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Researchers at Columbia University have identified a specialized neural circuit that could help researchers develop new ways of curbing our cravings for sugar. The research, which was carried out in mice, found that in addition to the taste receptors that signal to the brain when sugar hits the tongue, there are additional receptors in the gut that respond specifically to sugar. Artificial sweeteners don’t activate this sugar-sensing gut-brain circuit, providing new insights into why sugar substitutes are never quite as satisfying as the real thing. The research also points to new potential strategies for reducing sugar overconsumption, either by targeting this signaling circuit directly, or by developing artificial sweeteners that do activate it.

“We need to separate the concepts of sweet and sugar,” said Howard Hughes Medical Institute investigator Charles Zuker, PhD, a neuroscientist at Columbia University. “Sweet is liking, sugar is wanting. This new work reveals the neural basis for sugar preference … Uncovering this circuit helps explain how sugar directly impacts our brain to drive consumption. It also exposes new potential targets and opportunities for strategies to help curtail our insatiable appetite for sugar.”

Zucker and colleagues reported their findings in Nature, in a paper titled, “The gut-brain axis mediates sugar preference.” The studies build on decades of work by the Zuker lab to map the brain’s taste system.

The taste of sugar is one of the most basic sensory percepts for humans and other animals, the authors explained. “Sugar is a fundamental source of energy for all animals, and correspondingly, most species have evolved dedicated brain circuits to seek, recognize, and motivate its consumption.” Since the availability of refined sugar has become more widespread, consumption has rocketed. Back in the 1800s the average American would consume maybe 4.5 kg of sugar per year; average sugar consumption is now 45 kg per year, the authors noted. But increased consumption comes at a cost to health. Studies have linked excess dietary sugar to numerous health problems, including obesity and type 2 diabetes.

When we eat sugar, receptors in the mouth that recognize the sweet taste send hardwired signals to the brain. Zuker’s work had previously shown that sugar and artificial sweeteners switch on the same taste-sensing system, so artificial sweeteners also trigger these sweet receptors, and effectively co-opt the same taste-sensing system. However, despite this common signaling pathway, mice will still choose sugar over sweeteners.

Zuker’s team carried out an experiment comparing preference to sugar vs. the sweetener acesulfame K, which is used in diet soda, and other products. Mice offered water either with the sweetener or with sugar initially drank both, but within two days switched almost exclusively to the sugar water. “We reasoned this unquenchable motivation that the animal has for consuming sugar, rather than sweetness, might have a neural basis,” Zuker said.

Interestingly mice engineered to lack sweet receptors also showed a strong preference for sugar, a finding that has been reported in several other studies. “Thus, although taste-knockout mice cannot taste sugar or sweetener, they learn to recognize and choose the sugar, most probably as a result of strong positive post-ingestive effects,” the authors wrote. Studies have also shown that animals’ preference for sugar doesn’t depend on calorific content, indicating that there is a signaling system that recognizes the sugar molecule itself.

The authors set out to discover if there was another neural mechanism involved in sugar sensing. “We reasoned this unquenchable motivation that the animal has for consuming sugar, rather than sweetness, might have a neural basis,” Zuker said.

By visualizing brain activity when the rodents consumed sugar versus artificial sweetener or water, the researchers for the first time identified the caudal nucleus of the solitary tract (cNST) as the brain region that responds solely to sugar. Found in the brain stem, separate from where mice process taste, the cNST represents a hub for information about the state of the body.

Sugar-sensing neurons (pink) in cNST brain region of a mouse. [Hwei-Ee Tan/Zuker lab/Columbia’s Zuckerman Institute]
“We discovered that the cNST lit up with activity when we bypassed the sweet taste receptors on the animals’ tongues and delivered sugar directly to the gut,” said Alexander Sisti, PhD, the paper’s co-first author, and who completed his doctoral research in the Zuker lab. “Something was transmitting a signal, indicating the presence of sugar, from the gut to the brain.” Interestingly, mice didn’t develop a preference for sugar over sweetener when the function of cNST neurons was blocked. “… silencing the sugar-activated cNST neurons abolished their capacity to develop a preference for sugar over artificial sweetener, even after prolonged testing sessions,” the researchers noted.

The investigators then turned their attention to the vagus nerve, which is known to relay signals between the brain and the body’s organs. The scientists developed techniques to monitor the real-time activity of cells in the vagus nerve, and in a series of experiments in mice, they observed how these cells’ activity changed when sugar was delivered into the animals’ gut. “By recording brain-cell activity in the vagus nerve, we pinpointed a cluster of cells in the vagus nerve that respond to sugar,” said Sisti. “We saw, for the first time, sugar-sensing via this direct pathway from the gut to the brain.”

Further experiments revealed that inhibiting SGLT-1, which is the principal glucose transporter and sensor in the gut, also eliminated the animals’ neural response to sugar, indicating that SGLT-1 is a key sensor transmitting the presence of sugar from the gut to the brain. “ … these results place SGLT1 as an important component of the sugar-preference signaling circuit,” they wrote.

Through a final set of tests, the researchers also switched on the brain cells that normally respond to sugar signals from the gut. This time, however, they activated these cells every time the animal consumed a sugar-free Kool-Aid drink, in essence, hijacking the circuit. Remarkably, said Zuker, the animals acted as if they were getting real sugar. It was, in effect, fooling the brain into responding as if they were consuming sugar.

Taken together, the findings demonstrate the existence of two complementary, yet independent, systems for sensing energy-rich sugar, one getting input from the tongue, the other from the gut. “Together, these findings reveal a gut-to-brain post-ingestive sugar-sensing pathway critical for the development of sugar preference. In addition, they explain the neural basis for differences in the behavioral effects of sweeteners versus sugar, and uncover an essential circuit underlying the highly appetitive effects of sugar,” the authors concluded.

“The discovery of this specialized gut-brain circuit that responds to sugar—and sugar alone—could pave the way for sweeteners that don’t just trick our tongue but also our brain,” said Hwei-Ee Tan, PhD, the paper’s co-first author, who also completed his doctoral research in the Zucker lab. “When we drink diet soda, or use sweetener in coffee, it may taste similar but our brains can tell the difference … These findings could spur the development of more effective strategies to meaningfully curtail our unquenchable drive for sugar, from modulating various components of this circuit to potentially sugar substitutes that more closely mimic the way sugar acts on the brain.”

The results may also help to understand why the widespread availability of artificial sweeteners, which were introduced in consumer products 40 years ago, has had a negligible overall impact on decreasing sugar consumption, preference, and craving. “This may now be understood at the circuit level (that is, as—in contrast to sugar—they do not activate the preference circuit), and implies that it may be possible to develop a new class of sweeteners that activate both the taste-sweet receptor in the tongue and the gut-brain axis, and consequently help to moderate the strong drive to consume sugar.”

To better understand how the brain’s strong preference for sugar develops, the group is now studying the connections between this gut-brain sugar circuit and other brain systems, such as those involved in reward, feeding, and emotions.

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