Drugs or diet? – Developing novel therapeutic strategies targeting the free fatty acid family of GPCRs

Abstract

Free fatty acids (FFAs) are metabolic intermediates that may be obtained through the diet, synthesized endogenously, or produced via fermentation of carbohydrates by gut microbiota. In addition to serving as an important source of energy, FFAs are known to produce a variety of both beneficial and detrimental effects on metabolic and inflammatory processes. While historically, FFAs were believed to produce these effects only through intracellular targets such as peroxisome proliferator-activated receptors, it has now become clear that FFAs are also agonists for several GPCRs, including a family of four receptors now termed FFA1-4. Increasing evidence suggests that FFA1-4 mediate many of the beneficial properties of FFAs and not surprisingly, this has generated significant interest in the potential of these receptors as therapeutic targets for the treatment of a variety of metabolic and inflammatory disorders. In addition to the traditional strategy of developing small-molecule therapeutics targeting these receptors, there has also been some consideration given to alternate therapeutic approaches, specifically by manipulating endogenous FFA concentrations through alteration of either dietary intake, or production by gut microbiota. In this review, the current state of knowledge for FFA1-4 will be discussed, together with their potential as therapeutic targets in the treatment of metabolic and inflammatory disorders. In particular, the evidence in support of small molecule versus dietary and microbiota-based therapeutic approaches will be considered to provide insight into the development of novel multifaceted strategies targeting the FFA receptors for the treatment of metabolic and inflammatory disorders.

Complex Pharmacology of Novel Allosteric Free Fatty Acid 3 Receptor Ligands

“…Involvement of these receptors has now been demonstrated in this respect in relation to both metabolism and inflammation (Trompette et al, 2014), and this has stimulated interest in the receptors as novel therapeutic targets (Ulven, 2012;Dranse et al, 2013;Yonezawa et al, 2013). However, clearly defining the specific roles of FFA2 versus FFA3, and importantly, which would ultimately be a more effective therapeutic target in distinct pathologic conditions, has been challenging in the absence of selective pharmacological tool compounds.…”

“…Interestingly, the opposite may be true among the SCFA receptors, in which significant species differences have been described for both FFA2 and FFA3 orthosteric ligands (Hudson et al, 2012a(Hudson et al, ,b, 2013a, whereas the function of the allosteric ligands described in this study appears more similar across species. This may result from the nature of the SCFA receptors as nutritional sensors (Dranse et al, 2013;Milligan et al, 2014) that respond to ligands derived from fiber fermented by the gut microbiota. Specifically, as different species rely on markedly different amounts of fiber in their diet, they are exposed to significantly different concentrations of SCFAs (Bergman, 1990).…”

The Pharmacology and Function of Receptors for Short-Chain Fatty Acids

“…Although it has been reasoned that allosteric binding sites should be under less evolutionary pressure to be maintained than orthosteric sites because endogenously produced regulators do not bind to these regions (May et al, 2007;Hudson et al, 2013b), it is helpful that the allosteric ligands described earlier do display function at rodent orthologs of FFA2 and FFA3. Considering that different species ingest different amounts of fiber, and they are consequently exposed to varying concentrations of SCFAs (Dranse et al, 2013;Milligan et al, 2014), it is reasonable to imagine that this may have driven alterations in the orthosteric binding site between species . This could be extremely important in terms of drug development programs.…”

Distinct Phosphorylation Clusters Determine the Signaling Outcome of Free Fatty Acid Receptor 4/G Protein–Coupled Receptor 120

“…Rather than acting simply as sources of energy, fatty acids derived from the diet have recently been appreciated to also act as signaling molecules that play integrative roles in dietary homeostasis (Dranse et al, 2013;Hara et al, 2014;Offermanns, 2014). Key contributions of such fatty acids to metabolic and inflammatory control, as well as to dysregulation of processes that are associated with obesity and metabolic syndrome (Oh et al, 2014;Watterson et al, 2014;Sekiguchi et al, 2015), are produced via specific interactions with G protein-coupled receptors (GPCRs) present at the surface of cells within tissues (including the gut, pancreas, and adipose tissue) that control metabolite distribution, flux, and storage (Oh et al, 2014;Watterson et al, 2014;Sekiguchi et al, 2015).…”