Novel Fat Taste Receptor Agonists Curtail Progressive Weight Gain in Obese Male Mice.

The spontaneous preference for dietary lipids is principally regulated by 2 lingual fat taste receptors, CD36 and GPR120. Obese animals and most of human subjects exhibit low orosensory perception of dietary fat because of malfunctioning of these taste receptors. Our aim was to target the 2 fat taste receptors by newly synthesized high affinity fatty acid agonists to decrease fat-rich food intake and obesity. We synthesized 2 fat taste receptor agonists (FTA), NKS-3 (CD36 agonist) and NKS-5 (CD36 and 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. 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 mice but not in control mice. Our results show that targeting fat sensors in the tongue by novel chemical fat taste agonists might represent a new strategy to reduce obesity.