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.

Keywords: diet; free fatty acid; free fatty acid receptor; glucose homeostasis; gut microbiota; inflammation; metabolism; therapeutics.

Figure 1

Modulation of FFA activation can be achieved through several different methods to prevent and/or treat metabolic and inflammatory diseases. Changes in FFA1-4 activity can be achieved directly through small-molecule targeting of specific FFAs (A). FFA activity can also be modulated indirectly via changes in dietary intake (B) or modulation of gut microflora composition (C). Increased consumption and/or supplementation of the diet with fish, meats or omega-3 FAs will result in increased levels of LCFAs and FFA1 and FFA4 activation. Increased intake of complex plant polysaccharides will result in generation of SCFAs through fermentation by gut microbiota and activation of FFA2 and FFA3. Levels of SCFAs can also be altered indirectly via modulation of gastrointestinal microflora composition through administration of biotics or bacterial transplantation. Activation of FFAs has beneficial effects on a variety of physiological processes that are associated with metabolic and inflammatory processes.