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.