Sweet and Low on Leptin: Hormonal Regulation of Sweet Taste Buds

Since 1980, the incidence of obesity in the world has more than doubled (1), but most prescribed treatments still rely on voluntary modifications of eating behavior (dieting). Long-term compliance to dieting is difficult (2) as it requires eating less and forcefully deciding about what foods to eat. Sugar restriction, for instance, is a common theme in many weight-control diets and a must for patients with diabetes. The appetite for sugar is mediated by nutrient-sensing circuits in the brain, which play a role that seems to be conserved across species (3–5). These brain nutrient-sensing circuits are regulated to allow adaptive food intake behavior in response to the metabolic state and hormones such as leptin (6–9).

Leptin is an adipose tissue hormone that functions as an afferent signal in a negative feedback loop that maintains homeostatic control of adipose tissue mass (10,11). Leptin is synthesized by adipose tissue and released into the bloodstream in amounts that are proportional to the amount of fat, thus informing the brain about the status of energy reserves. Leptin is a primordial hormone in the regulation of energy homeostasis that acts in hypothalamic neurons to increase energy expenditure and reduce appetite (12). Moreover, leptin controls sugar reward via the central nervous system by acting on glucose-sensing neural circuitry (8,13,14).

While most studies have made progress in the identification of leptin action in the brain, Yoshida et al. (15) present a study revealing a role for leptin outside of the brain—in taste buds. They discovered that leptin regulates sweet taste responses in taste buds, thus putting forward the first peripheral mechanism linking sweetness to leptin.

In this study, the authors used in situ hybridization to investigate which types of taste cells (TCs) express the long form of the leptin receptor (Ob-Rb). Ob-Rb colocalizes with approximately 40% of taste receptor family 1 member 3 (T1R3)–expressing TCs, which are the sweet-sensing TCs. The study also included electrophysiological analyses of the effect of leptin on TC responses to different taste stimuli: sweet, sour, or bitter. Yoshida et al. discovered that leptin exhibits selective action on T1R3-expressing TCs, suppressing their response to natural sweet sweeteners, such as sucrose, and artificial sweeteners, such as sucralose and saccharin. This suppressive effect of leptin was reversible, dose-dependent, and did not extend to other sensory modalities, such as bitter or sour perception. The authors used mutant mice lacking Ob-Rb (db/db) to discover that the suppressive effect of leptin on TC responses to saccharin was mediated by Ob-Rb. In addition, the study demonstrated by in situ hybridization that the gene SUR1, which encodes for a K_ATP channel, was expressed in Ob-Rb/T1R3-expressing TCs. Pharmacological inhibition of this K_ATP channel blunts the suppressive effect of leptin on T1R3-expressing TC responses to saccharin. Reciprocally, pharmacological activation of K_ATP channels phenocopied the effect of leptin on saccharin-induced responses of T1R3-expressing TCs (Fig. 1).

Yoshida et al. also showed that diet-induced obesity blunts the suppressive effect of leptin on saccharin-sensitive TCs, but whether this effect is mediated by the regulation of K_ATP channels waits for further study. Moreover, the model proposed by this study relies mostly on extracellular electrophysiological recordings and needs behavioral validation. Would leptin-induced peripheral sweet blindness make sugar less interesting, or would this only apply to artificial sweeteners? Natural but not artificial sweeteners have a postingestive-rewarding effect that signals even in the absence of taste (16). Thus, this sensory model cannot account for preference for natural versus artificial sweeteners, as the authors report that leptin has a similar suppressive effect on sucrose-, saccharin-, and sucralose-mediated responses by T1R3-expressing TCs. Sensory and central systems are likely to have coevolved complementary strategies to modulate behavior. The regulation of sugar intake by leptin seems to be very complex, and Yoshida et al. (15) propose a model that adds another layer of regulation.