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. 2020 Feb;61(2):133-142.
doi: 10.1194/jlr.RA119000142. Epub 2019 Dec 5.

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

Babar Murtaza  1 , Aziz Hichami  1 , Amira S Khan  1 , Bharat Shimpukade  2 , Trond Ulven  2   3 , Mehmet Hakan Ozdener  4 , Naim A Khan  5
Affiliations

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

Babar Murtaza et al. J Lipid Res. 2020 Feb.

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.

Keywords: extracellular signal-regulated kinase 1/2; glucagon-like peptide-1; linoleic acid; obesity.

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Conflict of interest statement

The authors declare that they have no conflicts of interest with the contents of this article.

Figures

Fig. 1.
Fig. 1.
Effect of TUG891 on Ca2+ signaling in TBCs. The cultured TBCs were loaded with Fura-2/AM, and the changes in [Ca2+]i were monitored as described in the Materials and Methods section. A, B: The pseudo-colored images compare the changes in [Ca2+]i evoked by TUG891 (10 μM) in mouse and human TBCs, respectively. C, D: Shown is the effect of AH7614 on TUG891-triggered increase in [Ca2+]i in mouse and human TBCs, respectively. E: Shown is the dose-response curve of TUG891 on Ca2+ signaling in mTBCs. For this purpose, TBCs were preincubated for 15 min in the presence of 100 μM of AH7614 followed by addition of TUG891. The arrows indicate the time of addition of TUG891 without interruption in the recording. The traces show the identical images reproduced independently (n = 5).
Fig. 2.
Fig. 2.
TUG891 recruits [Ca2+]i mobilized by LA. The cultured mouse (A–C) and human (D–F) TBCs were loaded with Fura-2/AM, and the changes in [Ca2+]i were monitored as described in the Materials and Methods section. TBCs were stimulated by LA (50 μM) alone (A, D) and before or after TUG891 (10 μM) (B, C, E, F), and changes in [Ca2+]i were recorded. The arrows indicate the time of addition of LA or TUG891 without interruption in the recording. The traces show the identical images reproduced independently (n = 5).
Fig. 3.
Fig. 3.
Effect of TUG891 and LA on ERK1/2 phosphorylation in cultured TBCs. Mouse (A) or human (B) TBCs were untreated (control) or treated with LA (50 μM) or TUG891 (10 μM) in combination and in the presence or absence of AH7614 followed by Western blot analysis for the determination of phosphorylated protein expression, as described in the Materials and Methods. The histograms show the results of independent experiments (n = 3). The difference between values was determined by one-way ANOVA, followed by LSD test. P < 0.05 was considered as statistically significant.
Fig. 4.
Fig. 4.
Effect of TUG891 and LA on GLP-1 release from TBCs. Cultured mouse (A) and human (B) TBCs were untreated (control) or treated with TUG891 (10 μM) or LA (50 μM) in combination or after preincubation with AH7614 (100 μM). GLP-1 release from TBCs was determined by ELISA, as mentioned in the Material and Methods section. The histograms represent the results of independent experiments (n = 3). The difference between values was determined by one-way ANOVA, followed by LSD test. P < 0.05 was considered as statistically significant. *In comparison to LA; $In comparison to TUG891.
Fig. 5.
Fig. 5.
Effect of lingual application of TUG891 on the activation of the tongue-brain-gut axis. Experiments were conducted as described in the Materials and Methods section, and the concentrations of different peptides were measured in plasma samples by ELISA kits. A: The histogram expresses the flow rate of hepato-biliary secretions after lingual application of LA or TUG891. The other histograms show plasma concentrations of different hormones: ghrelin (B), CCK (C), GLP-1 (D), GLP-2 (E), and PYY (F). The histograms show the results of independent experiments (n = 3). The difference between values was determined by one-way ANOVA, followed LSD test. P < 0.05 was considered as statistically significant. *In comparison to LA; $In comparison to TUG891.
Fig. 6.
Fig. 6.
Effect of lingual application of TUG891 on adipokines and pro-inflammatory cytokines in mice. Different control and test agents were applied on tongues of anesthetized mice followed by euthanization. The histograms indicate the circulating concentrations of adiponectin (A), leptin (B), TNF-α (C), and IL-6 (D). Analyses were performed by using suitable ELISA kits as described in the Materials and Methods section. The histograms show the results of independent experiments (n = 3). The difference between values was determined by one-way ANOVA, followed by LSD test. P < 0.05 was considered as statistically significant. *In comparison to LA; $In comparison to TUG891.
Fig. 7.
Fig. 7.
Effect of TUG891 on fat preference in mice. In the first set of experiments involving a lickometer, each mouse was offered bottles containing different solutions and the number of licks was recorded for 1 (A) and 5 min (B). The control solution consisted of 0.3% xanthan gum, while the test solution contained 0.2% LA in 0.3% xanthan gum solution or TUG891 (100 μM). Individually caged mice were also subjected to a two-bottle preference test with a choice between control solution (water) and TUG891 (100 μM) (C). In other double-choice experiments, mice were offered the control (0.3% xanthan gum) and LA (0.2% in 0.3% xanthan gum) or control and LA solution containing TUG891 (100 μM) (D). Histograms show the results of independent experiments (n = 3). The difference between values was determined by one-way ANOVA, followed by LSD test. P < 0.05 was considered as statistically significant.
Fig. 8.
Fig. 8.
TUG891 will bind to lingual GPR120 in the TBCs and trigger a cascade of signalization (Ca2+ signaling and MAPK phosphorylation) leading to afferent signaling toward gustatory nerves that will bring the message to the brain. The central nervous system via vagus nerve will activate the gut axis and trigger release of gut hormone and other obesity-related mediators.
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