Unlocking the Molecular Secrets of Sweet Taste Perception

Our enjoyment of sweets can be traced to one subset of taste receptor cells – specialized sweet-sensing cells found in our taste buds – that initiate the chain of reactions driving our strong attraction and appetite for sugar.
 
Now, Howard Hughes Medical Institute Investigator Charles Zuker and members of his Columbia University lab have unveiled the structure of the human sweet receptor, adding fundamental insights into taste detection and our understanding of the taste system, and paving the way for modern-day confectioners to reduce the amount of sugar in consumer products – all without sacrificing sweetness. 

"By uncovering the structure of the sweet receptor, we gain knowledge into the molecular mechanisms that govern how we detect sweetness, and how a single receptor can recognize such a broad range of sweet-tasting molecules," says Zhang Juen, an associate research scientist in Zuker's lab, and co-first author of the paper published on May 7, 2025. "This discovery will greatly benefit the battle against our strong desire for sugar, and enable the rational design of modulators of the sweet receptor, which in turn may help alleviate the prevalence of obesity, diabetes, and cardiovascular disease." 
 
In 2001, Zuker's laboratory discovered the genes that encode the sweet receptor. When we enjoy our favorite candies and desserts, these foods taste sweet solely because they activate this receptor.
 
Now that Zuker and his team have revealed the structure of this receptor, they have opened the door to discovering how to modulate its function. This means that, instead of relying on artificial sweeteners to cut back on the amount of sugar and calories in products, food and beverage makers could simply use less sugar and add a modulator to their product. This way we should not only satisfy our sweet tooth, but ultimately consume far less sugar and fewer calories, says Zhengyuan Lu, a graduate student in Zuker's lab and co-first author of the study.

The Benefit of Sweetness

If an insatiable sweet tooth is tied to so many health challenges – including diabetes and obesity – why did humans evolve the ability to taste sweetness in the first place? 

All told, human taste buds consist of five basic receptor classes: sweet, umami (the taste of protein building blocks), salty, sour, and bitter. "During evolution, the mammalian taste system evolved to detect things that are required to ensure a complete diet [using the sweet, umami and salt taste cells], and to avoid eating things that will kill us," says Zuker. "Each of these five taste qualities sends a signal to the brain that says 'this is appetitive' or 'I am averse to this.'" We can think of our palate like a piano that consists of five basic keys. The combination of keys, and intensity with which the piano is played ultimately enables us to transform the chemicals we detect on our tongue into flavor we either enjoy or dislike. 

Souring on a Solved Mystery? No Way.

Even as Zuker and his lab work to solve the mysteries of what drives the human love for sweetness, it hasn't ruined the experience of indulging in a treat now and then, he says.

"Like everyone, I love sweet treats," Zhang adds. "I've always been curious about how my body recognizes sweet molecules. Determining the structure of the human sweet receptor fulfills not only my personal curiosity but also offers great potential for consumer applications. Moreover, it provided me with a valuable opportunity, as a neuroscientist, to expand my research scope into biochemistry and structural biology."

Zhang and Lu are not the only neuroscientists in the lab who have dabbled in disciplines once outside their comfort zone. Just last year, Zuker and his team also showed how a group of nerve cells in the brainstem act like a master controller of the body's response to an immune insult.

"In the Zuker lab, the only limitation is our creativity," Zhang says. "This lab provides a remarkable opportunity to leverage and expand our vision and ingenuity. My PhD and my first project in the Zuker lab focused on electrophysiology, neural circuits, and animal behavior. Before working on this project, I had no prior experience with structural biology. It was with great foresight and confidence that Dr. Zuker supported me in switching to a new research field and trusted me to be able to accomplish this risky and competitive project." 

This quest to follow the science where it leads has taken Zuker and his lab on all sorts of explorations of how the brain represents our sensory experiences. Over the past 20 years, it led to the near complete description of the biology of the sense of taste – from the tongue to the brain, and from molecules to circuits.

"A lot of our work now centers on brain control over body biology," says Zuker. In fact, pioneering research done in Zuker's lab previously revealed that the vagus nerve, which runs from the brain to the gut, serves as the main highway for carrying sugar and fat signals between the so-called gut-brain axis. This work uncovered the neural basis for our strong cravings and desire for fat and sugar, and exposed the fundamental difference between liking fat and sugar (the tongue) versus wanting fat and sugar (the gut-brain-axis). 

"Knowing how something works does not in any way minimize the magic," he says with a smile. "It only enhances the magic."

HHMI is a private biomedical research institution. Our scientists make discoveries that advance human health and our fundamental understanding of biology. We also invest in transforming science education into a creative, inclusive endeavor that reflects the excitement of research. Earlier this year, HHMI announced AI@HHMI, a $500 million investment over the next 10 years to support artificial intelligence-driven projects in the life sciences. HHMI's headquarters are located in Chevy Chase, Maryland, just outside Washington, DC.