Aspartylphenylalanine-methyl-ester, or Aspartame, is the by-product of an ulcer drug experimentation back in 1965, when a company chemist found an intermediate chemical to have a particularly sweet taste. About a decade later, Aspartame was approved by the FDA for restricted use in dry foods. Then it got on an experimental roller coaster of bans and re-approvals.

Today, Aspartame is a dietary “hot potato.” Still in widespread use by weight-conscious consumers, Aspartame has fervent fans but has not escaped the heavy criticism of scientific circles, who associate it with headaches, memory loss, seizures, vision loss, diabetes, Alzheimer’s, chronic fatigue and depression, even cancer.

We studied the impact of Aspartame on IAP and found it can indeed predispose to obesity and diabetes.- Konstantinos Economopoulos, Researcher

A new study from the Massachusetts General Hospital (MGH) comes to further distress the weight-conscious group of people who use Aspartame as a sugar substitute: Aspartame might actually prohibit weight loss.

The report, “Inhibition of the gut enzyme intestinal alkaline phosphatase may explain how Aspartame promotes glucose intolerance and obesity in mice,” was published in Applied Physiology, Nutrition and Metabolism. It found that Aspartame may not promote weight loss because it blocks the function of an enzyme vital for the prevention of metabolic syndrome (a group of symptoms associated with type 2 diabetes and cardiovascular disease).

“Indeed, our study confirms the observation made by scientists in the late 1960s, that phenylalanine (PHE) – a breakdown product of Aspartame – specifically inhibits the action of intestinal alkaline phosphatase (IAP),” said Konstantinos Economopoulos, Senior Research Scientist at the Organ Engineering and Regeneration Laboratory of the ‎Massachusetts General Hospital, and researcher of the same study.

“IAP is an enzyme, and when a substrate molecule interacts with the active site of IAP, an enzyme-substrate complex is formed and the enzyme is activated. Thus, the enzyme and substrate are said to fit together and function as a lock and a key. When phenylalanine interacts with the IAP-substrate complex, it inactivates it by producing a more thermodynamically stable IAP-PHE-substrate complex. The way you can picture this is like the lock, the IAP, after the addition of phenylalanine cannot be opened anymore with the same key-substrate, because there is another key behind the door, phenylalanine.”

Previously the team had found that feeding IAP to mice kept on a high-fat diet prevented the development of metabolic syndrome and reduced symptoms in animals already inflicted with the condition. The knowledge that phenylalanine impedes the action of IAP, and the fact that the former is produced upon Aspartame’s digestion urged the researchers to investigate whether Aspartame might actually retard weight loss.

The team followed four groups of mice for 18 weeks. Two groups were kept on a normal diet, one on water with Aspartame, and the other on plain water. The other two groups were fed a high-fat diet, as well as Aspartame-infused or plain water.

The study found that the high-fat diet mice that received Aspartame gained more weight than those on the same diet that received plain water while the difference between the weights of the two groups fed a normal diet was negligible. What is more, Aspartame-receiving mice in both diet groups were observed to have higher blood sugar levels than those fed the same diets without Aspartame, a fact that might point out glucose intolerance. Finally, both Aspartame-receiving groups had higher levels of the inflammatory protein TNF-alpha in their blood, which reveals a kind of systemic inflammation typical of metabolic syndrome.

What do these findings suggest for one of the most commercial (at least until stevia) and controversial artificial sweeteners? Can we imply that the ongoing anti-Aspartame polemic will render it a sweetener of the yore?

“We have no idea about whether substances like Aspartame will get banned,” answered Economopoulos. “They are in widespread use and generally considered safe for human consumption. We studied the impact of Aspartame on IAP and found it can indeed predispose to obesity and diabetes.”