Impaired Glucose Metabolism in Mice Lacking the Tas1r3 Taste Receptor Gene

Abstract

The G-protein-coupled sweet taste receptor dimer T1R2/T1R3 is expressed in taste bud cells in the oral cavity. In recent years, its involvement in membrane glucose sensing was discovered in endocrine cells regulating glucose homeostasis. We investigated importance of extraorally expressed T1R3 taste receptor protein in age-dependent control of blood glucose homeostasis in vivo, using nonfasted mice with a targeted mutation of the Tas1r3 gene that encodes the T1R3 protein. Glucose and insulin tolerance tests, as well as behavioral tests measuring taste responses to sucrose solutions, were performed with C57BL/6ByJ (Tas1r3+/+) inbred mice bearing the wild-type allele and C57BL/6J-Tas1r3tm1Rfm mice lacking the entire Tas1r3 coding region and devoid of the T1R3 protein (Tas1r3-/-). Compared with Tas1r3+/+ mice, Tas1r3-/- mice lacked attraction to sucrose in brief-access licking tests, had diminished taste preferences for sucrose solutions in the two-bottle tests, and had reduced insulin sensitivity and tolerance to glucose administered intraperitoneally or intragastrically, which suggests that these effects are due to absence of T1R3. Impairment of glucose clearance in Tas1r3-/- mice was exacerbated with age after intraperitoneal but not intragastric administration of glucose, pointing to a compensatory role of extraoral T1R3-dependent mechanisms in offsetting age-dependent decline in regulation of glucose homeostasis. Incretin effects were similar in Tas1r3+/+ and Tas1r3-/- mice, which suggests that control of blood glucose clearance is associated with effects of extraoral T1R3 in tissues other than the gastrointestinal tract. Collectively, the obtained data demonstrate that the T1R3 receptor protein plays an important role in control of glucose homeostasis not only by regulating sugar intake but also via its extraoral function, probably in the pancreas and brain.

Nutrient Sensing Systems in Fish: Impact on Food Intake Regulation and Energy Homeostasis

“…The expression of liver X receptor (LXR) (Mitro et al, 2007) responds to increased glucose levels eliciting a decrease in gluconeogenic capacity (Anthonisen et al, 2010; Archer et al, 2014). The sweet taste receptors (formed by type 1 taste receptor subunits (T1Rs) 2 and 3, and α-gustducin) respond to changes in glucose levels activating an intracellular signaling cascade (Ren et al, 2009; Kyriazis et al, 2014; Murovets et al, 2015; Herrera Moro Chao et al, 2016). Enhanced glucose levels induce increased expression of sodium/glucose co-transporter 1 (SGLT-1) (Díez-Sampedro et al, 2003; González et al, 2009; Thorens, 2012).…”

Sugar-induced cephalic-phase insulin release is mediated by a T1r2+T1r3-independent taste transduction pathway in mice

“…The first was to measure sugar-induced CPIR in B6 and T1r3 KO mice and assess its role in glucose tolerance. Prior studies have established that T1r2 KO and T1r3 KO mice display impaired glucose tolerance ( 12 , 28 , 29 , 38 ), but normal insulin sensitivity ( 38 ). However, because these prior studies administered the glucose postorally (i.e., intragastrically or intraperitoneally), they did not address the specific contribution of orally expressed T1r3 to insulin release and glucose tolerance.…”

Genetic controls of mouseTas1r3-independent sucrose intake

“…Glucose and insulin tolerance tests. We tested homozygous Scq1 congenic mice (C1) and 129 inbred mice twice (at 8 weeks and again at 36 weeks of age) for changes in plasma glucose in response to exogenous glucose (glucose tolerance test; GTT) or insulin administration (insulin tolerance test; ITT) [23]. All mice were tested during the light phase and had unrestricted access to food prior to testing.…”