Modulation of sweet taste sensitivities by endogenous leptin and endocannabinoids in mice.

KEY POINTS: Potential roles of endogenous leptin and endocannabinoids in sweet taste were examined by using pharmacological antagonists and mouse models including leptin receptor deficient (db/db) and diet-induced obese (DIO) mice. Chorda tympani (CT) nerve responses of lean mice to sweet compounds were increased after administration of leptin antagonist (LA) but not affected by administration of cannabinoid receptor antagonist (AM251). db/db mice showed clear suppression of CT responses to sweet compounds after AM251, increased endocannabinoid levels in the taste organ, and enhanced expression of a biosynthesizing enzyme of endocannabinoids in taste cells. The effect of LA was gradually decreased and that of AM251 was increased during the course of obesity in DIO mice. These findings suggest that circulating leptin, but not local endocannabinoids, is a dominant modulator for sweet taste in lean mice and endocannabinoids become more effective modulators of sweet taste under conditions of deficient leptin signalling. ABSTRACT: Leptin is an anorexigenic mediator that reduces food intake by acting on hypothalamic receptor Ob-Rb. In contrast, endocannabinoids are orexigenic mediators that act via cannabinoid CB1 receptors in hypothalamus, limbic forebrain, and brainstem. In the peripheral taste system, leptin administration selectively inhibits behavioural, taste nerve and taste cell responses to sweet compounds. Opposing the action of leptin, endocannabinoids enhance sweet taste responses. However, potential roles of endogenous leptin and endocannabinoids in sweet taste remain unclear. Here, we used pharmacological antagonists (Ob-Rb: L39A/D40A/F41A (LA), CB1 : AM251) and examined the effects of their blocking activation of endogenous leptin and endocannabinoid signalling on taste responses in lean control, leptin receptor deficient db/db, and diet-induced obese (DIO) mice. Lean mice exhibited significant increases in chorda tympani (CT) nerve responses to sweet compounds after LA administration, while they showed no significant changes in CT responses after AM251. In contrast, db/db mice showed clear suppression of CT responses to sweet compounds after AM251, increased endocannabinoid (2-arachidonoyl-sn-glycerol (2-AG)) levels in the taste organ, and enhanced expression of a biosynthesizing enzyme (diacylglycerol lipase α (DAGLα)) of 2-AG in taste cells. In DIO mice, the LA effect was gradually decreased and the AM251 effect was increased during the course of obesity. Taken together, our results suggest that circulating leptin, but not local endocannabinoids, may be a dominant modulator for sweet taste in lean mice; however, endocannabinoids may become more effective modulators of sweet taste under conditions of deficient leptin signalling, possibly due to increased production of endocannabinoids in taste tissue.

Modulation of sweet responses of taste receptor cells.

Taste receptor cells play a major role in detection of chemical compounds in the oral cavity. Information derived from taste receptor cells, such as sweet, bitter, salty, sour and umami is important for evaluating the quality of food components. Among five basic taste qualities, sweet taste is very attractive for animals and influences food intake. Recent studies have demonstrated that sweet taste sensitivity in taste receptor cells would be affected by leptin and endocannabinoids. Leptin is an anorexigenic mediator that reduces food intake by acting on leptin receptor Ob-Rb in the hypothalamus. Endocannabinoids such as anandamide [N-arachidonoylethanolamine (AEA)] and 2-arachidonoyl glycerol (2-AG) are known as orexigenic mediators that act via cannabinoid receptor 1 (CB1) in the hypothalamus and limbic forebrain to induce appetite and stimulate food intake. At the peripheral gustatory organs, leptin selectively suppresses and endocannabinoids selectively enhance sweet taste sensitivity via Ob-Rb and CB1 expressed in sweet sensitive taste cells. Thus leptin and endocannabinoids not only regulate food intake via central nervous systems but also modulate palatability of foods by altering peripheral sweet taste responses. Such reciprocal modulation of leptin and endocannabinoids on peripheral sweet sensitivity may play an important role in regulating energy homeostasis.

Responses to apical and basolateral application of glutamate in mouse fungiform taste cells with action potentials.

In taste bud cells, glutamate may elicit two types of responses, as an umami tastant and as a neurotransmitter. Glutamate applied to apical membrane of taste cells would elicit taste responses whereas glutamate applied to basolateral membrane may act as a neurotransmitter. Using restricted stimulation to apical or basolateral membrane of taste cells, we examined responses of taste cells to glutamate stimulation, separately. Apical application of monosodium glutamate (MSG, 0.3 M) increased firing frequency in some of mouse fungiform taste cells that evoked action potentials. These cells were tested with other basic taste compounds, NaCl (salty), saccharin (sweet), HCl (sour), and quinine (bitter). MSG-sensitive taste cells could be classified into sweet-best (S-type), MSG-best (M-type), and NaCl or other electrolytes-best (N- or E/H-type) cells. Furthermore, S- and M-type could be classified into two sub-types according to the synergistic effect between MSG and inosine-5'-monophosphate (S1, M1 with synergism; S2, M2 without synergism). Basolateral application of glutamate (100 µM) had almost no effect on the mean spontaneous firing rates in taste cells. However, about 10% of taste cells tested showed transient increases in spontaneous firing rates (>mean + 2 standard deviation) after basolateral application of glutamate. These results suggest the existence of multiple types of umami-sensitive taste cells and the existence of glutamate receptor(s) on the basolateral membrane of a subset of taste cells.

Gustatory signaling in the periphery: detection, transmission, and modulation of taste information.

Gustatory signaling begins with taste receptor cells that express taste receptors. Recent molecular biological studies have identified taste receptors and transduction components for basic tastes (sweet, salty, sour, bitter, and umami). Activation of these receptor systems leads to depolarization and an increase in [Ca(2+)](i) in taste receptor cells. Then transmitters are released from taste cells and activate gustatory nerve fibers. The connection between taste cells and gustatory nerve fibers would be specific because there may be only limited divergence of taste information at the peripheral transmission. Recent studies have demonstrated that sweet taste information can be modulated by hormones or other endogenous factors that could act on their receptors in a specific group of taste cells. These peripheral modulations of taste information may influence preference behavior and food intake. This paper summarizes data on molecular mechanisms for detection and transduction of taste signals in taste bud cells, information transmission from taste cells to gustatory nerve fibers, and modulation of taste signals at peripheral taste organs, in particular for sweet taste, which may play important roles in regulating energy homeostasis.

Reciprocal modulation of sweet taste by leptin and endocannabinoids.

Sweet taste perception is important for animals to detect carbohydrate source of calories and has a critical role in the nutritional status of animals. Recent studies demonstrated that sweet taste responses can be modulated by leptin and endocannabinoids [anandamide (N-arachidonoylethanolamine) and 2-arachidonoyl glycerol]. Leptin is an anorexigenic mediator that reduces food intake by acting on hypothalamic receptor, Ob-Rb. Leptin is shown to selectively suppress sweet taste responses in wild-type mice but not in leptin receptor-deficient db/db mice. In marked contrast, endocannabinoids are orexigenic mediators that act via CB(1) receptors in hypothalamus and limbic forebrain to induce appetite and stimulate food intake. In the peripheral taste system, endocannabinoids also oppose the action of leptin and enhance sweet taste sensitivities in wild-type mice but not in mice genetically lacking CB(1) receptors. These findings indicate that leptin and endocannabinoids not only regulate food intake via central nervous systems but also may modulate palatability of foods by altering peripheral sweet taste responses via their cognate receptors.