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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.)

A pentapeptide released from procolipase, enterostatin, selectively attenuates dietary fat intake when administered peripherally or centrally. Enterostatin may act through the afferent vagus nerve and in the hypothalamus and amygdala, primarily in the central nucleus of the amygdala. To investigate the physiological role of endogenous enterostatin, we created an enterostatin-deficient, colipase-sufficient (Ent(-/-)) mouse. Ent(-/-) mice are viable, normally active, and fertile. They exhibit normal growth on low-fat and high-fat diets. Furthermore, Ent(-/-) mice develop diet-induced obesity, as do Ent(+/+) mice, and have normal responses to a two-macronutrient choice diet and to a switch from a high-fat to a low-fat diet. Levels of total serum (P = 0.004) and non-HDL (P

Objective: The effects of a promising new appetite suppressor named "thylakoids" (membrane proteins derived from spinach leaves) were examined in a single meal in man. Thylakoids inhibit the lipase/colipase hydrolysis of triacylglycerols in vitro and suppress food intake, decrease body-weight gain and raise the satiety hormone cholecystokinin (CCK) in rats, but their effects in man remain unclear. The aim of this study was to investigate whether thylakoids, when added to a test meal, affect appetite regulation and blood parameters in healthy individuals., Material and Methods: In an intervention crossover study, healthy individuals of normal weight (n=11) were offered a high-fat meal with and without the addition of thylakoids. Blood samples were taken 0 (prior to meal), 30, 60, 120, 180, 240, 300 and 360 min after the start of the meal. Blood samples were analysed for satiety and hunger hormones (CCK, leptin and ghrelin), insulin and blood metabolites (glucose and free fatty acids)., Results: The CCK level increased, in particular between the 120 min time-point and onwards, the ghrelin level was reduced at 120 min and leptin level increased at 360 min after intake of the thylakoid-enriched meal. The insulin level was reduced, whereas glucose concentrations were unchanged. Free fatty acids were reduced between time-point 120 min and onwards after the thylakoid meal., Conclusions: The addition of thylakoids to energy-dense food promotes satiety signals and reduces insulin response during a single meal in man.

A high-fat diet easily promotes hyperphagia giving an impression of an uncontrolled process. Fat digestion itself however provides control of fat intake through the digestion itself, carried out by pancreatic lipase and its protein cofactor colipase, and through enterostatin, a peptide released from procolipase during fat digestion. Procolipase (-/-) knockout mice have a severely reduced fat digestion and fat uptake, pointing to a major role of the digestive process itself. With a normal fat digestion, enterostatin basically restricts fat intake by preventing the overconsumption of fat. The mechanism for enterostatin might be an inhibition of a mu-opioid-mediated pathway, demonstrated through binding studies on SK-N-MC-cells and crude brain membranes. Another target protein of enterostatin is the beta-subunit of F1F0-ATPase, displaying a distinct binding of enterostatin, established through an aqueous two-phase partition system. The binding of enterostatin to F1-ATPase was partially displaced by beta-casomorphin, a peptide stimulating fat intake and acting competitively to enterostatin. We frame a hypothesis that regulation of fat intake through enterostatin contains a reward component, which is an F1-ATPase-mediated pathway, possibly complemented with an opioidergic pathway.

A high fat intake, together with an inability to match lipid oxidation to fat intake, has been found to be correlated with obesity in humans. This review describes our current understanding of enterostatin, a peptide that selectively reduces fat intake. Enterostatin is formed in the intestine by the cleavage of secreted pancreatic procolipase, the remaining colipase serving as an obligatory cofactor for pancreatic lipase during fat digestion. Enterostatin is also produced in the gastric mucosa and the mucosal epithelia of the small intestine. Procolipase gene transcription and enterostatin release into the gastrointestinal lumen are increased by high-fat diets. After feeding, enterostatin appears in the lymph and circulation. Enterostatin will selectively inhibit fat intake during normal feeding and in experimental paradigms that involve dietary choice. Its anorectic effect has been demonstrated in a number of species. Both peripheral and central sites of action have been proposed. The peripheral mechanism involves an afferent vagal signaling pathway to hypothalamic centers. The central responses are mediated through a pathway that includes both serotonergic and opioidergic components. Chronically, enterostatin reduces fat intake, bodyweight, and body fat. This response may involve multiple metabolic effects of enterostatin, which include a reduction of insulin secretion, an increase in sympathetic drive to brown adipose tissue, and the stimulation of adrenal corticosteroid secretion. A possible pathophysiological role is suggested by studies that have linked low enterostatin production and/or responsiveness to strains of rat that become obese and prefer dietary fat. Humans with obesity also exhibit a lower secretion of pancreatic procolipase after a test meal, compared with persons of normal weight.

Central and peripheral administration of enterostatin have been reported to reduce fat or high-fat food intake in rats. Enterostatin is formed in the intestinal lumen by tryptic cleavage of pancreatic procolipase during intraluminal fat digestion. The present experiments were designed to test if enterostatin following intraintestinal infusion would affect food intake in a similar way as intracerebraventricularly or intravenously administered enterostatin. Female Sprague-Dawley rats were fitted with a duodenal catheter and adapted to feeding schedule for 6 hours each day. After 10 days enterostatin (5.65 and 11.3 nmol/kg/min) or saline were infused into the duodenum and food intake measured. Enterostatin significantly reduced high-fat food intake during the 6 hours of feeding, but had no inhibitory effect on low-fat food intake. Addition of tetracaine to the enterostatin infusates blocked the satiating potency of intestinal enterostatin. These results support the hypothesis of a preabsorptive site of action for enterostatin.

Enterostatin, a pentapeptide released with colipase from pancreatic procolipase in man, affects eating behaviour in animals. We report the first phase II study of intravenous (i.v.) enterostatin (D3800) in obese but otherwise healthy men. Eighteen men (mean age 37 years, mean body mass index 34.9 kg/m2) completed a double-blind, randomized, crossover placebo controlled trial. After in initial session, each man received i.v. 4 mg D3800, 16 mg D3800 or placebo in random order over three sessions, immediately before a test meal served on a universal eating monitor. No statistically significant effect of i.v. enterostatin on any uptake or rating variable was observed. Several factors may explain the lack of effect, e.g. the inability of i.v. enterostatin to reach a site of action, the time between i.v. administration and eating, and the possibility that the only human responders are those who express particular fat preferences.

Enterostatin, a peptide formed during the activation of pancreatic procolipase in the duodenum, is likely a mediator of satiety in the rat. The objective of this research was to determine whether administration of enterostatin into the lateral cerebral ventricle of sheep unfed for 2 h resulted in reduced feed intake. Bolus doses of 2 micrograms did reduce (P < .03) feed intake during the hour after injection by one- to two-thirds of control. Doses 20 micrograms or greater were not effective, and .2 microgram also did not have any statistically significant effect. This range of effective doses was similar to that observed in the rat, and the effective dose of 2 micrograms was approximately 10-fold greater on a per-animal basis, but less on a brain-size basis, than the amount needed to achieve a similar response in the rat. Therefore, enterostatin can reduce feed intake and thus may also be involved in satiety in sheep.

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 a cofactor for lipase and necessary for optimal fat digestion in the intestine during a meal. It is activated by trypsin in the intestine during release of an activation peptide, with the sequence Val-Pro-Asp-Pro-Arg in rat. This peptide, in the following termed VPDPR, was found to decrease food intake in rats. The human procolipase activation peptide with the sequence Ala-Pro-Gly-Pro-Arg (APGPR) had no effect on food intake in rats, nor the trypsinogen activation peptide with the sequence Phe-Pro-Val-Asp-Asp-Asp-Asp-Lys (FPVDDDDK). Procolipase added to standard pellets decreased the daily food intake in rats, whereas colipase added to pellets had no effect.