Novel GPR120 agonist TUG891 modulates fat taste perception and preference and activates tongue-brain-gut axis in mice

Abstract

GPR120 is implicated as a lipid receptor in the oro-sensory detection of dietary fatty acids. However, the effects of GPR120 activation on dietary fat intake or obesity are not clearly understood. We investigated to determine whether the binding of TUG891, a novel GPR120 agonist, to lingual GPR120 modulates fat preference in mice. We explored the effects of TUG891 on obesity-related hormones and conducted behavioral choice tests on mice to better understand the physiologic relevance of the action of TUG891. In cultured mouse and human taste bud cells (TBCs), TUG891 induced a rapid increase in Ca2+ by acting on GPR120. A long-chain dietary fatty acid, linoleic acid (LA), also recruited Ca2+ via GPR120 in human and mouse TBCs. Both TUG891 and LA induced ERK1/2 phosphorylation and enhanced in vitro release of glucagon-like peptide-1 from cultured human and mouse TBCs. In situ application of TUG891 onto the tongue of anesthetized mice triggered the secretion of pancreatobiliary juice, probably via the tongue-brain-gut axis. Furthermore, lingual application of TUG891 altered circulating concentrations of cholecystokinin and adipokines, associated with decreased circulating LDL, in conscious mice. In behavioral tests, mice exhibited a spontaneous preference for solutions containing either TUG891 or LA instead of a control. However, addition of TUG891 to a solution containing LA significantly curtailed fatty acid preference. Our study demonstrates that TUG891 binds to lingual GPR120 receptors, activates the tongue-brain-gut axis, and modulates fat preference. These findings may support the development of new fat taste analogs that can change the approach to obesity prevention and treatment.

Implication of TRPC3 channel in gustatory perception of dietary lipids

“…As expected, there was no loss of fat taste in ataxic mice. Besides, the lingual application immediately triggered the release of CCK and PYY in blood, probably via tongue-brain-gut axis, as we have recently reported, 9 and their secretion was blunted in TRPC3 −/− mice and in animals with tongue application of TRPC3-siRNA. These observations clearly demonstrate that lingual TRPC3 is triggering oro-sensory fatty acid perception, leading to physiological consequences such as CCK and PYY release.…”

“…In gustometer, TRPC3 −/− mice exhibited lower hedonic attraction for LA than WT mice ( Figure 2D,E). In order to test whether tongue TRPC3 is coupled with anticipatory physiological mechanisms, such as the release of gut anorectic peptides via tongue-brain-gut loop, 9 we determined the concentrations of cholecystokinin (CCK) and peptide YY (PYY) in blood. We observed that lingual application of LA to mouse tongue triggered their release in blood and this phenomenon was curtailed in TRPC3 −/− mice and in those having tongue application of TRPC3 siRNA ( Figure 2F,G).…”

Development of Free Fatty Acid Receptor 4 (FFA4/GPR120) Agonists in Health Science

“…TUG-891 was used to elucidate FFA4 function in the tongue in relation to taste preference for fats. In cultured mouse and human taste bud cells, TUG-891 treatment induced a rapid increase in intracellular Ca 2+ , induced ERK1/2 phosphorylation, and enhanced release of GLP-1 ( Murtaza et al ., 2020 ). Direct lingual application of TUG-891 altered circulating concentrations of cholecystokinin and adipokines, associated with decreased circulating LDL in conscious mice ( Murtaza et al ., 2020 ).…”

“…In cultured mouse and human taste bud cells, TUG-891 treatment induced a rapid increase in intracellular Ca 2+ , induced ERK1/2 phosphorylation, and enhanced release of GLP-1 ( Murtaza et al ., 2020 ). Direct lingual application of TUG-891 altered circulating concentrations of cholecystokinin and adipokines, associated with decreased circulating LDL in conscious mice ( Murtaza et al ., 2020 ). Binding of TUG-891 to lingual FFA4 seems to activate the tongue-brain-gut axis and modulate taste preference for fats ( Murtaza et al ., 2020 ).…”

“…Direct lingual application of TUG-891 altered circulating concentrations of cholecystokinin and adipokines, associated with decreased circulating LDL in conscious mice ( Murtaza et al ., 2020 ). Binding of TUG-891 to lingual FFA4 seems to activate the tongue-brain-gut axis and modulate taste preference for fats ( Murtaza et al ., 2020 ). TUG-891 was also used in a cisplatin-induced acute kidney injury model.…”