Cell death signalling tips the scales in obesity-associated disease

A major growing worldwide health problem is now better understood, with researchers identifying a key factor in the development of obesity and metabolic disease.

These conditions are major global health challenges linked to modern diets rich in saturated fat and refined carbohydrate, combined with less active lifestyles.

A project led by Hudson Institute of Medical Research in collaboration with eight other Australian institutions found that a single protein, Mixed Lineage Kinase Domain-Like pseudokinase (MLKL) is a key contributor to obesity and associated inflammatory metabolic diseases such as type II diabetes and metabolic dysfunction-associated fatty liver disease (MAFLD).

These findings make MLKL a target for future research on controlling these conditions.

Cell death, metabolic disease and obesity

MLKL plays a crucial role in necroptosis – an inflammatory form of programmed cell death that occurs when cells need to protect the body from infections or other threats.

MLKL is activated by another protein, RIPK3, and helps disrupt the cell membrane, leading to the release of cellular contents, triggering an immune response which can lead to dangerous inflammation if not controlled.

While it is well established that MLKL and RIPK3 work together to drive cell death and inflammation, the research team, led by Associate Professor Kate Lawlor, found that MLKL and RIPK3 act independently to promote distinct aspects of obesity-associated inflammatory and metabolic disease.

They determined that RIPK3 has a role in driving inflammation and disease in subjects fed a high-fat diet, but MLKL contributes to both obesity and metabolic disease in a manner largely independent of inflammation. MLKL in fact drives obesity through promoting the expression of molecules that are involved in lipid (fat) uptake, transport and metabolism.

According to Dr Timothy Gottschalk, one of the study co-leads, it’s a significant finding: “MLKL plays a distinct role in promoting obesity and metabolic disease by disrupting lipid metabolism, independent of inflammation or RIPK3 activity.”

“The subjects in which MLKL was switched off were protected from obesity, insulin resistance and fatty liver disease by reducing lipid uptake, synthesis and storage in the liver and fat tissues. “

Combating obesity and related diseases

The findings highlight MLKL as a potential therapeutic target for combating obesity and related diseases, which are major global health challenges.

“Rather than focussing on just addressing the symptoms, targeting MLKL could treat the underlying lipid metabolism dysfunction driving these diseases,” said study co-lead Dr Hazel Tye.

“This research provides new insights into the molecular mechanisms of obesity and associated disease, paving the way for innovative treatments to reduce the burden of metabolic disorders and improve public health outcomes. “

A/Prof Lawlor said these findings, published in Life Science Alliance, begin to answer how different modes of cell death contribute to obesity and MAFLD development, and reveal novel actions for MLKL in regulating lipid metabolism.

“This research potentially identifies cell death molecules that may be amenable to therapeutic targeting to treat obesity and metabolic disease. Our findings will help direct how newly emerging cell death inhibitors under development or in clinical trials may impact affected tissues and disease progression,” she said.