Endocrine Abstracts

Can we drug receptors for microbially-produced metabolic hormones and for what indications? G protein-coupled receptors (GPCRs) have been a major group of druggable cell surface receptors and therapeutics targeting many hormone-activated GPCRs have been developed. A number of products of the processing and metabolism of foodstuffs act in a hormone-like manner and these include both short and medium chain length free fatty acids. Short chain fatty acids produced in large amounts by the intestinal microbiota act on the receptors FFA2 and FFA3, whilst medium chain fatty acids activate the receptor GPR84. Various studies have suggested that activation or blockade of these receptors may be therapeutically attractive ways to treat various inflammatory conditions, as well as diseases ranging from diabetes to cancers. One challenge in assessing such questions in rodent models is that many identified ligands that target these receptors, although with high affinity at the human receptor have little or no effect at the rodent orthologues. I will discuss ways in which we have defined the molecular basis for such differences and then developed transgenic mouse models expressing modified forms of FFA2 and GPR84 to explore if these are worthy targets for therapeutic development.