Antidiabetic and anti-inflammatory lipids
"Good" fats for diabetes treatment
LifeSciencesToday based on Salk Institute materials: Scientists discover a 'good' fat that fights diabetesScientists from the Salk Institute for Biological Studies and the Beth Israel Deaconess Medical Center (BIDMC) have discovered a new class of molecules produced by the adipose tissue of mice and humans that protect against diabetes.
The researchers found that mice with the equivalent of type 2 diabetes treated with this new type of fat decreased elevated blood sugar levels, as described in detail in an article published in the journal Cell (Yore et al., Discovery of a Class of Endogenous Mammalian Lipids with Anti-Diabetic and Anti-inflammatory Effects). In addition, it turned out that the levels of these lipids are low in people at high risk of developing diabetes, which suggests the possibility of their use as a therapeutic agent for the treatment of metabolic disorders.
Lipids, in particular cholesterol, are usually associated with poor health. But recently, scientists have found that not all lipids are bad. Useful lipids include, for example, omega-3 fatty acids contained in fish oil.
The level of newly discovered lipids – fatty acid esters of fatty acids (fatty acid esters of hydroxy fatty acids, FAHFAs) – is lower in people with early stage diabetes and significantly higher in mice resistant to this disease.
The structure of a molecule of one of the FAHFAs isomers (a frame from the Salk Institute video) – VM.
"Based on their biology, we can add FAHFAs to a small list of useful lipids," says Alan Saghatelian, professor at the Salk Institute, from the Clayton Foundation Laboratories for Peptide Biology, one of the senior authors of the paper. "These lipids are amazing because they, among other things, reduce inflammation. This means that we may be able to find the possibility of therapeutic use of these molecules for the treatment of inflammatory diseases such as Crohn's disease and rheumatoid arthritis, as well as diabetes."
FAHFAs have not been seen in cells and tissues so far, as their concentrations are very low, which makes it difficult to detect them. Using the latest methods of mass spectrometry, Sagatelyan and Barbara Kahn, MD, deputy head of the BIDMC Department of Medicine, another senior author of the work, discovered FAHFAs when they examined the adipose tissue of diabetes-resistant genetically engineered mice.
The Glut4 protein moves to the cell surface to help transport glucose from the blood to the cells after eating. The left column shows the total amount of Glut4 (green) in the cell; the right column shows how much Glut4 (red) has bound to the cell surface. First row: in the absence of insulin, very little Glut4 moves to the cell surface (upper right, red). Second row: in the presence of a small amount of insulin, there is a certain amount of Glut 4 on the cell surface (in the center on the right, red). Third row: in the presence of the same amount of insulin and FAHFA lipid, there is significantly more Glut4 on the cell surface, which increases the amount of glucose entering the cell (lower right, red). Photo: Weill Cornell Medical Center, Salk Institute and Beth Israel Deaconess Medical Center."We created these genetically engineered mice so that there was more of a sugar transporter called Glut4 in their adipose tissue, as we had previously shown that with a low level of this transporter, people are prone to developing diabetes," explains Dr. Kang.
Studying how this sugar transporter can help protect against diabetes, the researchers noticed an increase in fatty acid synthesis in mice, which increased the activity of insulin. Scientists began to collaborate to find out which lipids were being synthesized.
"While the levels of many of the other lipids in normal and these diabetes–resistant mice were almost the same, the levels of FAHFA lipids in the latter were sixteen times higher – clearly a big change," comments Professor Saghatelyan. "After that, using mass spectrometry and chemical synthesis, we determined their structure. In fact, using these methods, we have discovered a completely new class of molecules."
After FAHFAs were identified as exactly the lipids that distinguished normal mice from diabetes-resistant mice, the researchers made another important discovery: in mice treated with FAHFAs with food, blood sugar levels decreased and insulin levels increased, indicating the potential therapeutic value of FAHFAs.
To determine whether this applies to the human body, the researchers measured FAHFA levels in people with insulin resistance (a condition often a precursor to diabetes) and found that FAHFAs levels in adipose tissue and blood were lower in such people. This suggested that changes in FAHFAs levels may contribute to the development of diabetes.
Enhanced lipogenesis in adipose tissue is associated with increased sensitivity to insulin. In mice with hyperexpression of the glucose transporter Glut4 in adipocytes, lipogenesis is enhanced and glucose tolerance is increased, despite the development of obesity in them with an increased level of circulating fatty acids. The analysis of the adipose tissue lipidome showed the existence of branched fatty acid esters of fatty oxy acids (FAHFAs), the level of which was increased in these mice by 16-18 times. FAHFAs isomers differ from each other in the position of the branched ester on fatty hydroxyacid (for example, palmitic-acid-9-hydroxy-stearic-acid, 9-PAHSA). PAHSAs are synthesized in vivo and regulated by fasting and a high-fat diet. PAHSA levels are strongly correlated with insulin sensitivity and are lowered in the adipose tissue and serum of people with insulin resistance. Administration of PAHSA to mice reduces glycemia and increases glucose tolerance by stimulating GLP-1 and insulin secretion. In addition, PAHSAs reduce inflammation in adipose tissue. In adipocytes, PAHSAs signal through GPR120 the need to increase insulin-stimulated glucose uptake. Thus, FAHFAs are endogenous lipids with potential use for the treatment of type 2 diabetes (Fig. Cell)."Higher levels of these lipids appear to be associated with positive effects in mice and in humans," says Dr. Kahn, a professor at Harvard Medical School.
"We have shown that these lipids work through several mechanisms. If the blood sugar level rises, for example, after eating, they quickly stimulate the secretion of a hormone that signals the pancreas to produce insulin. In addition, these new lipids directly stimulate the absorption of sugar by cells and suppress inflammatory reactions in adipose tissue and throughout the body."
Taken together, these effects make the therapeutic potential of FAHFA lipids enormous, the researchers say. In addition to being present in low concentrations in a number of vegetables, fruits and other foods, FAHFAs, unlike other known beneficial lipids, are produced and destroyed by the body. Potentially, the target of new drugs to control FAHFA levels may be the pathways of lipid synthesis or cleavage.
In addition, the researchers identified a cellular receptor (GPR120) with which FAHFAs bind by controlling how much glucose is absorbed into fat cells. They believe that an increase in FAHFAs levels in the body may also be a way to activate GPR120 and, consequently, a method of treating or preventing diabetes.
"This study suggests that changes in FAHFAs levels are a novel mechanism of diabetes development that was previously underestimated because these lipids were not known," says Saghatelyan. "We believe that this work gives reason to hope for new therapeutic agents that can increase the activity of blood sugar control pathways already existing in the body."
"Since we can detect a decrease in FAHFAs levels in the blood before a person develops diabetes, these lipids may become an early marker of the risk of this disease," adds Professor Kang. "We want to test whether restoring the levels of these lipids before diabetes can reduce the risk or even prevent this disease."
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