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Gut feelings: taste-independent circuits for sugar and fat preferences

Sensory systems are important for animals to perform appropriate behaviors. In Chapter 6 of Principles of Neurobiology, we learned about how the taste system, one of the major sensory systems, sense different types of tastants and guide the uptake of nutrients (Section 6.15–6.19). It has been long known and explicitly discussed in the textbook that the taste system detects tastants by taste receptor cells (TRCs) on the surface of the tongue and oral cavity. TRCs then transfer the information through gustatory nerves to the brain (Figure 6-32). However, recent studies have revealed another nutrient-sensing system via the gut.

Taking the sense of sugar as an example. Molecular and genetic evidence suggests that T1R2 and T1R3 are G-protein-coupled receptors on TRCs that respond to sugar (Section 6.16). Evidence from disrupting sweet taste suggests the existence of taste-independent signaling pathway for sugar detection. What is the neural basis for sweet-independent sugar preference?

To address this question, Tan et al. (2020) began with setting up a behavioral assay. They adapted the mouse two-bottle choice test (sugar versus water, Section 6.16) to sugar versus artificial sweetener, where both stimuli activate the sweet taste receptors in the tongue. Interestingly, they found that even though mice showed no preference at the beginning, they developed preference for sugar over time. This behavior occurred even in the absence of taste system, suggesting a taste-independent neural circuits underlying this phenomenon.

What are neural circuits responsible for this preference for sugar? The authors first identified caudal nucleus of the solitary tract (cNST) as the sugar activating neurons in the brain. This led them to test if the gut-brain axis plays a role, which involves vagal sensory neurons sending information to cNST. By abolishing specific neurons and performing viral tracing (Figure 14-33), they confirmed that vagal sensory neurons function in sugar sensing and are the direct upstream of cNST. The authors further identified sodium-glucose-linked transporter 1 (SGLT1) as the principal sugar receptor in gut using pharmacologically inhibition experiments. In a nutshell, Tan et al. suggested that the sugar signal is transduced from the SGLT1 in the gut to vagal sensory neurons and to the cNST in the brain as an interoceptive system independent of the taste system (Figure).

How about other nutrients, like fat? Li et al. (2022) investigated whether the taste-independent pathway can sense fat besides sugar. The two-bottle choice test was conducted for fat versus artificial sweetness, under the circumstance when both stimuli are equally attractive to a naive animal. They found a preference for fat over time. Similar to sugar, they revealed that the gut-brain axis is also crucial for fat preference. Using calcium imaging, they identified two distinct populations of vagal neurons that show different responses to fat and sugar (Figure 14-43). They further characterized the molecular differences underlying these two populations: VIP-expressing vagal neurons convey nutrient preference for sugar, proteins, and fat; while TRPA1-expressing vagal neurons mediate a fat-specific preference. They provided further evidence on the responding cells and receptors in gut. Pharmacologically inhibition experiments suggest Cholecystokinin (CCK)-expressing enteroendocrine cells (EECs) are important for nutrient preference. Genetic knockout experiments suggest GPR40 and GPR120 function as fat receptors (Figure).

Together, these two papers uncovered the molecular and circuits basis of the taste-independent systems that drive the preference for nutrients. This greatly broadens our understanding of how we sense the contents of food. The authors proposed that the taste system confers the “liking” of sweet and fat, while the gut-brain axis confers the “wanting” sugar and fat. Yet more questions remain to be answered. How is the information from the taste system and gut-brain axis integrated in the brain? Can we develop artificial “sweeteners” or “fat-mimetics” to activate the gut-brain axis as new ways to combat obesity?

Figure. Schematic summary for how the gut-brain axis detect sugar and fat. Adapted from Li et al., 2022.


Li, M., Tan, H. E., Lu, Z., Tsang, K. S., Chung, A. J., & Zuker, C. S. (2022). Gut–brain circuits for fat preference. Nature, 610(7933), 722-730.

Tan, H. E., Sisti, A. C., Jin, H., Vignovich, M., Villavicencio, M., Tsang, K. S., ... & Zuker, C. S. (2020). The gut–brain axis mediates sugar preference. Nature, 580(7804), 511-516.