereas ghrelin concentrations were reduced in the 2–4-h period compared with a control condition without thylakoid administration.101 Similarly, in pigs fed a high-fat meal with or without thylakoids, lipase and colipase secretion and portal blood CCK concentrations increased; however, insulin levels were lower with thylakoid supplementation.102

In animal studies, in periods ranging from 13 to 100 days, reductions in body weight and body fat have been demonstrated. The effects on food intake are less consistent. The increase in lipase and colipase secretion suggests that there was an increase in enterostatin, because it is produced in equivalent amounts to colipase. However, none of the studies measured enterostatin concentrations or thermogenesis to provide evidence of a role for enterostatin. The rise in CCK concentrations was consistent in the studies that evaluated CCK, but glucose and insulin concentrations were too inconsistent to arrive at any firm conclusions as to the effects of thylakoids on glucose metabolism from the animal studies. Although, ghrelin concentrations declined in one study and PYY showed no change, the effects on body weight and body fat in conjunction with a consistent increase in CCK release warrants investigation in human trials.

Human studies

In a crossover study including 11 subjects, the satiety effect of four pesto sandwich meals ranging in energy content from 2277 to 3006 kJ (544–718 kcal, 56–66% fat) and containing 0 g thylakoids, 25 g thylakoids, 50 g thylakoids or 25 g delipidated thylakoids were compared.16 The thylakoid-containing conditions increased serum CCK concentrations at 4 and 6 h, while ghrelin concentrations were reduced at 2 h compared with the control condition. The rise in CCK and decline in ghrelin occurred regardless of the thylakoid dose or type; however, leptin concentrations were lowered at 6 h in the 25 g and 50 g thylakoid conditions but not in the 25 g delipidated thylakoids condition. There was no difference in the plasma glucose concentrations among the conditions; but, thylakoid supplementation reduced the insulin response. Free fatty acids were reduced only in the 50 g thylakoid condition during the 4–6-h period.

Twenty women were included in a crossover study to test the effect of a high carbohydrate breakfast meal (71% energy from carbohydrates) supplemented with 0, 3.7 or 7.4 g of thylakoids from spinach on satiety and metabolic parameters.103 There was no dose–response relationship. Hunger motivation, which encompassed the scores for hunger, urge to eat and thoughts of food presented as a single score, decreased (P=0.05) over the 2–4-h period in the thylakoids group compared with the control group; however, the ratings for fullness were not significantly different.

There was a concurrent increase in the plasma CCK concentrations over the 2–4-h period (P=0.05). Although plasma concentrations of insulin increased, the area under the curve for blood glucose concentrations was not significantly different between the groups. However, the blood glucose concentrations peaked at 90 and 120 min under the thylakoids condition; whereas blood glucose declined below baseline at 60 min and continued to decrease in the control group. The authors contended that the thylakoids were important for control of body weight by prevention of postprandial hypoglycemia; however, the lowest average blood glucose concentration in the control group over a 4-h period was approximately 4.8 mmol l−1. This concentration does not reflect hypoglycemia. Nevertheless, the results of the CCK evaluation confirmed previous evidence.

In a placebo-controlled study including 38 overweight and obese women, 5 g of thylakoids consumed for 3 months caused a 5-kg reduction in body weight in the thylakoid-treated group, which was significantly greater than the control group.15 At study visits on days 1 and 90, participants consumed the thylakoids or a placebo prior to a standardized breakfast meal followed by ad libitum lunch and dinner meals 6 and 11 h later, respectively. Blood was drawn before breakfast and over a 6-h period following breakfast for assessments of glucose, insulin, ghrelin and GLP-1.

There were no differences in energy intake at meal tests conducted on day 1 and day 90, or subjective measures of hunger, fullness, urge for high carbohydrate foods and urge for savory foods, measured over the 11-h period. However, there was a time by treatment interaction showing a decreased urge for sweet foods (P=0.05) and chocolate (P<0.05) over the 3-h period following lunch in the thylakoid-treated group on day 90. Additionally, the area under the curve for plasma concentrations of GLP-1 increased on day 90 (P=0.04) in the thylakoids group; but, there were no differences in ghrelin, glucose or insulin concentrations between the groups. The study demonstrates that the inconsistencies in the effects of thylakoids on glucose and insulin displayed in single meal studies may stabilize over a period of 90 days or earlier. However, the effects on the glycemic response and body weight need confirmation in future studies.

In one study, 26 overweight women were placed on an energy-restricted diet supplemented with 5.6 g thylakoids extracted from spinach leaves, for 2 months. Compared with the control group, supplementation with thylakoids reduced the urge for chocolate measured on the first and last days of the study (time and treatment interaction, P<0.05). Serum leptin levels reduced (P=0.01), but there were no differences in body weight, body fat and subjective measures of satiety, urge for high carbohydrate foods and urge for savory foods. Additionally, there were no differences between the groups in the blood glucose, insulin and lipid concentrations.104

Regardless of the type of diet, adherence to a diet regimen that promotes energy restriction is difficult for most people.105 Following menus that were prescribed to meet a 15% energy restriction may have imposed an additional burden on the subjects. Moreover, individual energy requirements were assessed using the Harris Benedict equation, which may be lacking in predictive accuracy.106, 107 Nevertheless, the inconsistent effect of thylakoids intake on body weight compared with the previous study iterates the need for long-term studies evaluating the effect of thylakoids on body weight.

A placebo-controlled crossover trial was conducted to compare the effect of 5 g of thylakoids supplementation with a placebo on satiety and reward-induced eating behavior in 32 women.108 The results showed that hunger decreased (P<0.05) under the thylakoids condition over a period of 9 h, during which subjects were provided with standard breakfast and lunch meals as well as a snack buffet. The response to the question ‘How satiated are you?’ was also greater (P<0.01) under the thylakoids condition. Treatment with thylakoids reduced wanting (P<0.05) for snack foods considered highly desirable, including salty, sweet, and sweet and fat foods; however, the validity and reliability of the questionnaires used to measure wanting must be established in future studies. There was no effect on energy intake at the ad libitum snack buffet.

In a placebo-controlled crossover trial, 60 overweight and obese individuals ate a standardized breakfast and lunch meal.109 Immediately before lunch, 5 g of thylakoids or a placebo were administered. Satiety was measured over a period of 4 h following lunch, and reward-induced behavior was assessed at 4 h. Blood was drawn before breakfast and 2 h following lunch. Energy intake was assessed at an ad libitum pizza meal served 4 h after lunch. Compared with the placebo, fullness increased (P=0.04), and hunger (P<0.01), longing for food (P<0.01), prospective intake (P=0.01) and desire for something savory (P<0.01) decreased in the thylakoid group over 2 h, but there was no difference in the desire for something sweet in these study participants. There were no effects on satiety measured over 4 h. Energy intake at the pizza meal was not significantly different between the groups; however, males in the thylakoids group reduced energy intake of the high fat/savory pizza by 527 kJ (126 kcal). The difference was not statistically significant because the study was not sufficiently powered to detect gender differences.

There was a concurrent increase in plasma glucose concentrations; but, there were no significant differences in lipid concentrations between the groups. Further, subjective measures of liking and wanting measured at 4 h were not significantly different. The method used for measuring liking and wanting has not produced results that were completely consistent in the past.110 Although manipulating the reward system has great potential, it appears that questionnaires are unable to capture the dynamic nature of the reward system, and other methods such as neuroimaging may provide more accurate results.

In human trials, the effects of thylakoids on perceptions of satiety measured using visual analog scales have been inconsistent. Three studies provided evidence of an increase in satiety103, 108, 109 and two studies showed no effect on satiety.15, 104 Two studies demonstrated a decrease in the urge for sweet foods and chocolate among women measured subjectively,15, 104 and one study found that males reduced their intake at a pizza meal.109 Males display a yearning for savory foods and females prefer high-fat sweet foods such as chocolate.111, 112 Thus, thylakoids may influence food cravings which are a form of wanting or eating behavior that prompts approach toward and consumption of a reward.113

The increase in CCK concentrations has been consistent in the human16, 103 as well as the animal studies that measured the effect of thylakoids on CCK.95, 100, 101 CCK has been shown to reduce food intake in both human and animal species; but, the inhibitory effect is generally observed relatively shortly after food ingestion and is of a brief duration.45 Thus, CCK has been shown to be effective in meal termination, which reflects satiation rather than satiety.114 In the studies that found an increase in CCK after thylakoid supplementation, the rise was 2–3 h after ingestion, which suggests a delay in fat digestion; but the effect on blood concentrations of free fatty acids has been inconsistent.15, 16, 104, 109

The increase in GLP-1 at the end of 90 days of consuming the thylakoids was accompanied by a significant weight loss. CCK may regulate the effects of other gut hormones such as ghrelin and GLP-1.53, 54 Thus, it is likely that CCK released over a period of 3 months by influencing other hormones that mediate satiety, produced a sustained effect that promoted weight loss. Thus, thylakoids appear to have the potential to provide an effective therapy for regulating appetite, particularly the reward system; however, the need for well-controlled trials to assess its effects on weight management cannot be overemphasized.

Conclusions

Humans have a strong innate drive to acquire food not only to survive the present but to sustain life during lean periods. Shaped by natural selection, human awareness and motivation produces behavioral characteristics that provide a survival advantage. Thus, humans are prone to eat beyond their energy needs and in the absence of a metabolic need to eat. Foods that appeal to the palate are in no shortage in the modern environment. These foods can activate brain reward circuitry beyond their evolved ‘survival advantage’ limits.115 Foods high in fat invoke an undeniably pleasurable sensation and excessively stimulate the brain’s reward pathways leading to overconsumption. Moreover, consumption could occur without conscious control through the activation of reward pathways outside of awareness.

The gut possesses an intricate system of lipid sensing and induction of signals to the brain that precipitate satiation, satiety and modulation of reward-induced eating behavior. The interplay between neuronal pathways acting through endocrine and neuronal feedback signals from the periphery often results in the potentiation of signals. For instance, the anorectic effects of central leptin and peripheral CCK potentiate each other.116 Thus, the manipulation of fat metabolism to promote its presence in the GI tract may be a way to counteract forces that make resistance to its appeal especially difficult.

Thylakoid membranes act on ingested fat to stimulate satiety and perhaps blunt the rewarding value of fat. Although the results need to be confirmed in future studies, it is likely that thylakoids exert a sustained effect on appetite to reduce body weight. The mechanisms by which thylakoid membranes influence eating behavior are unclear. It could be the prolonged presence of fats in the GI tract stimulating the release of peptides involved in appetite regulation, or the endogenous production of enterostatin. Well-controlled human trials that include neuroimaging assessments are needed to elucidate the precise mechanisms by which thylakoid membranes influence appetite, particularly, reward-induced eating behavior. Nevertheless, by its actions on fat, thylakoids do offer a means to strengthen the resolve to refrain from eating especially in an environment where there is superfluous access to foods processed to deliver qualities that some may find irresistible. Strategies that curtail the overriding of well-regulated adaptive behaviors cannot be overlooked.

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Acknowledgements

This work is based in part upon work that was supported by the National Institute of Food and Agriculture, US Department of Agriculture, under award number from the USDA Hatch Project LAB 94209.

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Correspondence to F L Greenway.

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Rebello, C., O'Neil, C. & Greenway, F. Gut fat signaling and appetite control with special emphasis on the effect of thylakoids from spinach on eating behavior. Int J Obes 39, 1679–1688 (2015). https://doi.org/10.1038/ijo.2015.142

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