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Entry of ingested fat into intestines stimulates pancreatic secretion of lipase and colipase to facilitate digestion. Physiol Behav. 1991 Jun;49(6):1191-4.    Enterostatin (Valine-proline-aspartate-proline-arginine or VPDR) ,  a pentapeptide, is the  by-product formed when pro-colipase is cleaved to form colipase.  Obes Res. 1997 Jul;5(4):360-72.  and  is conserved across a number of species.  Enterostatin has been identified in  endocrine cells in the antral part of the stomach and the duodenum with decreasing levels in the distal parts of the intestine of rat. Peptides. 1996;17(4):609-14.   Enterostatin produced from pro-co-lipase in the exocrine pancreas as well as the gut endocrine cells contribute towards circulating Enterostatin levels.


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Intraperitoneal injection of Enterostatin  into starved Osborne-Mendel rats fed on high fat diet produced a reduction in food intake, while no effect was seen with carbohydrates or aminoacids.   Physiol Behav. 1991 Jun;49(6):1185-9. This may suggest that the predominant action of Enterostatin may be to regulate dietary fat intake.   Central  Brain Res. 1991 Mar 22;544(1):137-40.    as well as peripheral  injection   Physiol Behav. 1991 Jun;49(6):1185-9.   of Enterostatin into rats produces a reduction in fat intake by up to 50%.   The anorexigenic efficacy on central administration is more pronounced when injected into the amygdala rather than the paraventricular nucleus.  Peptides. 1997;18(9):1341-7.   This appetite reduction seems to be translated into weight reduction with chronic infusion of Enterostatin in rats.  Am J Physiol. 1998 Aug;275(2 Pt 2):R619-23.   It seems that a predominant chronic fat intake is necessary to produce Enterostatin's effect on reduction of fat intake. Am J Physiol. 1998 Aug;275(2 Pt 2):R619-23.   This could be attributed the possibility of fat intake stimulating gastrointestinal factors like CCK which might have a permissive role in Enterostatin's fat specific anorexigenic action.  In keeping with this, Otsuka Long Evans Tokushima Fatty (OLETF) rats which are deficient in CCK-A receptors with hyperphagia, obesity and diabetes, did not respond with feeding suppression to central or peripherally injected Enterostatin. Am J Physiol Regul Integr Comp Physiol. 2003 Aug;285(2):R321-8.  
Mechanism of Action

  A vagal mechanism of action has been proposed for Enterostatin's anorexigenic action since the peripheral effects are blocked by vagotomy or capsaicin treatment. J Gastroenterol. 2002 Nov;37 Suppl 14:118-27.  Enterostatin stimulation  has been shown to activate c-fos expression in the NTS, amygdala and supraoptic nucleus, implicating these centres in the vagal mediated action. Other pathways also seem to be involved in the actions of Enterostatin.  Anorexigenic doses of Enterostatin stimulates the sympathetic nervous system.  Brain Res. 1996 Feb 12;709(1):44-50. Enterostatin also seems to have effects on the serotoninergic system with increased serotonin turnover. Obes Res. 1997 Jul;5(4):360-72.   The inhibitory effect of Enterostatin on fat intake may reside in the cyclo-diketopiperazine molecule, cyclo-Asp-Pro.   Peptides. 1994;15(5):849-54.   There seems to be a narrow therapeutic window for anorexia production as higher doses of Enterostatin paradoxically produce increased appetite and food intake. Obes Res. 1998 Jan;6(1):54-61 Determination of ideal dosing would be crucial when studying effects in humans, where initial studies have not been promising. Appetite. 1995 Feb;24(1):37-42.