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Bacterial endotoxin is a potent inflammatory antigen abundant in the human intestine. Endotoxins circulate in the blood at low concentrations in all healthy individuals. Elevated levels of circulatory endotoxins may cause inflammation with the development of chronic disease, either affecting metabolism, neurological disease, or resistance to viral and bacterial infections. The most important endotoxin is LPS, being a superantigen. In this narrative review, the effect of various food components to postprandially elevate circulating LPS and inflammatory markers is described. There is evidence that the intake of food enriched in fat, in particular saturated fat, may elevate LPS and pro-inflammatory markers. This occurs in both normal-weight and obese subjects. In obese subjects, inflammatory markers are already elevated before meal consumption. The importance of food choice for endotoxemia and inflammatory response is discussed.

Background: Isolated thylakoid membranes, i.e. the photosynthetic membranes of green leaves, inhibit the activity of pancreatic lipase and colipase during hydrolysis of fat in vitro. This inhibition has been demonstrated to cause reduced food intake and improved hormonal and lipid profile in vivo. One of the reasons suggested for the inhibiting effect is binding of lipase-colipase to the thylakoid membrane surface. This prompted a study of the binding of lipase and colipase to thylakoids., Results: The results showed that lipase and colipase strongly bind to the thylakoid membrane surface. The dissociation constant was determined at 1.2 × 10⁻⁸  mol L⁻¹; binding decreased after treatment of thylakoids with pepsin/trypsin to 1.0 × 10⁻⁷ and to 0.6 × 10⁻⁷  mol L⁻¹ after treatment with pancreatic juice. Similarly, delipidation of thylakoids caused a decrease in binding, the dissociation constant being 2.0 × 10⁻⁷  mol L⁻¹., Conclusion: The binding of pancreatic lipase-colipase to the thylakoid membrane is strong and may explain the inhibition of lipase-colipase activity by thylakoids. After treatment with proteases to mimic intestinal digestion binding is decreased, but is still high enough to explain the observed metabolic effects of thylakoids in vivo., (© 2012 Society of Chemical Industry.)

Thylakoids are membranes isolated from plant chloroplasts which have previously been shown to inhibit pancreatic lipase/colipase catalysed hydrolysis of fat in vitro and induce short-term satiety in vivo. The purpose of the present study was to examine if dietary supplementation of thylakoids could affect food intake and body weight during long-term feeding in mice. Female apolipoprotein E-deficient mice were fed a high-fat diet containing 41% of fat by energy with and without thylakoids for 100 days. Mice fed the thylakoid-enriched diet had suppressed food intake, body weight gain and body fat compared with the high-fat fed control mice. Reduced serum glucose, serum triglyceride and serum free fatty acid levels were found in the thylakoid-treated animals. The satiety hormone cholecystokinin was elevated, suggesting this hormone mediates satiety. Leptin levels were reduced, reflecting a decreased fat mass. There was no sign of desensitization in the animals treated with thylakoids. The results suggest that thylakoids are useful to suppress appetite and body weight gain when supplemented to a high-fat food during long-term feeding., (Copyright (c) 2009 John Wiley & Sons, Ltd.)

Human obesity is a global epidemic, which causes a rapidly increased frequency of diabetes and cardiovascular disease. One reason for obesity is the ready availability of refined food products with high caloric density, an evolutionarily new event, which makes over-consumption of food inevitable. Fat is a food product with high caloric density. The mechanism for regulation of fat intake has therefore been studied to a great extent. Such studies have shown that, as long as fat stays in the intestine, satiety is promoted. This occurs through the fat-released peptide hormones, the best known being CCK (cholecystokinin), which is released by fatty acids. Hence, retarded fat digestion with prolonged time for delivery of fatty acids promotes satiety. Pancreatic lipase, together with its protein cofactor, co-lipase, is the main enzymatic system responsible for intestinal fat digestion. We found that biological membranes, isolated from plants, animals or bacteria, inhibit the lipase/co-lipase-catalysed hydrolysis of triacylglycerols even in the presence of bile salt. We propose that the inhibition is due to binding of lipase/co-lipase to the membranes and adsorption of the membranes to the aqueous/triacylglycerol interface, thereby hindering lipase/co-lipase from acting on its lipid substrate. We also found that chloroplast membranes (thylakoids), when added to refined food, suppressed food intake in rats, lowered blood lipids and raised the satiety hormones, CCK and enterostatin. Consequently, the mechanism for satiety seems to be retardation of fat digestion allowing the fat products to stay longer in the intestine.

High fat diets and obesity pose serious health problems, such as type II diabetes and cardiovascular disease. Impaired cognitive function is also associated with high fat intake. In this study, we show that just 4 weeks of feeding a diet rich in fat ad libitum decreased hippocampal neurogenesis in male, but not female, rats. There was no obesity, but male rats fed a diet rich in fat exhibited elevated serum corticosterone levels compared with those fed standard rat chow. These data indicate that high dietary fat intake can disrupt hippocampal neurogenesis, probably through an increase in serum corticosterone levels, and that males are more susceptible than females.

High-fat diets are often associated with greater caloric intake and weight gain. Since satiety during fat intake is induced by fat in the intestine we investigated the efficiency of a lipid compound that retards fat digestion to regulate fat intake. We found this compound to reduce high-fat food intake, body weight and blood lipids in Sprague-Dawley rats, without causing steatorrhea. The absence of steatorrhea is explained by an increased pancreatic lipase/colipase secretion, compensating the impaired lipolysis by the added compound. The animals also had an elevated CCK secretion. The satiety for fat may be the consequence of elevated CCK and procolipase/enterostatin levels. We conclude that compounds can be found that delay intestinal fat digestion and control high-fat food intake through the release of satiety signals, without causing steatorrhea. The absence of steatorrhea makes such compounds advantageous over lipase inhibitors in the treatment of obesity.

Palatable food is rich in fat and/or sucrose. In this study we examined the long-term effects of such diets on food intake, body weight, adiposity and circulating levels of the satiety peptide leptin and the hunger peptide ghrelin. The experiments involved rats and mice and lasted 5 weeks. In rats, we examined the effect of diets rich in fat and/or sucrose and in mice the effect of a high fat diet with or without sucrose in the drinking water. Animals fed with the palatable diets had a larger intake of calories, gained more weight and became more adipose than animals fed standard rat chow. Fasted animals are known to have low serum leptin and high serum ghrelin and to display elevated serum leptin and lowered serum ghrelin postprandially. With time, a sucrose-rich diet was found to raise the fasting level of leptin and to lower the fasting level of ghrelin in rats. A fat-rich diet suppressed serum ghrelin without affecting serum leptin; high sucrose and high fat in combination greatly reduced serum ghrelin and raised serum leptin in the fasted state. The mRNA expression of leptin in the rat stomach was up-regulated by sucrose-rich (but not by fat-rich) diets, whereas the expression of ghrelin seemed not to be affected by the palatable diets. Mice responded to sucrose in the drinking water with elevated serum leptin (fasted state) and to all palatable diets with low serum ghrelin. The expression of both leptin and ghrelin mRNA in the stomach was suppressed in fasted mice that had received a high fat diet for 5 weeks. We conclude that the expression of leptin mRNA in stomach and the concentration of leptin in serum were elevated in response to sucrose-rich rather than fat-rich diets, linking leptin with sucrose metabolism. In contrast, the expression of ghrelin and the serum ghrelin concentration were suppressed by all palatable diets, sucrose and fat alike. In view of the increased body weight and adiposity neither elevated leptin nor suppressed ghrelin were able to control/restrain the overeating that is associated with palatable diets.

Introduction: A diet containing a high amount of fat has been shown, in short-term studies, to increase the expression of pancreatic lipase and colipase., Aim: To investigate the effects of long-term high-fat-feeding (113 days) on the mRNA expression of pancreatic lipase, colipase, pancreatic lipase-related proteins (1 and 2), and uncoupling proteins during the development of obesity and glucose intolerance., Methodology: Mice were fed either a high-fat or standard diet and killed after 3, 13, 57, and 113 days. Brown and white adipose tissue and pancreas were collected for mRNA extraction [corrected]., Results: The high-fat-fed mice became obese and glucose-intolerant by 113 days. The high-fat diet increased lipase (p < 0.05) expression initially. At the end of the experiment, the lipase levels had decreased to the level of the control. Colipase levels did not change during the first 57 days of high-fat feeding but decreased below control levels by 113 days (p < 0.05). The high-fat diet increased brown adipose tissue uncoupling protein 1 (UCP1)(p < 0.005) expression but not the expression of uncoupling protein 2., Conclusion: Long-term high-fat feeding, leading to glucose intolerance, occurs with a simultaneous decrease in the mRNA expression of pancreatic lipase and colipase and an increase in UCP1 expression.

Nonshivering thermogenesis induced in brown adipose tissue (BAT) during high-fat feeding is mediated through uncoupling protein 1 (UCP1). UCP2 is a recently identified homologue found in many tissues. To determine the role of UCP1 and UCP2 in thermoregulation and energy balance, we investigated the long-term effect of high-fat feeding on mRNA levels in mice at two different ambient temperatures. We also treated mice with the anorectic peptide enterostatin and compared mRNA levels in BAT, white adipose tissue (WAT), stomach, and duodenum. Here, we report that high-fat feeding at 23 degrees C increased UCP1 and UCP2 levels in BAT four- and threefold, respectively, and increased UCP2 levels fourfold in WAT. However, at 29 degrees C, UCP1 decreased, whereas UCP2 remained unchanged in BAT and increased twofold in WAT. Enterostatin increased UCP1 and decreased UCP2 mRNA in BAT. In stomach and duodenum, high-fat feeding decreased UCP2 mRNA, whereas enterostatin increased it. Our results suggest that the regulation of uncoupling protein mRNA levels by high-fat feeding is dependent on ambient temperature and that enterostatin is able to modulate it.

Background & Aims: Procolipase, the cofactor for pancreatic lipase, was recently found in the rat stomach using immunohistochemistry. The aim of this study was to determine the sequence of rat gastric procolipase, to evaluate the expression and secretion during high-fat feeding, and to find out the conditions for activation of gastric procolipase to form colipase and enterostatin., Methods: Gastric procolipase was cloned from a rat complimentary DNA (cDNA) library using a 32P-labeled pancreatic procolipase probe for screening. For the expression of gastric procolipase, rats were fed a high-fat diet for 0, 1, 2, 5, and 14 days. Gastric mucosa was collected for isolation of RNA and gastric juice for measurement of procolipase. After treatment with pepsin, HCl, and trypsin, gastric juice was analyzed on high-performance liquid chromatography for identification of enterostatin., Results: The cDNA sequence for gastric procolipase was identical to that of pancreatic procolipase. High-fat diet decreased the expression of gastric procolipase. Enterostatin was present in the gastric juice, with pepsin and acid involved in the cleavage of gastric procolipase., Conclusions: Gastric procolipase is activated to release colipase and enterostatin. The role of gastric colipase may be to prepare lipase-catalyzed fat digestion already in the stomach. Gastric enterostatin may be involved in the onset of early satiety.

Enterostatin is a peptide which has been found to decrease food intake with a specificity for the fat contained in the food. In this work we have investigated the effect of enterostatin (Val-Pro-Asp-Pro-Arg) and its proteolytic fragments, des-arg-enterostatin (Val-Pro-Asp-Pro) and the tripeptide Asp-Pro-Arg, on insulin secretion. It was found that enterostatin and desarg-enterostatin inhibited insulin secretion from isolated rat islets by 55.3% (P < 0.05) and 53.6% (P < 0.05) at 1.6 x 10(-4) M concentration, while the tripeptide Asp-Pro-Arg at 1.6 x 10(-4) M concentration had no significant effect and increased insulin secretion by 33.0%. Enterostatin at 200 ng after intraventricular administration was found to inhibit the intake of a high-fat diet by 45.0%, while des-arg-enterostatin (200 ng) had no effect, in agreement with previous findings. The tripeptide Asp-Pro-Arg (200 ng) had no effect on the intake of a high-fat diet compared to saline injection. The ability of enterostatin to inhibit high-fat food intake and decrease insulin secretion may be important for the prevention of obesity and type II diabetes, conditions linked through hyperinsulinemia.

Enterostatin, the procolipase activation peptide, has been suggested in previous studies to act as a satiety signal for food intake, with a specificity for fat intake. In this study, by use of a competitive enzyme-linked immunosorbent assay with a detection limit of 4.115 nmol/L and within 6% intra- and interassay variation, the immunoreactive and chromatographic characterization of enterostatin in intestinal content was undertaken in Sprague-Dawley rats. Following intravenous infusion of cholecystokinin octapeptide (CCK-8; 200 pmol/kg/h) for 60 min, the concentration of intestinal enterostatin increased from a basal level of 2.0 +/- 0.7 microM to 5.64 +/- 1.1 microM at time point 60 min. The enterostatin level remained at 4.24 +/- 0.54 microM for 120 min after the CCK infusion had ceased. Pancreatic lipase and colipase activities in rat intestinal content also increased during the CCK-8 infusion. The enzyme activities reached the maximal level after 30 min of CCK infusion and thereafter progressively decreased to basal levels, remaining there during the following 2 h. The basal level of intestinal enterostatin in rats fed with standard pellets was found to be increased from 1.42 +/- 0.14 to 3.86 +/- 0.4, 3.17 +/- 0.54, and 5.02 +/- 1.6 microM on days 1, 3, and 7, respectively, after high-fat feeding. Parallel to the increase in intestinal enterostatin, there was a significant increase in pancreatic lipase and colipase activities in the intestine during the ingestion period of high-fat diet as compared with the control group. The estimated molecular mass of enterostatin immunoreactivity of intestinal content was similar to that of the synthetic pentapeptide. These results suggest that immunoreactive enterostatin (Val-Pro-Gly-Pro-Arg) is normally present in rat intestinal content, is significantly increased after stimulation with CCK-8, and is also increased after prolonged high-fat feeding.

The effect of enterostatin on high-fat food intake has been investigated. After 18 h of food deprivation, rats were injected intravenously with enterostatin (VPGPR). A dose of 38 nmol of enterostatin gave a significant inhibition of high-fat food intake, while at a higher dose of 76 nmol the inhibiting effect was lost. During the first hour, after injection of enterostatin, there was even a slight increase in food intake. Binding studies of tritiated enterostatin to crude brain membranes indicated one binding site with high affinity (Kd = 0.5 nM) and one with low affinity (Kd = 170 nM). The two dissociation constants suggest different receptor subtypes and could explain why enterostatin both can inhibit and, at high doses, stimulate fat intake in rats.

The effect of enterostatin, the amino-terminal pentapeptide of pancreatic procolipase, on high-fat food intake has been investigated after intracerebroventricular as well as after intravenous injection. After an overnight fast enterostatin given i.c.v. at doses of 167 pmol and 333 pmol produced a significant and dose-dependent reduction in high-fat food intake, while a higher dose of 667 pmol had no effect. Following intravenous injection of enterostatin the intake of high-fat food was suppressed at doses of 8.3 nmol and 16.7 nmol, while no effect was observed at higher doses. The inhibition of feeding started 3 h after the initiation of feeding and persisted to the end of the test period (6 h). Enterostatin at a dose of 16.7 nmol gave no sign of aversion in an aversion test comparing the effect of enterostatin, lithium chloride and saline on liquid intake. The data suggest that enterostatin may exert its satiety effect on high-fat feeding by being absorbed into the bloodstream.

The effect of enterostatin, the amino-terminal pentapeptide of pancreatic procolipase, on food intake was investigated in two strains of rat, the dietary fat-sensitive Osborne-Mendel (OM) rat and the dietary fat-resistant S5B/Pl rat. After an overnight fast, enterostatin inhibited intake of high-fat (HF) but not low-fat (LF) diets in OM rats, but had no effect in S5B/Pl rats. When fed a macronutrient three-choice diet, OM rats selected fat preferentially, whereas S5B/Pl rats selected carbohydrate. Enterostatin specifically inhibited the intake of fat in OM rats but not S5B/Pl rats fed a three-choice macronutrient diet. The activity of pancreatic colipase was increased in S5B/Pl rats on both HF and LF diets compared with OM rats. Pancreatic colipase activities were negatively related to the voluntary intake of fat on three-choice macronutrient diets. The data support the hypothesis that enterostatin may control the intake of dietary fat.

Pancreatic procolipase is activated by trypsin forming colipase, a cofactor for pancreatic lipase involved in intestinal fat digestion and a pentapeptide named enterostatin. Enterostatin with the sequence Val-Pro-Asp-Pro-Arg (VPDPR) was previously shown to decrease food intake in rats both after peripheral and central injection. In this work enterostatin has been shown to reduce specifically the consumption of a high-fat diet as opposed to a low-fat diet after central injection of Sprague-Dawley rats. After starvation for 18 hours the rats were given a free choice of a low-fat diet (5.2% fat by weight; 14.1% by energy) and a high-fat diet (17.8% fat by weight; 32.8% by energy) in separate containers. After injection of 200 ng of VPDPR into the lateral ventricle, the rats selectively decreased the intake of the high-fat diet by 45% (p less than 0.005), while the intake of the low-fat diet was unaffected compared to saline injection. VPDP after intracerebroventricular injection had totally lost the selective effect on the consumption of a high- fat and a low-fat diet. It is suggested that enterostatin formed during fat digestion from pancreatic procolipase may provide a feed-back signal for the intake of lipid.

Valine-proline-aspartate-proline-arginine (VPDPR), the amino terminal pentapeptide of pancreatic procolipase, produced a dose-dependent reduction in food intake when injected intraperitoneally into Osborne-Mendel rats that had been starved overnight. This inhibition of feeding was observed when the rats were fed a high-fat diet but not in rats fed a high-carbohydrate, low-fat diet. At higher doses of VPDPR, the inhibition of feeding was maintained for over 6 hours. An equimolar mixture of the free amino acids had no effect on food intake. In rats adapted to a three-choice macronutrient diet, VPDPR inhibited fat intake but had no effect on carbohydrate or protein intake. This selective inhibition of fat intake was observed in both overnight-fasted rats presented with food and in ad-lib-fed rats at the beginning of the dark-onset feeding period. It is suggested that this peptide may be a feedback signal to regulate the intake of dietary fat.