Key Questions for Translation of FFA Receptors: From Pharmacology to Medicines

Abstract

The identification of fatty acids as ligands for the G-protein coupled free fatty acid (FFA) receptor family over 10 years ago led to intensive chemistry efforts to find small-molecule ligands for this class of receptors. Identification of potent, selective modulators of the FFA receptors and their utility in medicine has proven challenging, in part due to their complex pharmacology. Nevertheless, ligands have been identified that are sufficient for exploring the therapeutic potential of this class of receptors in rodents and, in the case of FFA1, FFA2, FFA4, and GPR84, also in humans. Expression profiling, the phenotyping of FFA receptor knockout mice, and the results of studies exploring the effects of these ligands in rodents have uncovered a number of indications where engagement of one or a combination of FFA receptors might provide some clinical benefit in areas including diabetes, inflammatory bowel syndrome, Alzheimer's, pain, and cancer. In this chapter, we will review the clinical potential of modulating FFA receptors based on preclinical and in some cases clinical studies with synthetic ligands. In particular, key aspects and challenges associated with small-molecule ligand identification and FFA receptor pharmacology will be addressed with a view of the hurdles that need to be overcome to fully understand the potential of the receptors as therapeutic targets.

Acute and Repeated Treatment with 5-PAHSA or 9-PAHSA Isomers Does Not Improve Glucose Control in Mice

“…This result raises the salient question of whether a metabolite circulating in plasma at subnanomolar concentrations can exert biological effects through the activation of GPR120. Moreover, there is considerable controversy in the literature surrounding the beneficial effects of GPR120 on glucose metabolism (Suckow and Briscoe, 2017). Furthermore, Paulsen et al (2014) have excluded a major role for GPR120 in the regulation of GLP-1 secretion, and data from a chronic GPR120 agonist study in DIO mice revealed only modest effects on glycemic control with no clear influence on GLP-1 secretion or body weight (Oh et al, 2014;Suckow and Briscoe, 2017).…”

“…Moreover, there is considerable controversy in the literature surrounding the beneficial effects of GPR120 on glucose metabolism (Suckow and Briscoe, 2017). Furthermore, Paulsen et al (2014) have excluded a major role for GPR120 in the regulation of GLP-1 secretion, and data from a chronic GPR120 agonist study in DIO mice revealed only modest effects on glycemic control with no clear influence on GLP-1 secretion or body weight (Oh et al, 2014;Suckow and Briscoe, 2017). Thus, it may be concluded that 9-PAHSA can indeed activate GPR120 in cellular systems at very high concentrations (micromolar range); however, it seems unlikely that this potential translates into metabolic benefits in vivo.…”

Adipocyte JAK2 mediates aging-associated metabolic liver disease and progression to hepatocellular carcinoma

“…Adipose tissue dysfunction, and IR in particular, is highly associated with cancer and adipocytes have been proposed as mediators of tumor cell behavior (52). How insulin resistant adipocytes promote oncogenesis is unknown, but a role for fatty acid receptors has been proposed (53). In addition, metabolic re-programming in HCC is mediated by the master oncogene Myc (54) and MYC levels themselves are induced by cellular exposure to fatty acids (55).…”

Adipocyte JAK2 mediates spontaneous metabolic liver disease and hepatocellular carcinoma

“…Adipose tissue dysfunction, and IR in particular, is highly associated with cancer and adipocytes have been proposed as mediators of tumor cell behavior (53). How insulin-resistant adipocytes promote oncogenesis is unknown, but a role for fatty acid receptors has been proposed (54). In addition, metabolic reprogramming in HCC is mediated by the master oncogene Myc (55), and MYC levels themselves are induced by cellular exposure to fatty acids (56).…”