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Montmayeur JP, le Coutre J, editors. Fat Detection: Taste, Texture, and Post Ingestive Effects. Boca Raton (FL): CRC Press/Taylor & Francis; 2010.

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Fat Detection: Taste, Texture, and Post Ingestive Effects.

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Chapter 14Fat-Rich Food Palatability and Appetite Regulation



Two views are being debated around fat-rich food and appetite regulation. One is that fat intake has a weak satiety-signaling property, with the consequence being a passive overconsumption of fat-rich food, in turn leading to obesity (Westerterp, 2006). The other view is that fat intake is tightly regulated through specific signals, which when overstimulated leads to aversion (Jebb et al., 2006). Fat intake depends not only on the quantity but more importantly on the quality of fat ingested, whether it is saturated, monounsaturated, or polyunsaturated fat (Casas-Agustench et al., 2008). Another important feature relates to whether the fat is eaten with sucrose or with something that has a sweet taste (Erlanson-Albertsson, 2005a). In general this will lead to a blunted response. Endocannabinoids released after palatable food ingestion, such as food containing fat and sucrose, will promote hunger and energy storage. The following hormones have been found to regulate the appetite for fat. Galanin (Gaysinskaya et al., 2007), agouti-related peptide (AgRP) (Tracy et al., 2007), and ghrelin (Shimbara et al., 2004) stimulate fat intake, while enterostatin (Berger et al., 2004), apolipoprotein A-IV (Apo A-IV) (Tso and Liu, 2004a), peptide YY (PYY) (Boey et al., 2008), cholecystokinin (CCK) (Beglinger and Degen, 2004), and neuropeptide Y (NPY) (Primeaux et al., 2005) inhibit fat intake. Both galanin (Schneider et al., 2007) and ghrelin (Jerlhag et al., 2007) also stimulate the intake of ethanol, via pathways involving a link to the reward system. The inhibition of fat intake occurs through reduced gastric emptying and serotonin release (Ritter, 2004). A proper satiety for fat is possible only with complete fat digestion, fatty acids being important to release satiety hormones (Feinle-Bisset et al., 2005). For proper control of fat intake, fat digestion needs to be retarded without being inhibited (Albertsson et al., 2007).

Why we overeat fat?

  • Energy dense
  • Gastrointestinal processing too rapid
  • Satiety signals too weak
  • Hunger signals too strong


Several studies indicate that fat promotes overeating. The reasons for overconsumption are the high energy density coupled with the strong positive palatability of high-fat foods (Blundell and MacDiarmid, 1997) (Figure 14.1). However, there seems to be at least two types of responses to high-fat diets. Some do become obese, whereas others with a high-fat intake stay lean. These two types have been analyzed (Blundell et al., 2005). The overeaters are characterized by a strong liking or preference for fat and a strong attraction to palatable food, the palatability hence overriding any satiety signal being released from fat (Erlanson-Albertsson, 2005b). Such a scenario suggests a weak satiety for fat. It was also demonstrated that the high-fat eaters had higher levels of a diet-induced thermogenesis as well as higher leptin levels suggesting that some individuals stay lean with high-fat due to a specific genotype (Blundell and Cooling, 1999).

FIGURE 14.1. Reasons associated with overconsumption of fat: When satiety signals are weak the consumption of calorie-dense foods such as fat is promoted.


Reasons associated with overconsumption of fat: When satiety signals are weak the consumption of calorie-dense foods such as fat is promoted. Fat digestion is known to be rapid which leads to an empty intestine triggering hunger signals.


The most important issue regarding fat intake is the quality of the fat product consumed, whether it is saturated, monounsaturated, or polyunsaturated omega-3 fat or omega-6 fat. The saturated fats and trans fats are considered “bad” while the others are known as “good” fat. One reason is that saturated fat promotes fat accumulation in the body. Thus, a diet containing saturated fat in the form of tallow and corn oil was found to be more obesogenic than polyunsaturated fat diets (Jang et al., 2003). The unsaturated fatty acids promote satiety which will help the body to establish energy balance. In one study, Lawton et al. (2000) found that polyunsaturated fat exerted a relatively stronger satiety than monounsaturated fat and saturated fat. They studied the postingestive satiety for a fixed carbon length of the fat (C18). One meal consisted mainly of oleic acid (monounsaturated fat, C18:1 w9), another of linolenic acid (polyunsaturated fat, C18:2 w6), and the third of stearic acid (saturated fat, C18:0). Subjects gained significantly more energy after consumption of the lunch containing saturated fat than after the lunches containing either mono or polyunsaturated fat; additionally, there was a trend that these effects continued in the following days (Lawton et al., 2000).


One explanation for the different satiety responses with saturated and unsaturated fat may be linked to a differential expression of appetite regulating peptides in the brain. In one study (Dziedzic et al., 2007), it was found that rats fed with saturated fat became more obese compared with rats given either omega-3 fat or omega-6 fat, both of the polyunsaturated type. The rats receiving unsaturated fat had elevated levels of the satiety hormone pro-opiomelanocortin (POMC), whereas it was unchanged in the animals receiving saturated fat (Dziedzic et al., 2007). Such a difference in expression could explain the hyperphagia observed with the saturated fat. Furthermore the omega-3 fat caused a specific decrease in the expression of the hunger hormone melanin concentrating hormone (MCH), whereas there was no change in the other diet regimens. This suggests that there is a difference in appetite-regulating signals between the omega-3 fat and the omega-6 fat, omega-3 fat being more satiating (Dziedzic et al., 2007).


The secretion of satiety hormones in the intestine relating to the type of fat ingested may also be of importance. French et al. (2000) found that the satiety hormone CCK was released by infusion of fat into the intestine and that the degree of CCK released was related to the type of fat being infused. Intralipid, which is an emulsion of soybean oil (containing predominantly C18:2 fatty acids) with egg phospholipids, released the largest amount of CCK, whereas oleic acid, stearic acid, and linoleic acid gave a similar CCK response. All responses were significantly greater than the control. However, there was no direct relationship between CCK release and satiety, suggesting that other fat-specific peptides such as Apo A-IV or enterostatin might be involved. More importantly, Intralipid was the most satiating lipid, followed by linoleic acid, whereas stearic and oleic acid had no significant effect on satiety or food intake. It is thus clear that the satiety potency of fat is related to the small intestine area where receptors were exposed to fat. It is also clear that fatty acids, as opposed to triglycerides, are the critical stimuli for satiety response.


Trans-fatty acids in the diet have been examined in pregnant rats as well as in their offspring (Albuquerque et al., 2006). It was found that during pregnancy, rats receiving trans fat had lower levels of eicosapentanoic acid as well as insulin receptor and insulin receptor substrate 1. Among the offspring, it was seen that control animals responded to insulin given to induce hypophagia but not the offspring of trans fat-fed mothers, even though they were now given a control diet. The data suggest that early exposure to hydrogenated fat rich in trans-fatty acids programs the hypothalamic feeding centre in such a way that insulin-induced satiety mechanisms are lost. Furthermore, it suggests that the type of fat eaten is relevant not only to the current satiety state but will also affect fetal satiety programming during pregnancy (Albuquerque et al., 2006).

The effect of different types of fat on single meal experiments could not be observed in a study involving overweight young men (Flint et al., 2003). After an overnight fast, these men were served a breakfast, with 60% of its energy coming from fat that varied only in the source of C18 fatty acids. Energy expenditure, subjective satiety, and hunger were continuously measured for 5 h after feeding. There was no statistically significant effect using monounsaturated, trans fat or polyunsaturated fat on energy expenditure or on appetite ratings. It may be that overweight subjects have a blunted response to dietary fat, regarding both satiety and energy expenditure. Another explanation may be that the feeding protocol needs to be of a longer duration.


Another reason that high-fat diet promotes obesity in some individuals but not in others could be the role of endocannabinoids (Osei-Hyiaman et al., 2005). Endocannabinoids are released by high-fat feeding; their subsequent interaction with the hepatic endocannabinoid receptor CB1 increases the gene expression of the lipogenic transcription factor sterol regulatory element binding protein isoform 1c (SREBP-1c), which in turn activates lipogenic enzymes like acetyl-CoA-carboxylase-1 as well as fatty acid synthase (FAS). This could explain why high-fat feeding induces obesity. Such a hypothesis is supported by the failure of CB1-knockout mice to develop obesity following high-fat feeding as well as the reduced body weight gain observed after blockage of the CB1-receptor (Osei-Hyiaman et al., 2005). The endocannabinoids not only have a peripheral action in the liver, but also act centrally in the hypothalamus where FAS present in hypothalamic neurons was found to be activated by endocannabinoids. FAS is an important regulator of appetite as shown by studies using C75, an inhibitor of this enzyme which was found to curb the appetite (Loftus et al., 2000). Furthermore, C75 inhibited the expression of the hunger signal NPY in the hypothalamus, at the same time targeting malonyl-coenzyme A. Hence, fatty acid synthesis appears to be tightly linked to overeating and obesity, since inhibition of fatty acid synthesis in the hypothalamus inhibits feeding and promotes weight loss.


Since endocannabinoids play an important role in the promotion of obesity in animal models, is there reason to believe that they will have the same role in humans? In a study where normal weight subjects were compared to obese subjects, it was found that the obese subjects had elevated levels of the endocannabinoids anandamide and 2-arachidonoylglycerol, which were elevated by 35% and 52%, respectively compared to lean subjects (Engeli et al., 2005). Besides the brain, the CB1 receptor is highly expressed in the stomach as well as in the adipose tissue. In obese subjects, CB1 receptor gene expression is decreased, suggesting that the body is trying to reestablish energy balance through a negative feedback loop. Since there was no change in endocannabinoid levels or in receptor expression following a 5% weight loss in the obese subjects, it was suggested that the endocannabinoids and their receptor system might be a cause of obesity rather than a consequence (Engeli et al., 2005).

There is thus a strong coupling between highly palatable food, such as high-fat food and the promotion of obesity.


Opioids are part of a group of hormones or neurotransmitters promoting high-fat feeding (Welch et al., 1996). They act both in experimental animal models as well as in humans. There is a clear interaction between the host and its diet. Osborne–Mendel rats are known to become obese on high-fat diet, whereas S5B/P1 rats prefer a low-fat diet and are resistant to high-fat diet-induced obesity (Ookuma et al., 1998). In experiments in which Osborne–Mendel rats had a two-choice paradigm between high-fat diet and low-fat diet, it was found that high-fat intake was suppressed by norbinaltorhimine, a kappa-opioid-antagonist, whereas low-fat intake was not affected (Ookuma et al., 1998). This suggests that opioids and opioid receptors are involved in the regulation of fat intake. It was also found that S5B/P1 rats were unaffected by norbinaltorphimine which had no effect on low- or high-fat food intake (Ookuma et al., 1998). Additionally, this study showed that an infusion of U50488, a selective kappa-agonist, into the third cerebroventricle in sated rats, potently stimulated the intake of a high-fat diet in Osborne–Mendel rats but not in S5B/P1-rats. It was concluded that the enhanced preference and consumption of the high-fat diet by the Osborne–Mendel rats is due to an activated or sensitive opioid receptor system specific for kappa-opioids (Ookuma et al., 1998).

Subsequently, Zhang and Kelley showed that high-fat food intake is stimulated not only by kappa-opioids but also by mu-opioid receptor agonists like the enkephalin analogue DAMGO [D-Ala(2), NMe-Phe(4), Gly-ol(5)]-enkephalin acting on the nucleus accumbens (Zhang and Kelley, 2000). A mapping study based on c-fos activation was performed to identify brain regions that were important for the appetite promoting effect of palatable food. In addition to the nucleus accumbens, the lateral and ventral regions of the striatum were found to be activated (Zhang and Kelley, 2000).

Similar results were obtained by Barnes et al. (2003), who fed male Wistar rats either a high-fat diet or a low-fat diet for 12 weeks. At the end of the feeding regimen, the high-fat fed animals were found to have increased body fat, plasma leptin, and plasma insulin levels. Immunohistochemistry and in situ hybridization studies of their brains demonstrated that the high-fat fed rats had increased hypothalamic levels of mu-opioid receptors compared to controls, hence supporting the importance of the mu-opioid system in mediating high-fat diet-induced overeating and body weight gain. The increased mu-opioid receptor expression could also contribute to the higher mean arterial pressure and renal sympathetic nerve activity observed in these animals (Barnes et al., 2003).


Following high-fat intake, diet-induced thermogenesis including the increased expression of uncoupling proteins acts as a defense mechanism against weight gain (Erlanson-Albertsson, 2002). The increased heat produced by uncoupling proteins not only helps increase energy expenditure but also promotes satiety, thereby establishing energy balance. Diet regimens with pure fat, the so-called ketogenic diets, have been introduced and demonstrated to cause rapid weight loss. One reason for this is the difficulty these patients demonstrate to overeat pure fat without any carbohydrates. The long-term effects of high-fat diets are similar to the low-fat diets in regard to weight loss and metabolic parameters. Sucrose in a mixture with fat is reported to weaken the satiety signals for fat.


Several peptides are specifically active in the regulation of fat intake. Galanin, ghrelin, and AgRP have been demonstrated to stimulate fat intake (Figure 14.2), whereas enterostatin, Apo A-IV, CCK, PYY, and NPY have been shown to inhibit fat intake (Figure 14.3). Below is a description of the peptides and their properties specific to the regulation of fat intake.

FIGURE 14.2. Hunger signals for fat.


Hunger signals for fat. Ghrelin is the only signal produced in the periphery; AgRP and Galanin are produced in the brain, where the hunger mechanism is acting. It may be that the centrally produced ghrelin stimulates fat intake. Both ghrelin and galanin (more...)

FIGURE 14.3. The satiety signals for fat are mostly situated in the periphery, except for NPY, which is produced in the hypothalamus.


The satiety signals for fat are mostly situated in the periphery, except for NPY, which is produced in the hypothalamus. CCK and enterostatin are early satiety signals, whereas PYY is a late satiety signal released upon arrival of fat in the ileum and (more...)

14.11.1. Galanin

Galanin is a 30 amino acid peptide that has been found to regulate ingestive behavior. Galanin has been described to stimulate fat intake after central administration into the paraventricular nucleus (PVN) of the hypothalamus in rats (Leibowitz, 1994). High-fat diets cause a rapid upregulation of galanin expression in the PVN, suggesting a feed-forward process. It has also been found that the injection of Intralipid into the peritoneum, which causes an increased level of triglycerides, also leads to increased expression of galanin in the PVN (Wortley et al., 2003). This suggests that the postprandial fat by-products induce continued dietary fat intake. The food intake promoting effect of galanin was blocked by the nonselective galanin receptor antagonist M40 (Bartfai et al., 1993).

However, the capacity of galanin to stimulate fat intake has been questioned with arguments emphasizing the possibility that its specificity may be dependent on the endogenous preference of the animal species (Smith et al., 1997).

Central galanin also has anabolic effects, shifting energy utilization from fat to carbohydrates, thereby stimulating the deposition of fat in adipocytes (Yun et al., 2005). In rodents, an increased fat mass was observed with chronic administration of galanin (Gaysinskaya et al., 2007). Galanin decreases energy expenditure and the sympathetic drive to brown adipose tissue (Nagase et al., 1997), which may be one mechanism promoting energy storage. Physiological Role of Galanin in the Regulation of Fat Intake

The physiological role of galanin in the regulation of fat intake has been investigated with the use of various galanin receptor antagonists. Such studies have demonstrated contradictory results, from no effect to a decrease in spontaneous fat intake (Bartfai et al., 1993; Leibowitz, 1994). There are three G-protein–coupled receptors for galanin. In one study, galanin receptor 1 −/− mice were used (Zorrilla et al., 2007); this study demonstrated that the food intake was the same as in control mice. However, the galanin receptor −/− mice lost their ability to adapt to a high-fat diet while the normal mice decreased their food intake. The results are somewhat the opposite of what should be expected, since the galanin receptor knockout mice had a larger consumption of a high-fat diet than the control animals. Moreover, the galanin receptor knockout mice demonstrated an impaired glucose tolerance, suggesting a maladaptation to palatable food. Galanin Expression Is Stimulated by High-Fat Feeding

The increased feeding with a high-fat diet may be explained by an activation of the opioid system triggered by orexigenic peptides like galanin. Gaysinskaya et al. (2007) have found that galanin in the PVN and orexin in the perifornical lateral hypothalamus were increasingly expressed when a high-fat diet was given as a preload to induce overeating. The overeating following the preload of high-fat food was accompanied by elevated circulating triglyceride levels while there was no change in leptin or insulin levels during these short-term experiments. These experiments suggest that high-fat feeding-induced overconsumption occurs rapidly and this is due to an increased expression of orexigenic hormones in the hypothalamus and/or elevated levels of blood lipids rather than changes in leptin and/or insulin levels (Leibowitz et al., 2004). It is as if overfeeding stimulates its own progress. Galanin Stimulates Alcohol Intake

Galanin not only stimulates fat intake but has also been found to stimulate the intake of ethanol. In rats training to drink ethanol, injection of galanin into the PVN increased the intake of ethanol over the next few hours, without affecting consumption of water or food (Schneider et al., 2007). Injection of M40, a galanin antagonist, or of the nonselective opioid receptor antagonist, naloxone methiodide, prevented the intake of ethanol indicating the importance of the galanin signaling pathway and its link to the opioid system in terms of ethanol ingestion. Galanin is thus a mediator of reward, bridging nutrients like fat with rewarding food like ethanol. A similar finding is observed with ghrelin, which also stimulates fat as well as ethanol consumption after central injection in experimental animal models. Transgenic mice overexpressing galanin in noradrenergic neurons showed decreased morphine withdrawal signs, indicating that galanin helps against withdrawal symptoms (Zachariou et al., 2003). In short, galanin has the ability to stimulate fat intake and promote energy storage as well as drive reward.

14.11.2. Agouti-Related Peptide

AgRP is a peptide signaling hunger synthesized in the arcuate nucleus with the property of a hunger signal. AgRP is an endogenous melanocortin receptor antagonist coexpressed with NPY in the arcuate nucleus; both peptides display orexigenic effects (Broberger et al., 1998). Transgenic mice overexpressing AgRP are obese and hyperphagic (Graham et al., 1997). Further evidence supporting AgRP as a physiological hunger signal came from the observation that its expression both at the mRNA and protein level is increased in the hypothalamus following fasting (Hahn et al., 1998; Li et al., 2000). AgRP is colocalized with NPY, (Hahn et al., 1998) and there are several common physiological links between the two peptides. The neurons producing the peptides contain receptors for leptin, which regulate the expression of NPY and AgRP. Since NPY has been suggested as a hunger signal for carbohydrate intake (Wang et al., 1998), the question of whether AgRP would be a hunger signal for fat intake arose. AgRP and Fat Intake

Several lines of evidence support AgRP as a hunger signal specifically stimulating fat intake. In a two-choice paradigm between high-fat and low-fat food, AgRP was found to significantly stimulate high-fat (41 energy percent) food intake during the 4 h following an injection into the third ventricle, whereas low-fat (11 energy percent) food intake was not affected (Hagan et al., 2001). The fact that such a preference for fat also occurs in animals with chronic overexpression of Agouti-protein is supported by the finding that the agouti mice (Ay/a), when given a three-choice diet between fat, protein, and carbohydrates, chose to eat fat, thus inducing a significant weight gain (Koegler et al., 1999). The increased fat preference was immediate and persisted throughout the 7-week long experiment. Agouti-protein interacts with the same receptor as AgRP, the melanocortin receptors 3 and 4. Further support for a specific ability of AgRP to regulate fat intake is the finding that enterostatin, a peptide that inhibits fat intake was found to decrease the expression of AgRP (Lin et al., 2007). Hence, fat intake appears to be regulated through a melanocortin pathway. Mechanism of Increased Fat Intake by AgRP

AgRP interacts with the melanocortin receptors 3 and 4. In an experiment during which MTII, a melanocortin receptor antagonist, was administered (Samama et al., 2003), it was found that rats receiving a three-choice macronutrient of protein-fat-carbohydrate diet decreased their fat intake. The suppression of fat intake did not occur in MC4 (−/−) mice, suggesting that fat intake was regulated through the melanocortin pathway.

The way in which AgRP stimulates fat intake could be related to preingestive factors such as taste and palatability or postingestive factors such as the release of certain gut peptides or even a rapid digestion. In further experiments, it was found that AgRP increased the appetite response of fat, suggesting that the AgRP pathway is important for the anticipation of fat consumption (Tracy et al., 2007). Such an anticipatory response was not observed with sucrose, indicating that AgRP is not a general factor regulating the intake of palatable food, but is specific to fat.

Since high-fat intake has been found to be mediated through activation of opioid pathways, the involvement of opioid receptors in the regulation of fat intake by AgRP was investigated (Hagan et al., 2001). It was found that naloxone when injected intraperitoneally significantly reduced high-fat food intake that had been stimulated with AgRP over 4 h, whereas there was no response with the low-fat food. These experiments thus suggest that fat intake is stimulated by AgRP and that the mechanism occurs through the activation of an opioidergic pathway. The exact site for the interaction of AgRP with opioid receptors is not known. Such a circuit might be important in mediating overeating and obesity that occurs in humans following exposure to high-fat diets. Physiological Implications of AgRP in Obesity

In Western societies, high-fat foods are readily available and the passive consumption of high-fat diets due to their low satiety has been claimed to be one important factor in the ongoing epidemic of overweight and obesity. AgRP has also been associated with high body fat in humans (Argyropoulos et al., 2003). Diets aimed at losing weight are often not working; rather the original body weight and sometimes even a higher body weight is regained in a short time at the end of the dieting period. This process is known as yo-yo dieting. Since AgRP has an increased expression following fasting or restriction of energy intake, one could imagine it to be a signal promoting overeating of high-fat food. It is thus important to find strategies to block this upregulation of AgRP following fasting. AgRP-Deficiency Increases Life Span

AgRP is increased by fasting and when overexpressed in transgenic mice, it leads to hyperphagia and the development of obesity (Redmann and Argyropoulos, 2006). Global AgRP knockout mice, on the other hand, display a relative minor phenotype of age-dependent leanness or no phenotype at all. Redmann and Argyropoulos (2006) found that female −/− mice were lean while consuming a low-fat diet but identical to wild-type animals when fed a high-fat diet. Male −/− mice were heavier on a low-fat diet while similar to control mice on a high-fat diet. Unexpectedly, AgRP deficient mice, both females and males, had a lifespan 10% longer (Redmann and Argyropoulos, 2006). This tells us that fat intake may be an important factor in shortening lifespan. Experiments aimed at identifying bioactive compounds that will suppress AgRP expression have produced candidates that may assist in regulating fat intake and perhaps increase lifespan.

14.11.3. Ghrelin

Ghrelin is a peptide produced in the stomach (Ariyasu et al., 2001), and was discovered as an endogenous ligand of the growth hormone receptor (Kojima et al., 1999). Ghrelin has been described as a hunger signal, stimulating food intake when administered to rodents or humans (Wren et al., 2001). Ghrelin secretion is increased during fasting and suppressed after the start of food intake. Conditions that promote a negative energy balance like starvation, insulin-induced hypoglycemia, and anorexia nervosa as well as physical activity cause an upregulation of ghrelin secretion (Cummings et al., 2004). Conditions that induce a positive energy balance such as overeating, obesity, and hyperglycemia induce a suppression of ghrelin levels (Tschop et al., 2000; Lindqvist et al., 2005; Cummings, 2006). Ghrelin Is Downregulated after Fat and Carbohydrate Intake

Macronutrients differ in their ability to suppress ghrelin secretion after the start of a meal. Fat or carbohydrate containing meals suppress ghrelin secretion (Nakagawa et al., 2002) whereas proteins are ineffective (Beck et al., 2002). This is surprising considering that proteins are the most satiating macronutrients (Erdmann et al., 2003). Fat’s ability to reduce ghrelin levels occurs only after fat digestion suggesting that fatty acids are an important signal suppressing ghrelin secretion. The addition of tetrahydrolipstatin, an inhibitor of gastric lipases, leads to a marginal decrease of ghrelin level (Feinle-Bisset et al., 2005) suggesting that fatty acids released in the gastro-intestinal tract play an important role in this process (Feltrin et al., 2006). The exact mechanism underlying the suppression of ghrelin secretion following fat consumption is not known yet. It has been reported that PYY, a peptide that inhibits fat intake is secreted 15 min after infusion of lipids into the stomach. Thus, PYY is a likely candidate for ghrelin suppression (Batterham et al., 2003). Central Ghrelin Enhances Fat Intake

Most studies on ghrelin have used single-choice diet paradigms. In a two-choice paradigm between high-fat and high-carbohydrate diets, ghrelin, when given centrally, was found to specifically enhance fat intake in rats (Shimbara et al., 2004). This effect was observed 1 h after ghrelin injection and reached maximal effect 2 h after injection. The enhancement of fat intake was in the same order as that of galanin (Shimbara et al., 2004).

Since fat intake was stimulated after central administration of ghrelin, it is suggested that centrally produced ghrelin, i.e., the ghrelin produced in the arcuate nucleus (Lee et al., 2002) regulates fat intake. In animals and humans, the appetite for fat is at its peak at the end of the feeding period, thus suggesting that ghrelin is released during that period. In studies where rats were given sucrose, ghrelin levels continued to rise (Lindqvist et al., 2005) suggesting that ghrelin signals the need for energy in the form of fat rather than carbohydrate. Further studies are needed to understand the regulation of fat intake by ghrelin. Ghrelin Promotes Addiction

It has been demonstrated that in the case of ghrelin, there is a neurochemical overlap between the reward system and the appetite regulating system. Intracerebroventricular administration of ghrelin was found to stimulate the intake of ethanol (Jerlhag et al., 2006) through a mechanism linked with increased dopamine secretion from the nucleus accumbens as well as increased locomotor activity (Jerlhag et al., 2006) in the same way as would occur after ethanol consumption (Jerlhag et al., 2007). Furthermore, ghrelin was found to activate a cholinergic-dopaminergic reward link much as ethanol does. A role ghrelin has on brain rewards could be to increase the incentive values of motivated behavior, e.g., food searching. Alcoholics were also found to have higher levels of ghrelin in their circulation. Ghrelin thus has a role in brain reward in addition to regulating energy balance.

14.11.4. Enterostatin

The first discovery of enterostatin as a feeding-related peptide was in 1988 when during immunization of rabbits with enterostatin the animals lost their appetite. In systematic studies in rat, we found that enterostatin decreased food intake after intraperitoneal administration (Erlanson-Albertsson and Larsson, 1988). Enterostatin is a pentapeptide released from the N-terminal end of pancreatic procolipase by proteolytic cleavage (Figure 14.4). The residual product called pancreatic colipase is a protein cofactor for pancreatic lipase during intraduodenal hydrolysis of fat (Erlanson-Albertsson, 1992). Since enterostatin and colipase are released more specifically during the intake of fat, experiments were performed to elucidate whether enterostatin had any specific effect on fat intake. In studies during which food was given either as a three-choice diet between fat, protein, and carbohydrate (Okada et al., 1991) or as a two-choice paradigm with high-fat and low-fat diets (Erlanson-Albertsson et al., 1991), it was found that enterostatin inhibited fat intake as opposed to carbohydrate or protein intake. Furthermore, it inhibited high-fat intake as opposed to low-fat intake. The effect was observed after both central administration and peripheral administration of enterostatin.

FIGURE 14.4. Enterostatin is formed by the proteolytic cleavage of procolipase.


Enterostatin is formed by the proteolytic cleavage of procolipase. Procolipase is found in the stomach, pancreas, the intestine as well as in the hypothalamus. The receptor for enterostatin is the beta-subunit of the F1-ATPase. The receptor protein is (more...) Occurrence of Enterostatin

Not surprisingly enterostatin was found to be present in the intestinal contents of rats and humans (Mei et al., 1993; Erlanson-Albertsson and York, 1997). Enterostatin was found to be present at micromolar levels in rats and increased two- to threefold following consumption of a high-fat diet (Mei et al., 1993). This occurred as soon as 24 h after the switch to a high-fat diet, indicating a rather rapid and robust adaptation of procolipase and enterostatin to high-fat feeding. In the gastro-intestinal tract, enterostatin was also found to be present in the gastric mucosa, secreted by chief cells. Cloning of gastric procolipase revealed that this molecule is identical to the pancreatic procolipase (Winzell et al., 1998).

Enterostatin has also since been identified in the brain in the form of procolipase (York et al., 2006; Rippe et al., 2007). Procolipase and enterostatin immunoreactivity was demonstrated in PVN, ARC, supraoptic nuclei, amygdala, and dorsal median thalamus (York et al., 2006). These regions are associated with the regulation of food intake and energy expenditure. Procolipase was seen as dense particles in the cytoplasm, whereas enterostatin immune reactivity was observed in nerve fibers. This suggests that procolipase is produced and processed in the neuronal cell body, whereas enterostatin is transported down the nerve fiber to be released at the nerve terminal (York et al., 2006). Since enterostatin is particularly active when injected into the amygdala, the endogenous production of enterostatin in this nucleus suggests that this might be important for regulation of fat intake. Enterostatin was also present in cells lining the third ventricle, where it could be secreted into the cerebrospinal fluid, as confirmed by Imamura et al. (1998). Thus the procolipase gene is expressed in the brain, translated to protein, and cleaved to release enterostatin.

In further studies, the hypothalamic procolipase was found to be upregulated by a high-fat diet in a similar fashion as the pancreatic procolipase (Rippe et al., 2007). Since diets rich in fat are energy-dense, the upregulation of hypothalamic procolipase seems to be an adequate event to induce satiety and energy balance. Other palatable food like mono- and disaccharides (glucose, fructose, and sucrose) had no significant effect on the expression of hypothalamic procolipase, indicating that the procolipase expression was unresponsive to sugars. Fasting overnight caused a threefold downregulation of hypothalamic procolipase, which is in agreement with the activity of a satiating agent. There was no expression of classical lipase in the hypothalamus, supporting a role of procolipase in the hypothalamus in the production of enterostatin (Rippe et al., 2007).

The presence of enterostatin and its precursor procolipase in the pancreas, the stomach, and the central nervous system is another example of a peptide regulating food intake present both in the gut and in the brain, much like CCK, ghrelin, and galanin. Mechanism of Action of Enterostatin

Enterostatin acts through both direct and indirect pathways. The direct pathway involves the interaction of enterostatin with its receptor, the β subunit of F1-ATPase (Berger et al., 2002; Park et al., 2004) while the indirect pathways involve serotonin, CCK, and melanocortin. The β-Subunit of F1-ATPase as a Receptor for Enterostatin

Using purified rat membranes, Berger et al. (2002) were able to demonstrate specific binding of enterostatin to a 60 kDa protein, which was sequenced through MALDITOF analysis and found to be β-subunit of F1-ATPase. The identification of the β-subunit of F1-ATPase as a receptor for enterostatin was confirmed by Park et al. (2004) (Figure 14.4) who established the binding constant to be 1.7 × 10−7 M using surface plasmon resonance technique. Using an aqueous two-phase system, the binding between enterostatin and its receptor was found to be equal to 1.5 × 10−7 M (Berger et al., 2004). There was no binding using the whole multimeric protein (Park et al., 2004). Strikingly, Park et al. (2004) reported the presence of the β-subunit of F1-ATPase in the plasma membranes of liver cells as well as in amygdala (Park et al., 2004). Lindqvist et al. (2008) later reported the presence of β-subunit of F1-ATPase in the plasma membrane of INS-1 cells which were used originally to demonstrate the enterostatin effect and the activation of the receptor (Berger et al., 2002). It was also found that incubation of the INS-1 cells with enterostatin caused a threefold upregulation of the expression of the β-subunit of F1-ATPase on the plasma membrane (Lindqvist et al., 2008). Likewise, fatty acids were found to stimulate the translocation of F1-ATPase to the plasma membrane (Lindqvist et al., 2008). The fact that fat upregulates the receptor for enterostatin may explain the need to feed animals high-fat diets before they respond to enterostatin (Lin and York, 1998). Indirect Pathways Mediating Enterostatin’s Action

In the amygdala, enterostatin functions with a serotonin receptor to reduce fat intake (Lin and York, 2004). With a 5HT1b receptor antagonist, the response of enterostatin was abolished. Since enterostatin does not interact directly with a serotonin receptor, the mechanism of action could involve the ability of enterostatin to release serotonin (Koizumi and Kimura, 2002). Serotonin has been described as a signal specifically related to satiety for fat, which seems to be a likely mechanism to promote satiety.

Another component that is important for the enterostatin response is the presence of CCK A receptors (Lin et al., 2003). This is based on studies using the OLEFTA rat which lacks CCK A receptors that were found to be unresponsive to enterostatin.

The third pathway for enterostatin is the melanocortin pathway. In this pathway enterostatin is able to decrease the expression of AgRP in the amygdala and in the hypothalamus (Lin et al., 2007). Since AgRP stimulates fat intake, this inhibition could explain a decreased fat intake by enterostatin. At the same time, enterostatin caused an increased expression of the satiety hormone POMC (Lin et al., 2007). Since enterostatin does not interact with the melanocortin receptor, it is suggested that enterostatin causes the release of melanocyte-stimulating hormone (MSH), a satiety hormone, in the PVN. The involvement of the melanocortin receptor pathway is supported by the fact that enterostatin failed to show any feeding inhibitory effect in MC4R knockout mice. Moreover, an antagonist to the MC4 receptor blocked the effect of enterostatin on the inhibition of fat intake (Lin et al., 2007). Intracellular Mechanisms Mediating Enterostatin’s Effect

Intracellular enterostatin has been found to activate different pathways depending on cell type and intracellular events. Regarding the stimulation of fatty acid oxidation in myocytes, enterostatin was demonstrated to act through phosphorylated AMP kinase (Lin et al., 2006). Enterostatin was found to act through cAMP with regard to the regulation of insulin secretion whereas the regulation of AgRP expression seems to be under the control of the cAMP as well as the MAP kinase ERK pathway (Park et al., 2008).

In further studies aimed at understanding enterostatin’s mechanism of action, the human hepatoma cell line (HepG2 cells) was used and subjected to glucose deprivation to induce angiogenesis (Park et al., 2008). In this situation, enterostatin was found to inhibit angiogenesis (Park et al., 2008). Phosphyrolated AMP kinase (pAMPK) and vascular endothelial growth factor A (VEGP-A) mRNA were significantly elevated by glucose deprivation, but this activation was inhibited by the presence of enterostatin (Park et al., 2008). These data suggest that enterostatin has an antiangiogenic effect occurring through inhibition of the AMPK activity (Park et al., 2008). The inhibition of angiogenesis by enterostatin also occurred in adipocytes (Park et al., 2008). The blocking effect may be important to induce weight loss. In the ob/ob mouse, the loss of body fat was associated with decreased food intake and increased fatty acid oxidation (Rupnick et al., 2002). In human obesity, a number of angiogenic factors are increased including VEGF (Silha et al., 2005). It is therefore possible that the antiangiogenic effect of enterostatin may contribute to the loss of body weight and body fat during chronic administration of enterostatin. Enterostatin Stimulates Energy Expenditure

Enterostatin is an example of a peptide that regulates both feeding and energy expenditure. Chronic injection of enterostatin either intracerebrovascularly (ICV) or peripherally caused a greater weight loss than could be accounted for by the reduction of food intake (Lin et al., 1997; Berger et al., 2002). Additionally, enterostatin was found to enhance sympathetic activation of brown adipose tissue (Nagase et al., 1997). Enterostatin was also found to enhance the expression of uncoupling protein 1 expression in brown adipose tissue in mice fed a high-fat diet, leading to increased heat production (Rippe et al., 2000). The increased energy expenditure served to achieve energy balance during high-fat feeding.

In INS-1 cells enterostatin was found to increase heat production as well as oxygen consumption (Berger et al., 2002), an effect believed to occur through an interaction with the β-subunit of F1-ATPase. Enterostatin was also found to activate AMP-activated kinase and beta-oxidation of fatty acids (Lin et al., 2006). AMPK is now recognized to have a central role in regulating energy balance between anabolic and catabolic pathways (Ruderman and Prentki, 2004). AMP-kinase’s activation leads to increased fatty acid oxidation and glucose transport in muscle as well as decreased fatty acid synthesis and gluconeogenesis. Phosphorylation and subsequent activation of AMPK by enterostatin has been linked to increased energy expenditure in myocytes (Lin et al., 2006).

Enterostatin’s stimulation of energy expenditure could occur through a central or a peripheral pathway. The amygdala is believed to be the site of action of enterostatin when inhibiting fat intake, whereas the PVN could be the site of action linked to the stimulation of energy expenditure. Enterostatin as an Endogenous Regulator of Fat Intake

The question of whether enterostatin is an endogenous regulator of fat intake is answered by the fact that the receptor antagonist beta-casomorphin has the ability to increase fat intake (Lin et al., 1998; Berger et al., 2002). There are also studies demonstrating an increased food intake after intracerebroventricular administration of enterostatin antibodies (Unpublished, York, 2007). Voluntary fat intake in rodents was demonstrated to be inversely related to the amount of procolipase/enterostatin (Okada et al., 1992) suggesting that endogenous enterostatin regulates fat intake.

14.11.5. Apolipoprotein A-IV

Apo A-IV is a small protein with a molecular weight of 43 kDa. It is synthesized in both the liver and the intestine. In the intestine Apo A-IV is synthesized by epithelial cells found mostly in the jejunum in the upper portion of the villi (not in the crypts). The intestinal Apo A-IV is stimulated by lipid feeding (Fukagawa et al., 1994) and is released into the circulation. The release of Apo A-IV occurs during the process of assembly and transport of intestinal chylomicrons. Inhibition of chylomicron formation totally abolishes Apo AI-V secretion (Hayashi et al., 1990). Apo A-IV is secreted only upon feeding with fat containing long-chain fatty acids (>C14), since these are taken up into chylomicrons (Kalogeris et al., 1996).

Intravenous infusion of Apo A-IV has been found to decrease food intake in rats in a dose-dependent way (Fujimoto et al., 1992). This suggested that Apo A-IV is a circulating satiety signal released by the small intestine in response to fat ingestion. The mechanism of inhibition of Apo A-IV on feeding has been suggested to occur at a central level. Central infusion of Apo A-IV was 50 times more potent than peripheral administration (Fujimoto et al., 1993). Apo A-IV was also detected by RT-PCR in the arcuate nucleus of the hypothalamus (Liu et al., 2001). A specific effect of Apo A-IV may be to inhibit the onset of feeding, rather than promote the end of feeding. Regulation of Apo A-IV Synthesis

In the intestine, the level of Apo A-IV is increased with accrued consumption of fat. In the hypothalamus, the level of Apo A-IV was found to decrease upon fasting, whereas it was increased upon lipid feeding as could be expected for a satiety factor responsible for fat intake (Liu et al., 2001; Tso et al., 2004). Thus, the regulation of Apo A-IV in the intestine and in the brain follows the same pattern.

Somewhat surprisingly, central infusions of NPY increased the expression of Apo A-IV (Liu et al., 2003). One possible explanation for this phenomenon could be that since NPY relieves anxiety by increasing food intake and fat is in itself anxiety relieving, preventing fat intake with Apo A-IV would not alter NPY’s anxiety relieving effect.

The synthesis of Apo A-IV was reported to be downregulated by leptin (Doi et al., 2001). Leptin is a peptide that is synthesized and secreted by the adipocyte. Plasma leptin levels are elevated when animals are maintained on a high-fat diet (Frederich et al., 1995). It could be speculated that obesity, a condition with high leptin levels, is self-filling, because several hunger hormones are promoted, like galanin and NPY, whereas some satiety signals are suppressed or made inefficient. In this context, Apo A-IV would fit in the pattern of a candidate hormone promoting obesity by being downregulated by leptin.

In conclusion, Apo A-IV is a peptide that is released into the circulation following uptake of lipids from the intestine. The exact role of Apo A-IV in the regulation of fat intake is not known, and so are the target protein and receptor for Apo A-IV.

14.11.6. Peptide YY

“Ileal break” is a phenomenon described as an inhibition of food intake through infusion of nutrients into the ileum. Various peptides produced in the distal ileum have been proposed to mediate this effect. However, the most likely candidate is PYY (Pappas et al., 1986), which causes an inhibition of intestinal motility (Savage et al., 1987). The “ileal break” phenomenon was formerly considered operative only during malabsorption states when undigested nutrients reach the distal gut. However, it is now recognized that nutrients reach the distal gut even under normal conditions (i.e., when gastric emptying occurs rapidly). It has been documented that 10%–15% of a given amount of lipid reaching the upper small intestine is recovered in the distal ileum (Tso and Liu, 2004b).

PYY is synthesized by endocrine cells located in the ileum and colon (Adrian et al., 1987) and released by nutrients such as long-chain fatty acids. In the presence of tetrahydrolipstatin, an irreversible blocker of pancreatic lipase the release of PYY is completely abolished (Feinle-Bisset et al., 2005). The use of PYY is being tested as a drug to reduce fat intake.

14.11.7. Cholecystokinin

It is well established that CCK functions as a satiety signal (Ritter, 2004; Woods, 2004). CCK is released from enteroendocrine cells in the presence of lipids and proteins (Sayegh and Ritter, 2003). Proteins are stronger releasers of CCK than amino acids. In contrast, fatty acids, especially long-chain fatty acids, are better at releasing CCK than triacylglycerol (Lieverse et al., 1994; Ledeboer et al., 1998). CCK works by activating a specific receptor, the CCK1 receptor (or CCKA receptor), present on vagal afferents innervating the intestinal mucosa (Moran et al., 1997). The vagal afferent fibers project to the nucleus of the solitary tract and are involved in feeding termination. CCK inhibits food intake, both in rodents and in humans (Lieverse et al., 1994). Administration of devacepide, a CCK receptor antagonist, was reported to increase food intake (Reidelberger and O’Rourke, 1989). The CCK1 receptor −/− mice had, however, the same body weight as normal mice, although their eating pattern was different (Bi et al., 2004).

The CCK1 receptor seems to be responsible for the size and duration of a meal, especially during a high-fat meal (Lo et al., 2007). When given a high-fat diet, CCK1-receptor −/− mice were unable to decrease meal size and therefore adapt their feeding, whereas wild-type mice were able to (Whited et al., 2006). The normal mice decreased their meal size when receiving high-fat food, whereas the −/− mice continued to eat the same meal size as with the low-fat diet. Thus, the CCK1 receptor plays an important role in the adaptation of meal size when fed energy-dense meals (Savastano and Covasa, 2007). Mechanisms underlying this effect involve activation of the 5-HT3 receptor at the central level (Savastano and Covasa, 2007) as well as inhibition of gastric emptying, a feature important for satiety (Reidelberger et al., 2001). Donovan et al. (2007) found that the CCK effect was most pronounced for the actual meal rather than for the subsequent meal. Role of Fat Digestion in Satiety

There are several pieces of evidence indicating that a proper digestion of fat is needed for optimal satiety (Figure 14.5). When measuring the release of hunger and satiety hormones during fat digestion, it was reported that addition of tetrahydrolipstatin, a lipase inhibitor, completely abolished the release of CCK (Goedecke et al., 2003; Beglinger and Degen, 2004) suggesting that CCK is released only upon complete fat digestion. This is also true for the satiety hormone GLP-1 which is released only after proper fat digestion and not after administration of tetrahydrolipstatin (Feinle et al., 2003; Sahin et al., 2007). In these experiments carried out in healthy humans, there was also a lower degree of satiety when the lipase inhibitor was added to the lipids consumed.

FIGURE 14.5. Mechanism by which CCK induces satiety for fat.


Mechanism by which CCK induces satiety for fat. This mechanism works through CCK-A receptors acting in the gastrointestinal tract to inhibit gastric emptying as well as through CCK-B receptors acting centrally to release serotonin (5-HT). The fatty acids (more...) Interaction of Enterostatin and CCK

Since CCK and enterostatin are both involved in the suppression of fat intake, an experiment was carried out to investigate whether there was an interaction between the two systems. In OLETF rats lacking the CCK-A receptor, enterostatin failed to inhibit high-fat food intake (Covasa and Ritter, 2005). Addition of enterostatin failed to inhibit high-fat food intake whereas the control LETO rats still were responsive (Lin et al., 2003). Thus, CCK receptor expression was necessary for enterostatin action. There was, however, no direct synergism between CCK and enterostatin (Lin et al., 2003). Since enterostatin does not interact directly with the CCK-A receptor, it is possible that there is a cross-talk downstream of receptor activation.

14.11.8. Neuropeptide Y

NPY is an important orexigenic peptide in the central nervous system (Beck et al., 2002). The peptide is found in several places in the brain especially in the neurons projecting from the arcuate nucleus to the PVN. When NPY is injected ICV, food intake is increased (Beck et al., 2002). Following administration of NPY, rats tested with a three-choice paradigm between fat, carbohydrates, and proteins presented a preference for carbohydrates (Stanley et al., 1985; Jhanwar-Uniyal et al., 1993). If carbohydrates were excluded and rats had to choose between fat and proteins, the animals chose proteins. When rats were under continuous NPY administration and had to choose between a high-fat and a high-carbohydrate diet, both diets were eaten (Beck et al., 2002). The preference for the high-fat diet lasted only 2 days; thereafter, the animals consumed the sweet tasting high-carbohydrate diet. In fully sated rats, NPY injected animals chose the diet with the highest sucrose or artificial sweetener concentration (Lynch et al., 1993). NPY has also been shown to stimulate the intake of milk over water in newborn rats (Capuano et al., 1993). The specific role of NPY on the stimulation of carbohydrate intake is related to the original preference of the rat for either carbohydrate or fat (Welch et al., 1994; Smith et al., 1997).

The endogenous role of NPY has been demonstrated through the use of antibodies and antisense oligodeoxynucleotides (Beck, 2000). Destruction of NPY neurons by neurotoxic agents such as monosodium glutamate (MSG) lead to a decreased food intake (Stricker-Krongrad and Beck, 2004). NPY acts by reducing the lag time before eating, thus in the −/− NPY mice, a pronounced delay in feeding was observed (Sindelar et al., 2005). NPY also increases the motivation to eat, thus stimulating the animals to work harder to get food (Jewett et al., 1995). Furthermore, NPY is involved in the consumption of palatable food as demonstrated by the fact that the endocannabinoid receptor antagonist Rimonabant prevented the release of NPY (Gamber et al., 2005). Blocking of the opioid system also prevented the NPY-induced feeding (Israel et al., 2005). Factors Regulating NPY Expression

Food deprivation is an important regulatory factor for NPY. When rats were deprived of food, the expression of NPY was markedly increased and refeeding returned NPY expression to a normal level (Beck, 2006). Fasting leads to a drop in blood and brain glucose which, through glucose sensing neurons present in the arcuate nucleus, could be a factor stimulating the expression of NPY. In fact, it has been reported that NPY is reactive to moderate hypoglycemia to induce feeding (Akabayashi et al., 1993) and its secretion is inhibited by hyperglycemia (Rowland, 1988). This phenomenon was not seen if fructose was injected, the reason being that fructose is not metabolized by the brain. Other explanations put forward implicate a decrease in leptin receptors upon fasting which could be an explanation for an upregulation of NPY expression (Van Vugt et al., 2006) as well as glucocorticoids (Larsen et al., 1994). There is also a diurnal variation of NPY. In rats, hypothalamic NPY peaks 1 h before dark onset, i.e., 1 h before the natural feeding period (Jhanwar-Uniyal et al., 1990). NPY decreased 1 h after lights were turned-off. Hence, food intake in the beginning of the dark period is associated with high NPY release. NPY, thus, has the general properties of an appetite stimulating peptide that promotes the intake of carbohydrates, particularly sweet tasting carbohydrates. It may be a surprise that NPY, when injected centrally, could inhibit fat intake as discussed below. NPY Is Anorexogenic and Decreases Fat Consumption

NPY’s anorexogenic activity has been brought to light in experiments in which rats were presented with either high-fat (56% fat, 20% carbohydrate) or low-fat food (10% fat, 66% carbohydrate) and NPY was injected in the amygdala. As a result, a significant decrease of high-fat food intake was reported after 24 h whereas the low-fat food intake was unaffected (Primeaux et al., 2005). One potential explanation for the observed effect is a decrease in anxiety by NPY, substituting the anxiety relief normally provided by palatable food. NPY has been shown to display an important anxiolytic effect mediated through NPY1 receptors in the amygdala, which plays a critical role in anxiety related situations (Primeaux et al., 2005).

It is important to note that this decrease in fat food intake occurred after 24 h as opposed to the early effect observed when NPY is injected in other parts of the brain. The slow onset of response suggests that indirect mechanisms are acting to suppress fat intake. The decrease in fat intake, however, was substantial and not a consequence of malaise. Since NPY itself reduces anxiety and fat is known to relieve stress, it could be hypothesized that the decrease in fat intake is due to NPY’s anxiety releasing property normally attributed to high-fat food (Primeaux et al., 2005).

There are also other factors determining the effects of NPY on food intake. For instance, NPY was found to stimulate (Benoit et al., 2005), show no effect (Seeley et al., 1995), or inhibit consumption of sucrose solutions (Ammar et al., 2000) depending on the training the animals received.

The biological action of NPY is mediated through eight receptors subtypes, Y1–Y8. The different NPY receptors activate different pathways. Y5 receptor activation leads to consumption of food and is also important for the reduction of energy expenditure during diet restriction (Widdowson, 1997). The Y1 receptor has been linked to inhibition of food intake (Day et al., 2005) and could hence be involved in situations where NPY inhibits feeding, e.g., decrease fat intake. Thus, the regulation of palatable food intake by NPY is complex and dependent on the situation, the site of action and which receptors are activated.


Strategies aiming to block peptides stimulating fat intake are currently being tested. Antibodies against ghrelin are being tried in animal experiments, which would be an elegant way of controlling appetite for fat. Other strategies include the use of lipase inhibitors which will actually inhibit uptake of fat in the intestine. Although tetrahydrolipstatin promotes body weight loss, it has the drawback of delivering fatty stools and accelerating gastric emptying (O’Donovan et al., 2004) which lead to a reduced production of satiety hormone such as CCK and GLP-1 (O’Donovan et al., 2004). Another approach developed in our laboratory is adding components that retard fat digestion without actually inhibiting fat digestion (Albertsson et al., 2007). Thylakoids are natural components isolated from green leaves constituted of galactolipids and proteins (Albertsson et al., 2007). They have been shown to prolong fat digestion (Figure 14.6) and at the same time cause an upregulation of satiety hormones like CCK and enterostatin (Albertsson et al., 2007). Their efficiency has been proven both in animal studies and human studies (Köhnke et al., 2009). Long-term studies in humans are currently underway since this strategy seems to be very promising.

FIGURE 14.6. Thylakoids are membranes from plant cells containing galactolipids and membrane proteins.


Thylakoids are membranes from plant cells containing galactolipids and membrane proteins. They have been found to reduce the rate of fat digestion by pancreatic lipase and colipase by covering the lipid droplet as well as interfering with the lipase–colipase (more...)


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