Ghrelin

Ghrelin is a 28-residue peptide secreted mainly by endocrine cells of the gastric fundus, and it is the endogenous ligand for the growth hormone secretagogue receptor GHS-R1a. Its defining feature is a post-translational modification found nowhere else in mammalian biology: ghrelin O-acyltransferase attaches an eight-carbon octanoyl group to the serine at position 3, and without that fatty acid the peptide cannot activate the receptor. Acyl ghrelin is the signalling form and the minority species, while des-acyl ghrelin makes up most of the immunoreactive total and does not stimulate GHS-R1a at all.

It was identified in 1999 by Kojima and colleagues through a search for the natural ligand of an orphan receptor that synthetic secretagogues were already known to hit. Concentrations rise before meals and fall after eating, and they rise rather than fall after diet-induced weight loss, which is part of the physiology of weight regain. It is the only well-established circulating hormone that increases food intake. Anamorelin, an orally active ghrelin receptor agonist, illustrates the therapeutic problem: it increases body weight and lean mass in cancer cachexia and has a national approval in Japan, but the FDA and EMA declined it because handgrip strength did not improve.

The structural point that matters is that appetite and growth hormone release run through the same receptor, so the two effects are not easily separated by dosing or analogue design.

The measurement trap is severe enough to invalidate whole comparisons. The octanoyl ester is labile, and unless blood is collected with a protease inhibitor and acidified promptly, acyl ghrelin degrades during handling. Many published studies report only total ghrelin, which is dominated by the inactive species, so a reported fall may say nothing about the signalling pool.