Transient receptor potential (TRP) canonical (TRPC) channels play a critical role in sensory physiology. We assessed the implication of diacylglycerol (DAG)-responsive TRPC channels like TRPC3, TRPC6 and TRPC7, in oro-sensory perception of dietary lipids. We employed different biochemical techniques including, RT-qPCR, western blotting, and calcium imaging studies. All procedures on mice or humans were performed according to standard guidelines and were approved by the institutional ethical committees. We observed that mouse lingual taste bud cells (mTBC) expressed only TRPC3, but not TRPC6 or TRPC7, channels. Linoleic acid (LA), a long-chain fatty acid, triggered Ca2+ influx via the opening of TRPC3 channels in mTBC. Mass spectroscopy revealed that 1-stearoyl-2-linoleoyl-sn-glycerol (SLG), a DAG species, was produced by LA stimulation of mTBC. Consequently, an increase in [Ca2+]i, triggered by LA, SLG and 1,2-dioctanoyl-sn-glycerol (DiC8), an exogenous DAG analogue, was abolished in mTBC, treated with pyrazole-3 (Pyr-3), a TRPC3 channel blocker. Similarly, DAGs-induced increases in [Ca2+]i were curtailed in mTBC from TRPC3-/- mice, and also in mTBC in which TRPC3 expression was decreased by siRNA. Behavioral studies showed that spontaneous preference for a fatty acid was abolished in TRPC3-/- mice. Furthermore, while maintained on a high-fat diet or normal diet, the TRPC3-/- mice developed more severe obesity than wild-type animals, and TRPC3-signaling in mTBC was altered in obese mice. To study the implications of these findings in humans, we employed the “dominant model” to for genotyping analysis of rs11732666 TRPC3 single nucleotide polymorphism (SNP) in Algerian obese (n=57) and lean (n=59) children (n=116). It was revealed that Algerian obese children with heterozygous or mutated AA/AG genotype (n=24) exhibited significantly higher (p<0.05) fatty acid detection thresholds than homozygous GG genotype (n=33). Our study shows, for the first time, that lingual TRPC3 channels are implicated in lipid taste perception and, consequently, in obesity in mice and humans.