Activity of dietary fatty acids on FFA1 and FFA4 and characterisation of pinolenic acid as a dual FFA1/FFA4 agonist with potential effect against metabolic diseases

Abstract

Various foods are associated with effects against metabolic diseases such as insulin resistance and type 2 diabetes; however, their mechanisms of action are mostly unclear. Fatty acids may contribute by acting as precursors of signalling molecules or by direct activity on receptors. The medium-and long-chain NEFA receptor FFA1 (free fatty acid receptor 1, previously known as GPR40) has been linked to enhancement of glucose-stimulated insulin secretion, whereas FFA4 (free fatty acid receptor 4, previously known as GPR120) has been associated with insulin-sensitising and anti-inflammatory effects, and both receptors are reported to protect pancreatic islets and promote secretion of appetite and glucose-regulating hormones. Hypothesising that FFA1 and FFA4 mediate therapeutic effects of dietary components, we screened a broad selection of NEFA on FFA1 and FFA4 and characterised active compounds in concentration -response curves. Of the screened compounds, pinolenic acid, a constituent of pine nut oil, was identified as a relatively potent and efficacious dual FFA1/FFA4 agonist, and its suitability for further studies was confirmed by additional in vitro characterisation. Pine nut oil and free and esterified pure pinolenic acid were tested in an acute glucose tolerance test in mice. Pine nut oil showed a moderately but significantly improved glucose tolerance compared with maize oil. Pure pinolenic acid or ethyl ester gave robust and highly significant improvements of glucose tolerance. In conclusion, the present results indicate that pinolenic acid is a comparatively potent and efficacious dual FFA1/FFA4 agonist that exerts antidiabetic effects in an acute mouse model. The compound thus deserves attention as a potential active dietary ingredient to prevent or counteract metabolic diseases.

Complex Pharmacology of Free Fatty Acid Receptors

“…138,139 Although the current consensus appears to be that FFA1 is not responsible for the detrimental chronic effects of LCFA exposure, recent studies have continued to suggest FFA1 may play some role in lipotoxic effects of LCFAs. 140−142 One possible explanation could be, given the diversity of LCFAs known to activate FFA1, that efficacy differences reported among LCFAs, 129 or perhaps even signaling bias in their effects at FFA1, could account for these discrepancies. The concept of signaling bias in GPCRs with multiple endogenous ligands is not unusual and, indeed, has been widely reported within the chemokine receptor family.…”

“…For example, analysis of the widest group of fatty acids yet reported found that nearly all MCFAs and LCFAs tested had potencies falling within the range of 1−20 μM, and indeed, even the SFAs, which typically have not been associated with FFA4 agonism, have comparable potency to the n−3 PUFAs at FFA4. 129 However, it must be noted that although the potency does appear to be broadly similar across the MCFAs and LCFAs, efficacy differences among the fatty acids are apparent.…”

Dietary Fatty Acids and Their Potential for Controlling Metabolic Diseases Through Activation of FFA4/GPR120

“…Oleic acid and palmitoleic acid activate both FFA4 and FFA1, with palmitoleic acid being 5-to 10-fold more potent on FFA4 (Table 1) (18,43). Interestingly, the endogenous synthesis of palmitoleic acid has been connected to FFA4 through regulation of SCD1/ 9D (48).…”

“…This is interesting in light of the fact that LA and n-6 fatty acids have been viewed as predominantly proinflammatory. ALA and LA are both among the most potent fatty acids on FFA1 and FFA4 ( Table 1) (9,18,43,50,59), which is notable because of their abundance in diet.…”

“…The association of the AA cascade with proinflammatory messenger molecules is the basis for the notion that a diet high in AA might lead to aggravated inflammation; however, apart from being important in infant nutrition, AA supplements have not been strongly associated with either detrimental or beneficial effects (12). GLA, DGLA, and AA are all active on FFA4 and FFA1 at levels corresponding to other PUFAs, with GLA being particularly potent at FFA4 ( Table 1) (9,18,43,50,59).…”