Mechanism of action of ghrelin and obestatin in the regulation of appetite under normal and pathological conditions.

The peptide ghrelin, discovered in 1999, was isolated from the rat stomach and identified as the first orexigenic peptide derived from the periphery that plays a key role in the hormonal pathway between the gut and the brain via its effect on the vagus. Ghrelin increases body weight by stimulating food intake but also by decreasing fat utilization. Ghrelin also stimulates gastric emptying which may contribute to appetite signaling. Recently, it was reported that another peptide, obestatin, is derived from the ghrelin precursor. This peptide was reported to have opposite effects to those of ghrelin: it inhibits GI motility and reduces food intake. Interestingly, obestatin appears to be the endogenous ligand of the GPR-39, a receptor structurally related to the motilin-ghrelin receptor family. However, a lot of controversy exists concerning these findings. In the current project we aim to further elaborate the role and mechanism of action of ghrelin and obestatin, in the regulation of food intake and gastrointestinal motility. The effect of these peptides will be studied on the activity of the stomach, the vagus and the brain, three centres implicated in the control of appetite. The effect on gastric emptying will be studied in ghrelin receptor knockout and GPR39 knockout mice. To further investigate the interaction with vagal afferents, neuronal activation of cultured neurons from the nodose ganglia by ghrelin or obestatin will be investigated using single cell fluorescent Ca2+ imaging. In addition, we aim to investigate whether ghrelin/obestatin interact with the AMPK and mTOR pathway, two energy sensors, in the hypothalamus to stimulate food intake.

Keywords:AMPK/mTOR, vagus, gastric emptying, obestatin, ghrelin, maaglediging, AMPK, ghreline, GPR39, diabetes

Disciplines:Physiology, Endocrinology and metabolic diseases, Gastro-enterology and hepatology