Gregory W. Aponte
Ph.D. (Nutrition), University of California, Davis, 1982
A number of neuropeptides and peptide hormones, which can alter cellular metabolism as well as organismal behavior, are secreted in response to diet. For example, we have demonstrated that peptide YY (PYY) secretion is directly induced by dietary free fatty acids (FFAs) and that PYY is released in sufficient concentration to alter intestinal cellular differentiation and potentially food intake behavior (1,2). Neuropeptides such as PYY exert their effects through the activation of receptors. PYY receptors belong to a class of receptors called G protein-coupled receptors (GPCRs). When the PYY receptors are activated, a number of signaling events are initiated leading to cell proliferation, growth, and differentiation. Recently, more attention is given to a family of these peptides comprising neuropeptide Y (NPY) and PYY because of their profound effects on food intake as well as nutrient assimilation and metabolism. The mechanism(s) and signaling pathways by which PYY and NPY activate their family of receptors, and the subsequent downstream effects, are likely shared among other neuropeptides.
Most bioactive peptides found in the intestine and nerves, which are released in response to nutrients, such as PYY and NPY, have receptors that are expressed in peripheral tissues as well as the central nervous system (CNS). This phenomena may allow the organism the means to integrate behavioral and metabolic responses to dietary stimulus as well as the means to effect synchronous changes in expression of genes and proteins that are involved in nutrient assimilation. Although most neuropeptides act through GPCRs, there is little understanding as to how these receptors are activated by nutrients and the subsequent alterations in physiological responses.
Using PYY and NPY as model neuropeptides has helped us understand how dietary nutrients can act as signal molecules, and to identify several new GPCRs (such as GPR93) that are directly activated by nutrients (3,4). Similar to the NPY/PYY receptors, these receptors are expressed in areas of the body involved in energy/nutrient homeostasis, such as the feeding centers in the brain (hypothalamus), intestinal mucosa, and pancreas. Our laboratory is focused on the characterization of these new nutrient responsive GPCRs. This characterization includes establishing the signaling pathways involved when they are activated, the structural requirements and potential ligands to induce this activation, and the regulation of the targeted gene product. Understanding the mode of action of these new GPCRs common to the intestine and the brain could elucidate new pathways for mucosal adaptation to environmental cues in the form of diet, and also new mechanisms whereby the brain can alter peripheral cellular responses in response to nutrient signals.
1) Aponte GW, Park K, Hess R, Garcia R, and Taylor IL. 1989. Meal-induced peptide tyrosine tyrosine inhibition of pancreatic secretion in the rat. FASEB J 3: 1949-1955.
2) Lee M, Hadi M, Halldén G, and Aponte GW. 2005. Peptide YY and neuropeptide Y induce expression, reduce adhesion, and enhance migration in small intestinal cells through the regulation of CD63, matrix metalloproteinase-3, and Cdc42 activity. J Biol Chem 280: 125-36.
3) Choi S, Lee M, Shiu AL, Yo SJ, and Aponte GW. 2007. Identification of a protein hydrolysate responsive G protein coupled receptor in enterocytes. Am J Physiol Gastrointest Liver Physiol 292: G98-G112.
4) Choi S, Lee M, Yo SJ, Shiu AL, Halldén G, and Aponte GW. 2007. GPR93 activation by protein hydrolysate induces CCK transcription and secretion in STC-1 cells. Am J Physiol Gastrointest Liver Physiol 292: G1366-1375.
5) A key discovery finds nutrient molecules that send message to the brain. Article featured in BREAKTHROUGHS magazine.