Impaired metabolism of white fat cells promotes type 2 diabetes

Breaking new ground 24. apr 2022 2 min Postdoctoral Fellow Salwan Maqdasy Written by Kristian Sjøgren

Researchers have identified how impairment in the cellular energy system of white adipose tissue promotes inflammation. This system may be the determining factor when people with obesity develop type 2 diabetes, and the researchers say that the finding also suggests possible new targets for treating people with obesity who develop type 2 diabetes.

Globally, the twin epidemics of obesity and type 2 diabetes are galloping away.

The two diseases are closely linked through inflammation in tissues, including adipose (fat) tissue. Nevertheless, researchers have not been able to pinpoint the exact mechanism linking obesity with inflammation and type 2 diabetes.

But in a new study, researchers showed that having overweight changes the phosphocreatine metabolism of white fat cells, leading to the development of inflammation. Once the fat tissue is inflamed, type 2 diabetes can rapidly develop.

The research has been published in Nature Metabolism.

“In white fat cells from both humans and mice with obesity, disturbances in the phosphocreatine–creatine ratio in the fat tissue promote a proinflammatory profile. This is a previously unidentified mechanism of inflammation in obesity and a possible target for new treatments to reduce the risk of developing type 2 diabetes,” explains a researcher behind the study, Salwan Maqdasy, Postdoctoral Fellow, Karolinska Institutet, Stockholm, Sweden.

Mapping the link between obesity and type 2 diabetes

The researchers wanted to determine how obesity is linked with type 2 diabetes through inflammation.

They examined differences in the quantities of all types of metabolites in white fat cells from people with obesity versus people with normal weight.

The researchers discovered that there was a striking difference in the concentration of phosphocreatine, which was elevated relative to that of creatine in the fat cells of people with obesity versus normal weight.

Phosphocreatine acts as an energy sensor in the cells and harmoniously balances the energy consumption of the cells and tissues based on the prevailing requirements. When cells need more energy, phosphocreatine is broken down into creatine, a high-energy molecule.

The researchers then investigated the possible reason for the increased concentration of phosphocreatine in the white fat cells of people with obesity and found reduced concentration of the creatine kinase-B enzyme, which breaks down phosphocreatine.

Finally, in experiments in mice, the researchers found that when phosphocreatine metabolism declines because of low concentrations of creatine kinase-B, this alters adenosine monophosphate–activated protein kinase activity.

Adenosine monophosphate–activated protein kinase is involved in how cells take up glucose, and changes in activity are associated with an increased risk of developing insulin resistance. Altered activity of the protein kinase simultaneously leads to a proinflammatory cell profile, with elevated levels of various proinflammatory molecules.

“Reduced creatine kinase-B among people with obesity contributes to an energy crisis in the fat cells, resulting in inflammation, which is a precursor to the development of type 2 diabetes,” says another researcher behind the study, Scott Frendo-Cumbo, who is also a postdoctoral fellow at Karolinska Institutet.

Possible target for new treatment

Both researchers think that the study provides useful perspectives on possible treatments for people with obesity who are developing type 2 diabetes.

The researchers confirm that their translational research in both mice and humans already shows that the results from mice probably also apply to humans.

“One strength of the study is that we started by identifying the imbalance in phosphocreatine metabolism in human cells. This means that we know that the findings so far in mouse models and those we will find in the future are probably also relevant to humans,” explains Salwan Maqdasy.

The study also indicates that using drugs to increase the levels of creatine kinase-B in the fat tissue of people with obesity can restore the balance in phosphocreatine metabolism, thereby reducing the development of inflammation and insulin resistance.

This will tend to reduce the risk that inflammation will lead to the development of type 2 diabetes.

“From a therapeutic viewpoint, inducing higher levels of creatine kinase-B pharmaceutically could be useful in an attempt to correct the levels of phosphocreatine and thus reduce inflammation,” concludes Scott Frendo-Cumbo.

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