(CNN) Could the no-calorie sweetener you rely on to replace sugar in your diet actually cause weight gain instead of the weight loss you were expecting?

The answer may be yes, according to a new study.

"Artificial sweeteners are not risk-free," said Brian Hoffmann , assistant professor in the Department of Biomedical Engineering at the Medical College of Wisconsin and Marquette University, and a lead author of the study. "They are a very controversial topic when it comes to health and nutrition ... but they're so prevalent in society that I think we owe it to ourselves to try and figure out what's actually going on."

Hoffmann presented his new research Sunday at the annual Experimental Biology meeting in San Diego. Relying on rats and human cell cultures, his team identified a number of pathways linking artificial sweeteners with metabolic changes at the genetic level that could lead to diabetes and obesity. Specifically, the researchers found that three weeks of exposure to aspartame and acesulfame potassium -- two artificial sweeteners frequently combined in products such as Equal -- altered the expression of certain genes responsible for lipid metabolism in the cells of both rats and humans.

"Aspartame had some significant changes, and one of those was an increase in lipids in the bloodstream and a decrease in a biomolecule that is involved in clearing (lipids) from the bloodstream. And we saw the exact same thing with the acesulfame potassium," Hoffmann said.

"We then took those particular sweeteners and put them on endothelial cells -- the cells that line the blood vessels and would be exposed to them in the body -- and we detected a marked dysfunction, suggesting why sweeteners and diet soda have been linked to potential cardiovascular problems," he added.

What was perhaps most surprising, according to Hoffmann, was that these metabolic changes did not occur in the presence of natural sugars such as glucose and fructose. This suggests that artificial sweeteners could contribute to metabolic disorders such as diabetes and obesity by an entirely different mechanism than natural sugars, he said.

Artificial sweeteners appear to contribute to metabolic disorders by altering the activity of certain genes responsible for the breakdown of macromolecules such as fats and proteins, Hoffmann said. This is different from normal sugars, which contribute to cardiovascular disease through insulin resistance and by damaging the cells lining the body's blood vessels.

"People are generally consuming non-nutritive sweeteners believing they are a 'healthy choice,' but this may not be true," said research scientist Meghan Azad of the University of Manitoba in Winnipeg, who was not involved in the new study.

"This is especially important given the widespread and increasing consumption of artificial sweeteners in the general population and the increasing use of artificial sweeteners in our food supply," said Azad, who has authored a paper that reviewed a number of studies on the potential downside of artificial sweeteners on weight and health.

According to Azad, over 40% of adult Americans consume no-cal sweeteners on a daily basis, and studies that measure the sweeteners in blood and urine show that many people who report not using artificial sweeteners are unknowingly consuming them.

It's the latest assault in the ongoing debate over artificial sweeteners and their impact on health -- a debate that began when one of our most popular foods, sugar, turned sour in terms of health.

The need for a sugar substitute

How can something as good as sugar be bad for us?

Actually, it's not, if you keep to the newest dietary guidelines from the US Department of Agriculture: only 10 teaspoons of sugar a day for the average person. Unfortunately, that equals just one 16-ounce bottle of regular soda.

To satisfy our sweet tooth, many of us turn to the fake stuff: artificial sweeteners. There are just five approved by the Food and Drug Administration for use in the United States: acesulfame potassium (sold as Sunett and Sweet One), aspartame (sold as Equal, Nutrasweet and Sugar Twin), neotame (sold as Newtame), saccharin (sold as Sweet'N Low, Sweet Twin and Necta Sweet) and sucralose (sold as Splenda). One more, cyclamate, is widely used in more than 100 countries but banned in the United States.

The FDA says all five approved sweeteners are safe as long as they are used in moderation. That means no more than 23 packets a day of Splenda, Sweet One or Newtame, 45 packets a day of Sweet'N Low or 75 packets a day of Equal.

Sounds doable. So besides weight gain, which isn't proven, why do so many people still consider artificial sweeteners dangerous?

Partly it's due to our suspicion of putting anything chemical or artificially manufactured in our bodies. It's also due to a long history of overly publicized, poorly designed, badly executed animal studies that the FDA now says falsely linked artificial sweeteners to cancer

Here's a history on where we've been and where we stand on today's major artificial sweeteners. Get ready; it's a roller-coaster ride.

Saccharin and cyclamate

1879: First artificial sweetener, saccharin, is finger-lickin' good-for-you

Chemist Constantin Fahlberg filed for the first patent on saccharin.

Russian chemist Constantin Fahlberg was eating dinner when he made an amazing discovery: The roll he'd just bitten into tasted extremely sweet. Realizing that the sugary, metallic taste had come from his own hands, he rushed back to the lab to find the source. After tasting everything in sight -- not exactly good lab safety protocol -- he discovered that the sweetness came from an accidental chemical reaction between coal tar derivatives (yum!), producing benzoic sulfinide

That's one version of the story. Another account says Fahlberg's boss, Dr. Ira Remsen, was the diner who forgot to wash up before eating. Regardless, it was Fahlberg who realized the commercial viability of saccharin as an inexpensive sugar substitute that isn't metabolized by the body, has no calories and doesn't cause tooth decay. He soon applied for patents and began offering saccharin in powder and pill form as a "nonfattening" alternative to sugar.

1908: Weight-watching President Roosevelt keeps saccharin from being banned

Early in the 20th century, food horror stories like Upton Sinclair's "The Jungle" started to frighten the American public. In reaction, Congress passed the Pure Food and Drug Act in June of 1906, to protect the public from "adulterated or misbranded or poisonous or deleterious foods, drugs or medicines." It wasn't long before saccharin was in the crosshairs.

"Poison Squad" participants were fed borax, saccharin, other food additives.

The charge was led by Dr. Harvey Wiley, chief of the USDA's chemical division. Wiley was well known for his "Poison Squad," a group of civil servants who were given free room and board if they would eat food heavily laced with widely used chemical preservatives, including saccharin. Wiley then studied their urine and feces samples to test the impact on the body.

Certain that saccharin was a danger, Wiley took his case to President Theodore Roosevelt. But Roosevelt would have none of it, as he was using saccharin to manage his weight. Wiley describes the President's reaction in his autobiography: "'You say saccharin is injurious to health? Why, Doctor Rixey gives it to me every day. Anybody who says saccharin is injurious to health is an idiot.'"

Wiley didn't give up, and he was able to get saccharin banned from use in processed foods, but direct sales to consumers were permitted. As the years went on, science couldn't find any hard evidence that saccharin was harmful, and widespread sugar shortages during World Wars I and II fanned consumer desire.

1937: Diabetics rejoice as cyclamate meets saccharin

Michael Sveda, a University of Illinois student chemist, was working with a compound called cyclamate when he discovered his cigarettes tasted like sugar (obviously he was smoking on the job). Introduced to the US market in 1950 by Abbott Labs, cyclamate was initially marketed to diabetics for insulin control.

But cyclamate's biggest role was in cutting the bitter, metallic taste of saccharin. Normally added at a ratio of 10 parts cyclamate to 1 part saccharin, that preparation became the basis of the popular brand Sweet'N Low and was soon sold in millions of snack foods and diet sodas. In 1958 the FDA gave cyclamate GRAS status: Generally Recognized As Safe.

1977: Warning: Saccharin will give you cancer, if you're a lab rat

A 1969 study found sperm and chromosomal breaks in rats exposed to cyclamates. Then, a 1970 study found feeding high doses of the chemical to lab rats (5% to 7.5% of the diet) caused bladder cancer in the rodents. The FDA quickly acted, completely banning the use of cyclamate in 1970. Cumberland Packing Corp., the owner of Sweet'N Low, just as quickly switched to an all-saccharin version.

Sweet'N Low was required for a while to display a warning label.

But by that point, cyclamate and saccharin were intertwined, in studies and in the public consciousness. Another 1970 study found bladder tumors in eight of 80 rats fed a high-dose mixture of the two. More research followed, finding urinary, lung, stomach and reproductive tumors . Despite warnings that the studies were flawed, by 1976 the FDA announced a plan to ban saccharin.

Congress -- pushed partly by lobbyists in the food industry, partly by a public outcry against losing access to the noncaloric sweetener -- took a softer approach. Instead of a ban, Congress decreed in 1977 that any food sweetened with saccharin must carry a scary warning label: "Use of this product may be hazardous to your health. This product contains saccharin which has been determined to cause cancer in laboratory animals."

2000: Saccharin will not give you cancer, even if you're a lab rat

Research into saccharin continued. A review study in the Annals of Oncology found over 20 studies analyzing the effects of high-dose exposure in rats, yet only one showed any evidence of bladder lesions. A closer look at that study discovered that researchers used a breed of rat frequently infected with a parasite that would leave it susceptible to bladder cancer.

Rats fed saccharin got cancer, but it turned out to be due to other causes.

Another set of studies looked at second generation rats and also found bladder cancer. But then it was discovered that feeding rats vitamin C at the same levels as saccharin would also produce bladder cancer. It turned out rats have different urine components than humans, and it was those components that were interacting with the sweeteners and leading to the bladder damage. Studies done on primates found no bladder tumors, and human studies in Denmark, Britain Canada and the United States showed no connection either.

In 2000, Congress removed the warning label . Saccharin was OK again. But by then, several competitors had arrived on the scene and taken over a greater share of the exploding marketplace.

Aspartame

1965: Another accidental find, in many ways 'Equal' to its predecessors

Chemist James M. Schlatter was looking for an anti-ulcer drug when he stumbled upon the sweet taste of aspartame by (you guessed it) licking his finger. A mix of aspartic acid and phenylalanine, two naturally occurring amino acids, aspartame entered the growing artificial sweetener market in 1973. Today, we know it as Equal, Nutrasweet or Sugar Twin.

Unlike the other artificial sweeteners, which are usually excreted unchanged, aspartame can be metabolized, so it does have minimal calories (about 4 per gram). It also has some known health concerns . It should not be used by anyone with the genetic disorder phenylketonuria or certain rare liver disorders, or pregnant women with high levels of phenylalanine in their blood, because it doesn't metabolize properly in those individuals. The FDA requires any food made with aspartame to put that restriction on the label.

1996: Charges that aspartame causes brain tumors, proven and unproven

Aspartame has had its share of health scares.

Reaction was swift, with some calling for a ban on aspartame . But others pointed out the " ecological fallacy " in Olney's argument. Why not call foul on VCRs, home computers or the hole in the ozone layer, which were also newly present during the same time period?

A case-controlled study on children with brain tumors soon put the matter to rest, finding "little biological or experimental evidence that aspartame is likely to act as a human brain carcinogen."

The next generation: Sucralose, neotame and acesulfame potassium

1967: Another brave chemist tastes his delicious experiment

What ever happened to safe lab protocol? Yes, acesulfame potassium, also known as acesulfame K, Ace-K or ACK, was discovered by Karl Clauss and Harald Jensen in Frankfurt, Germany, when they combined fluorosulfonyl isocyanate and 2-butene. Clauss spilled some and then (of course) licked his finger. The tabletop version is called Sweet One, but it's often used in combination with other artificial sweeteners to better mimic the "real" taste of sugar.

1976: Another one bites the sweet dust

Scientists were working with a chlorinated sugar compound in 1976 when one of the researchers decided to (what else?) taste it. Sucralose was born. It's made by replacing three hydrogen and oxygen atoms in sucrose with chlorine atoms, making it about 600 times sweeter than sugar.

Splenda is one of many sweeteners discovered by chemists who licked their fingers.

Today, we know this chlorine-based sugar derivative as Splenda. As the most heat-stable of all the artificial sweeteners, it's popular with food manufacturers.

2002: The final artificial sweetener birth was planned

Unlike those of its predecessors, neotame's was a planned birth. With the market for artificial sweeteners in the billions, scientists around the world were playing with chemicals to find the next big hit. They also wanted to improve on older models: fix the bitter aftertaste and develop higher heat stability and a higher sweetness factor (so you could use less and save money).

Developed by Monsanto, the owners of Nutrasweet, neotame certainly delivered on at least two of those goals: It is heat-stable, and the intensity of its sweetness is 7,000 to 13,000 times greater than sugar. But the sweetness takes a while to develop in the mouth, it lingers longer, and it can have a licorice-like quality, so neotame is most often used in combination with other artificial sweeteners.

2005: Diet sodas cause weight gain

By 2005, millions of people were using artificial sweeteners for weight control. So it was a shock when researchers at the University of Texas found that conventional wisdom was wrong, when they analyzed eight years of data from the San Antonio Heart Study. The more diet sodas a person drank, the more likely he or she was to gain weight.

To this day, no one knows why. Was it due to the artificial sweetener? Was it something else in the soda? Does drinking a diet soda make it more likely a person might order a double burger and fries? As several reviews point out , it remains a riddle.

2012: Artificial sweeteners probably safe, but some lingering health concerns

Studying the effects of specific artificial sweeteners is a challenge in today's world, as many soda and food manufacturers create mixtures of sweeteners to mimic sugar and make their products taste unique. So it's hard to tease out which of the sweeteners might be a problem.

Could diet soda be linked to Type 2 diabetes? The jury's still out.

But studies continue to find concerns that bear watching. A 2008 study f ound that drinking more than two servings of diet soda a day doubled the risk for kidney decline in women. A 2012 study suggested a possible connection between diet sodas and an increased risk for vascular events. If you use a ton of sweetener -- more than 1,680 milligrams a day, and that's a lot -- you could have a somewhat higher risk of bladder cancer. And several studies have discovered that daily consumption of diet soda may be linked to metabolic syndrome -- a sort of prediabetes -- and Type 2 diabetes, perhaps because it alters people's gut bacteria

Oh, and for the record, a 2013 review says there is still evidence that diet soda helps with weight loss.

2017: More evidence of weight gain

A review by the University of Manitoba's Azad and her colleagues, published in July in the journal of the Canadian Medical Association, combed the medical literature for the latest randomly controlled trials about artificial sweeteners and weight. Azad said they found little connection to weight loss except in long-term trials that were sponsored by the artificial sweetener industry.

A separate review of a larger sample of observational studies found people who used artificial sweeteners over time gained weight and had a larger waist circumference, as well as a higher incidence of hypertension, metabolic syndrome, type 2 diabetes and cardiovascular events.

"Based on all of the research done so far, there is no clear evidence for a benefit, but there is evidence of potential harm from the long term consumption of artificial sweeteners," Azad said. "This should inspire consumers to think about whether they want to be consuming artificial sweeteners, especially on a regular basis, because we do not know if they are a truly harmless alternative to sugar.

"More importantly," she added, "our results send a strong message to researchers and research funding bodies that more studies are needed to understand the long term health impact of artificial sweeteners."

Stay tuned

So where does this leave us? The FDA feels you can be pretty darn sure that a moderate dose of the artificial stuff won't give you cancer. If you're a heavy consumer -- and that's a lot of sweetener -- that's another story.

As for connections to kidney or cardio problems and weight loss (or gain), stay tuned. We're sure more studies proving (and disproving) those concerns are on their way.

In the meantime, the stance of the Academy of Nutrition and Dietetics is that non-nutritive sweeteners can help limit calorie intake as a strategy to manage weight or blood glucose.