CONTAINS zero calories! Countless soft drinks are emblazoned with that slogan as a come-on for those of us locked in a never-ending battle to rein in a spreading waistline. Calorie-free sweeteners certainly have a lot to offer. Food and drink manufacturers have become so good at blending sugar substitutes into their products that it can be almost impossible to tell them apart from the real thing - sucrose - in taste tests.
But while artificial sweeteners may be able to confuse our taste buds, the suspicion is growing that our brain is not so easily fooled. Could it be that our cravings for sugary foods run deeper than a liking for sweetness? If so, a whole bunch of weight-loss strategies may need rethinking.
Non-sugar sweeteners have come a long way. One of the first, and perhaps the worst, was lead. Romans boiled grapes in lead pots, leaching the sweet-tasting metal into their food. The practice outlived the Roman empire by many centuries, and is thought to have led to the deaths of a number of notables, including Pope Clement II, who perished in 1047. Indigenous peoples in South America use a herb called stevia, which contains chemicals that taste sweet but aren't metabolised in the human gut. These early experimenters weren't worried about shedding the kilos - just searching for a way to sweeten food in a world where refined sugar was scarce.
Saccharin, the first of the industrially manufactured artificial sweeteners, was discovered late in the 19th century and soon became popular. Taxes and restrictive patents kept the cost high, and a black market sprang up throughout Europe: a report in 1911 claimed there were 129 saccharin smugglers in the Swiss city of Zurich alone. It does, however, have a potent aftertaste. Not for nothing has it earned itself a place in the English lexicon as the epitome of sickly sweetness. Since then, a parade of sweeteners has come on stream, including cyclamate, aspartame, the sucrose-like (and very sweet) sucralose, and several others, including one called Rebiana, derived from a South American herb.
Even as manufacturers get better at blending these agents to avoid peculiar tastes, their ability to help us cut down on calories and keep our weight in check is coming into question. A handful of studies, starting in the 1980s, suggested that regular use of artificial sweeteners might even make people eat more, rather than less, by sti
mulating their appetites without satisfying them. Though the methodology of some of these studies was questionable, the doubts continued.
More recently, the hunt has been joined by Guido Frank, a psychiatrist at the University of Colorado in Denver who has a particular interest in eating disorders. To compare how the brain responds to sucralose and sucrose, he fed the sweetener and the sugar to 12 women, adjusting the concentrations so that the sweetness of the two matched. "They consciously could not distinguish them," Frank says. Yet when he looked at their brain responses with functional magnetic resonance imaging (fMRI), he saw clear differences.
Pleasure response
Sucrose produced stronger activation in the "reward" areas of the brain that light up in response to pleasurable activities such as eating and drinking. Sucralose didn't activate these areas as strongly, but it synchronised the activity in a whole constellation of taste-associated brain areas - and it did this more strongly than sucrose did (NeuroImage, vol 39, p 1559). Frank suggests that sucralose activates brain areas that register pleasant taste, but not strongly enough to cause satiation. "That might drive you to eat something sweet or something calorific later on," he says.
Similar results emerged from brain-scanning experiments by Paul Smeets, a neuroscientist at Utrecht University Medical Center in the Netherlands, in which he fed volunteers two versions of an orangeade drink. One was sweetened with sugar and one with a blend of the non-calorific sweeteners aspartame, saccharin, cyclamate and acesulfame potassium. Both drinks evoked similar patterns of brain activation, except that the calorie-free blend failed to light up a cherry-sized lump of tissue within a reward area called the caudate nucleus. Smeets presented his results at a meeting of the Organization for Human Brain Mapping in June 2009 in San Francisco.
A study that goes beyond brain mapping, published in July by Edward Chambers of the University of Birmingham, UK, adds weight to the idea that there's more to the appeal of sugary foods than sweetness. Chambers made eight cyclists perform 60-minute workouts on a stationary bike while measuring their work rate. During workouts on separate days he told them to rinse their mouth with a solution of either glucose or saccharin, without swallowing either one. The glucose mouth rinse improved the cyclists' performance by a small but consistent amount compared to saccharin. It was as if the taste suggesting that more calories are on the way was enough to inspire the tired athletes' brains to drive their legs harder.
There's more to the appeal of sugary foods than sweetness. The brain has a way of detecting calories
The really surprising result came later, however, when Chambers had the cyclists rinse their mouths with either saccharin alone or saccharin plus a calorific - but non-sweet - sugar called maltodextrin. The cyclists did slightly better when they rinsed their mouths with maltodextrin - even though both solutions carried identical saccharin tastes (The Journal of Physiology, vol 587, p 1779).
All these results suggest the brain has some way of detecting calories while food is still in the mouth. "It's an unconscious response," says Chambers - and it's independent of sweetness perception. When Chambers performed fMRI scans on his athletes, he got a glimpse of that unconscious response. The combination of saccharin and maltodextrin activated two reward-associated brain areas - the striatum and anterior cingulate - which saccharin alone failed to touch.
While this discovery might seem like bad news for zero-calorie drinks, it could be the beginning of real progress in finding ways to help people reduce their calorie intake. One approach focuses on information that has come in over the past decade describing the role of the receptor proteins on our taste buds. It is these receptors that detect the flavour molecules in our foods. While we seem to have about 30 different receptors for bitter tastes, there seems to be just one receptor for sweetness, formed by a pair of proteins called T1R2 and T1R3. It sits on taste buds near the tip of the tongue and, not surprisingly, binds to both sugars and artificial sweeteners.
These receptors have become the focus of efforts to create better sugar stand-ins - and could solve the problem of aftertaste that has long plagued artificial sweeteners (see "Lingering on") - but they tell us little about the brain's apparent ability to discriminate between sugar and artificial sweeteners. Instead, it may be texture that is the key factor says Jayaram Chandrashekar, a neuroscientist at Howard Hughes Medical Institute in Janelia Farm, Virginia, who helped identify many taste receptors.
Because saccharin is several hundred times sweeter than sugar, Chambers used far less of it - with the result that the glucose and maltodextrin drinks were more viscous than the saccharin-only drink. The brain may take these subtle texture cues into account, Chandrashekar says.
"When you eat something sweet you may activate two pathways, one for sweetness and one for texture," Chandrashekar says. "Together they give you a better feeling than just the sweet pathway alone." A non-calorific bulking agent to thicken up the zero-calorie drink might solve the problem. Such bulkers are already used in a variety of products, from smoothies to enchiladas.
An alternative approach is under investigation at Senomyx in San Diego, California. The company has developed a tasteless molecule called S6973 that does not activate the sweet receptor directly, but changes it in a way that makes it bind more tightly to sucrose. "This will cause the sugar molecule to stay on the receptor maybe two times as long," says Grant DuBois, a flavour chemist at The Coca-Cola Company in Atlanta, Georgia, which has financed research at Senomyx. "You can take a beverage that may normally contain 10 per cent sugar and make it with 5 per cent sugar, and it tastes the same."
S6973 might still disappoint those of us who like to compensate for a million-calorie festive meal by drinking zero-calorie sodas - after all, drinks with sweetener enhancers will still contain as much as half the sugar of regular drinks. But that could actually be a plus if, unlike their zero-calorie cousins, these drinks manage to convince the brain that it is getting the calories it craves.
Never mind the taste test; they might even pass the brain-scan test.
Lingering on
Aftertaste has been the Godzilla of problems for zero-calorie sweeteners. "They all have this problem of slow sweetness onset and sweetness linger," says Grant DuBois, a chemist who develops sweeteners at The Coca-Cola Company in Atlanta, Georgia. In a study published earlier this year, he and Andrew James, a neuroscientist at Emory University, also in Atlanta, reported the first known neural signature for aftertaste (NeuroReport, vol 20, p 245).
DuBois and James ran fMRI brain scans on subjects as they sipped solutions of either sucrose or the artificial sweetener aspartame. When the researchers compared scans they discovered that a marble-sized nugget of tissue in an area called the insula, which is known for responding to sweet tastes, turned on for 15 seconds when people sipped sucrose, but for 30 seconds with aspartame. "Only in the insula did we see this prolonged response," says James. "We conclude that we were seeing a neural response which corresponds with aftertaste."
Such studies could provide the first objective tool for measuring aftertastes of up-and-coming sweeteners. But developing those aftertaste-free molecules will be tricky, says DuBois, who has studied artificial sweeteners on and off since the 1970s. "Over my career I have tasted in the ballpark of 1000 compounds," he says. "None of these compounds has sugar-like tastes. They all linger."
This may be down to a fundamental conflict that comes with using artificial sweeteners. They are expensive to produce, so they are only economic if they work in trace amounts. They must therefore be potent. Aspartame, for example, is 200 times sweeter than sucrose, and DuBois believes that this potency is what causes the problem. "You're just not going to find a high-potency [sweet] compound that has no aftertaste," he says.
No one knows for sure why there is this link between potency and aftertaste, but Michael Naim, a food chemist at the Hebrew University of Jerusalem, Israel, has an idea. When sweetness receptors bind to sugars, the cell sends sweetness signals to nearby nerves for a few seconds, until a protein switch inside the cell flips, turning off the signal. But zero-calorie sweeteners are soluble in both water and fat - a property which may contribute to their potency by making them bind strongly to the receptor - and so can do something that sugars can't, Naim reasons. They ooze across the cell's fatty membrane, and once inside they gum up the stop switch, so the sweetness lingers.
DuBois has designed around 100 chemicals which resemble sugars more closely - and so shouldn't cross the cell membrane - in the hope that they would be useful replacements for sucrose. Sure enough, they were sweet, but unfortunately none were sweeter than sucrose, making them non-starters as industrial sweeteners.
Douglas Fox is a writer based in San Francisco
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