Appetite regulation is highly complex and involves a large number of orexigenic and
anorexigenic peptide hormones. These are small, processed, secreted
peptides derived from larger prepropeptide precursors. These
peptides are important targets for the development of
therapeutics for
obesity, a global health epidemic. As a case study, we consider the
ghrelin axis. The
ghrelin axis is likely to be a particularly useful
drug target, as it also plays a role in energy homeostasis, adipogenesis,
insulin regulation and reward associated with food intake.
Ghrelin is the only known circulating gut orexigenic
peptide hormone. As it appears to play a role in diet-induced
obesity, blocking the action of
ghrelin is likely to be effective for treating and preventing
obesity. The
ghrelin peptide has been targeted using a number of approaches, with
ghrelin mirror-image
oligonucleotides (Spiegelmers) and
immunotherapy showing some promise. The
ghrelin receptor, the
growth hormone secretagogue receptor, may also provide a useful target and a number of antagonists and inverse agonists have been developed. A particularly promising new target is the
enzyme which octanoylates
ghrelin,
ghrelin O-
acyltransferase (GOAT), and drugs that inhibit GOAT are likely to circumvent pharmacological issues associated with approaches that directly target
ghrelin or its receptor.