Study explains why sweeteners do not satisfy sugar cravings

A paper published in the journal Nature by Howard Hughes Medical Institute investigator Charles Zuker and colleagues reports that sugar triggers specialised taste buds on the tongue and switches on an entirely separate neurological pathway that begins in the gut. In the intestines, signals heralding sugar’s arrival travel to the brain, where they nurture an appetite for more, as revealed through experiments with mice. This gut-to-brain pathway appears picky, responding only to sugar molecules — not artificial sweeteners.

Scientists are already aware of sugar’s unique control over the brain. A 2008 study showed that mice without the ability to taste sweetness can still prefer sugar. Researchers’ discovery of a sugar-sensing pathway helps explain why sugar is special — and points to ways to curb cravings for it.

“We need to separate the concepts of sweet and sugar. Sweet is liking, sugar is wanting. This new work reveals the neural basis for sugar preference,” said Zuker, a neuroscientist at Columbia University.

The term sugar encompasses a number of substances the human body uses as fuel. Eating sugar activates the brain’s reward system, making humans and mice alike feel good. However, in a world with vast quantities of refined sugar, this ingrained appetite can run amok. The average American’s annual sugar intake has increased from less than 10 pounds in the late 1800s to more than 100 pounds today. Studies have linked excess sugar consumption to numerous health problems, including obesity and Type 2 diabetes.

Zuker’s work showed that sugar and artificial sweeteners switch on the same taste-sensing system. Once in the mouth, these molecules activate the sweet-taste receptors on taste buds, initiating signals that travel to the part of the brain that processes sweetness. But sugar affects behaviour in a way that artificial sweetener doesn’t. Researchers ran a test pitting sugar against the sweetener Acesulfame K, which is used in diet soda, sweetening packets and other products. When offered water with the sweetener or with sugar, mice initially drank both, but switched almost exclusively to sugar water within two days.

“We reasoned this unquenchable motivation that the animal has for consuming sugar, rather than sweetness, might have a neural basis,” Zuker said.

Scientists visualised brain activity when the rodents consumed sugar versus artificial sweetener or water, and identified the brain region that responds solely to sugar: the caudal nucleus of the solitary tract (cNST). Found in the brain stem, separate from where mice process taste, the cNST provides information about the state of the body. The path to the cNST begins in the lining of the intestine. There, sensor molecules spark a signal that travels via the vagus nerve, which provides a direct line of information from the intestines to the brain.

This gut-to-brain circuit favours one form of sugar: glucose and similar molecules, and ignores artificial sweeteners. This could explain why these additives cannot fully replicate sugar’s appeal. It also overlooks other types of sugar, notably fructose, which is found in fruit. Glucose is a source of energy for all living things. That could explain why the system’s specificity for the molecule evolved.

Scientists have previously speculated that sugar’s energy content, or calories, explained its appeal, as many artificial sweeteners lack calories. However, research indicates that this is not the case, since calorie-free, glucose-like molecules can also activate the gut-to-brain sugar-sensing pathway. To determine how the brain’s preference for sugar develops, researchers are now studying the connections between the gut-to-brain circuit and other brain systems, like those involved in reward, feeding and emotions. Although the studies are in mice, Zuker believes that essentially the same glucose-sensing pathway exists in humans.

“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,” Zuker said.

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