The new finding, reported in Cell, describes a completely new class of lipid that have been uncovered in humans and mice – and suggests that the newly discovered ‘good fat’ could play a vital role in reducing diabetes risk by improving blood sugar management.
Led by researchers at the Salk Institute and Beth Israel Deaconess Medical Center (BIDMC) in Boston, the team noted that in recent years, researchers have discovered that not all lipids are bad for you, such as the much touted omega-3 fatty acids that are found in fish oils.
They revealed that the newly discovered lipids, called fatty acid hydroxy fatty acids (FAHFAs) were lower in humans with early stages of diabetes and were much higher in mice resistant to diabetes.
"Based on their biology, we can add FAHFAs to the small list of beneficial lipids," said Professor Alan Saghatelian of Salk – a senior author of the work. "These lipids are amazing because they can also reduce inflammation, suggesting that we might discover therapeutic opportunities for these molecules in inflammatory diseases, such as Crohn's disease and rheumatoid arthritis, as well as diabetes."
"We were blown away to discover this completely new class of molecules," added co-senior author Professor Barbara Kahn of BIDMC and Harvard Medical School.
The team report that giving this new lipid to mice with the equivalent of type 2 diabetes lowered their elevated blood sugar, adding that unlike omega-3 fatty acids, which are not made in mammals, FAHFAs are actually produced and broken down inside the human body - making them a potential biomarker or target for future research.
"This important feature gives FAHFAs an advantage in terms of therapeutic development because we can potentially modify the rate of production and breakdown throughout the body," noted Kahn.
"Because we can measure FAHFA levels in blood, low levels may turn out to be an early marker for the risk of developing type 2 diabetes. Consequently, if restoring FAHFA levels in insulin resistant individuals proves to be therapeutic, we may potentially be able to intervene before the development of frank diabetes."
Saghatelian added that the lipids have also been identified in 'a lot of the foods that we eat' noting that they "have alwasy been there, its just that we havn't had the technology."
"I've been conducting these analyses for more than a decade and FAHFA is one of only two new classes of lipids that we've uncovered," he noted. "This is a rare discovery."
Uncovering a new fat
The team noted that FAHFAs had not been noticed previously in cells and tissues because they are present in low concentrations, making them difficult to detect. Using the latest mass spectrometry techniques, however, the team uncovered the FAHFAs when they examined the fat of a diabetes-resistant mouse model developed by Kahn.
"We engineered these mice to have more of a sugar transporter, called Glut4, in their fat because we had shown that when levels of this transporter are low, people are prone to developing diabetes," explained Kahn.
By examining how this sugar transporter might help protect against diabetes, the team noticed more fatty acid synthesis in mice that had improved insulin activity, and thereby were less likely to develop diabetes. The team then collaborated to find out what lipids were involved.
“While many of the other lipids were essentially the same between normal mice and these diabetes-resistant mice, we saw these FAHFA lipids elevated by sixteen fold in mice that were resistant to diabetes, standing out really clearly as a big change," said Saghatelian. "After that, we elucidated their structures using a combination of mass spectrometry and chemical synthesis.”
“We basically uncovered a whole new class of molecules using these techniques."
Once the teams had identified FAHFAs as being the lipid that was different between normal mice and these diabetes-resistant mice, they found something else important - when the mice eat FAHFAs, blood sugar levels dropped and insulin levels rose, indicating the potential therapeutic value of FAHFAs.
What about humans?
To determine whether FAHFAs are also relevant in humans, the team then measured FAHFA levels in humans who are insulin-resistant, finding that their FAHFA levels were lower in fat and blood - suggesting that changes in FAHFA levels may contribute to diabetes.
"The higher levels of these lipids seem to be associated with positive outcomes in mice and humans," said Kahn.
"We show that the lipids work through multiple mechanisms,” she added. “When blood sugar is rising, such as after a meal, the lipids rapidly stimulate secretion of a hormone that signals the pancreas to secrete insulin. In addition, these novel lipids also directly stimulate sugar uptake into cells and reduce inflammatory responses in fat tissue and throughout the body."
Kahn added that because it is possible to detect low FAHFA levels in blood before a person develops diabetes, the lipids could serve as an early marker for diabetes risk.
"We want to test whether restoring the lipids before diabetes develops might potentially reduce the risk or even prevent the disease," she said.
Aside from being produced and broken down in the body, the team noted that FAHFAs have been identified at low levels within a wide range of vegetables, fruits and other foods.
Published online ahead of print, doi:10.1016/j.cell.2014.09.035
"Discovery of a Class of Endogenous Mammalian Lipids with Anti-Diabetic and Anti-inflammatory Effects"
Authors: Mark M Yore, Ismail Syed, et al