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Novel fat taste receptor agonists curtail progressive weight gain in obese male mice

Open AccessPublished:November 18, 2022DOI:https://doi.org/10.1016/j.jcmgh.2022.11.003
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      Abstract

      BACKGROUND & AIMS

      The spontaneous preference for dietary lipids is, principally, regulated by two lingual fat taste receptors, i.e., CD36 and GPR120. Obese animals and most of human subjects exhibit low oro-sensory perception of dietary fat because of malfunctioning of these taste receptors. Our aim was to target the two fat taste receptors by newly synthesized high affinity fatty acid agonists to decrease fat-rich food intake and obesity.

      METHODS

      We synthesized two fat taste receptor agonists (FTA), i.e., NKS-3 (CD36 agonist) and NKS-5 (CD36 & GPR120 agonist). We determined their molecular dynamic interactions with fat taste receptors, and the effect on Ca2+ signaling in mouse and human taste bud cells (TBC). In C57Bl/6 male mice, we assessed their gustatory perception and effects of their lingual application on activation of tongue-gut loop. We elucidated their effects on obesity and its related parameters in male mice, fed a high-fat diet.

      RESULTS

      The two FTA, NKS-3 and NKS-5, triggered higher Ca2+ signaling than a dietary long-chain fatty acid in human and mouse TBC. Mice exhibited a gustatory attraction for these compounds. In conscious mice, the application of FTA onto the tongue papillae induced activation of tongue-gut loop, marked by the release of pancreato-bile juice into collecting duct, and cholecystokinin and peptide-YY into blood stream. Daily intake of NKS-3 or NKS-5 via feeding bottles decreased food intake and progressive weight gain in obese, but not in control, mice.

      CONCLUSIONS

      Our results show that targeting fat sensors in the tongue by novel chemical fat taste agonists might represent a new strategy to reduce obesity.

      Graphical abstract

      Keywords

      Abbreviations used in this paper:

      BMI (body mass index), [Ca2+]i (intracellular calcium), FAS (fatty acid synthase), GPCRs (G protein-coupled receptors), GLP-1 (glucagon-like pepetide-1), GPR120 (G protein coupled receptor 120), GPR40 (G protein coupled receptor 40), HFD (High-fat diet), IPGTT (intraperitoneal glucose tolerance test), LA (Linoleic acid), LCFA (long-chain fatty acid), OA (oleic acid), PPAR-γ (peroxisome proliferator-activated receptor-γ), SCD1 (stearoyl-CoA desaturase-1), SREBP1c (sterol-regulatory element-binding transcription factor 1c), SSO (sulfo-N-succinimidyl oleate), TBC (taste bud cells)