Enterostatin: a peptide regulator of fat ingestion.

Enterostatin is the activation pentapeptide of procolipase, a 101 amino acid peptide that is synthesized in the exocrine pancreas and stomach of rats. Differences in endogenous secretion may determine the variable selection of dietary fat within and between different rat strains. After either peripheral or central intracerebroventricular administration, enterostatin selectively inhibits the intake of dietary fat in a number of experimental feeding paradigms and during the normal daily feeding cycle. The peripheral effects appear to be dependent upon the hepatic vagal afferents through which signals activate specific brain nuclei, including the paraventricular and supraoptic nucleus and the nucleus tractus solitarius. Ingestion of dietary fat increases the production and secretion of pancreatic colipase. Studies with a range of analogues suggest that all the biological activity and selectivity toward dietary fat may be contained in the cyclodiketopiperazine ring structure of cyclo-aspartyl-proline (cycloDP). The dose-response curves to enterostatin and cycloDP are U-shaped, suggesting the presence of two receptor subtypes. Maximum inhibition of food intake occurs between 0.1 and 1.0 nanomoles intracerebro-ventricular administration, whereas at doses above 10 nanomoles food intake is increased. The low affinity stimulating site is also activated by beta-casomorphin1-7. Enterostatin does not bind to either galanin or neuropeptide Y-Y1 receptors. However, studies with kappa-opioid agonist and antagonist suggest that enterostatin inhibits a kappa-opioid feeding system that is selective for dietary fat. Enterostatin may also have independent effects on insulin and corticosterone secretion. It is hypothesized that enterostatin, or its biologically active product, may act as a signal to regulate fat appetite and be an important determinant of the susceptibility to develop obesity on high-fat diets.