Left: A high-fat diet can lead to the storage of fats in the liver (red). This can trigger the development of fatty-liver disease and diabetes. Right: When Ceramide Synthase 6 is inactivated, mice are protected from the excessive storage of lipids in the liver, despite eating the high-fat diet. Importantly, also the glucose metabolism of these mice improves.

© MPI for Metabolism Research

Intervention in fat metabolism

Improved diabetes in spite of obesity

Eating too much fat and sugar makes you overweight and unhealthy – even young children know that. But why is that, and is there anything we can do about it?

In a study published in the journal Cell, Prof. Jens Brüning's research group at the Max Planck Institute for Metabolism Research in Cologne has shown how altering fat metabolism in the liver can make obese mice thinner, despite eating an unhealthy diet. The process also improves the glucose metabolism of the mice. This is achieved by switching off a protein, called ceramide synthase 6.

Adipose tissue in our body stores fat. At some point prolonged eating of a diet that is too high in fats leads to storage of these fats in other places, like muscle and liver. This can lead to fatty liver disease, insulin resistance, and ultimately type 2 diabetes mellitus. Researchers have known for some time that this process involves a specific group of fats known as ceramides. These are produced in the body by various ceramide synthases.

Recommended article

Photo

Good boy, indeed

Diabetes: Dogs can help manage hypoglycaemic episodes

New research by the University of Bristol in collaboration with Medical Detection Dogs has found that the best trained alert dogs have the potential to vastly improve the quality of life of people living with Type 1 diabetes. As reported in PLOS One, on average trained dogs alerted their owners to 83 per cent of hypoglycaemic episodes in over 4,000 hypo- and hyper-glycaemic episodes that were…

"Other research groups have already shown that blocking ceramide production in mice prevents the development of insulin resistance. However, this is associated with a large number of side effects. If, for example, ceramide synthesis is completely inhibited it can adversely affect the development of the animals," explains Philipp Hammerschmidt, a doctoral student in Brüning's research group and first author of the study. The researchers, therefore, investigated precisely which of the various ceramide synthases are involved in the development of insulin resistance, in the hope of providing more specific therapeutic targets.

They discovered that ceramide molecules of a particular length, formed by both ceramide synthases 5 and 6, accumulate in the liver when mice become obese on a high-fat diet. “Interestingly, only the genetic inactivation of ceramide synthase 6 in mice, resulted in protection from obesity, fatty liver, and insulin resistance. However, losing ceramide synthase 5 activity, did not have these effects", explains Hammerschmidt.

Same product – different function

The mice continue eating the high-fat diet, nevertheless their glucose metabolism improves

Philipp Hammerschmidt

"This was very surprising, as these two synthases produce exactly the same ceramide product but have completely different effects on the metabolism of the mice," said Hammerschmidt. The scientists discovered that the two proteins are active at different locations within the cell. Ceramide synthase 6 regulates the ceramide content in mitochondria, the cell's energy generators, influencing their structure and function.

The fact that the mice become overweight and unhealthy on a poor diet is, probably, in part due to the accumulation of ceramides formed by ceramide synthase 6, in mitochondria. This leads to impairment of their function. The discovery allowed the researchers to identify key proteins in mitochondria, which bind ceramides specifically from ceramide synthase 6 but not ceramides from the related ceramide synthase 5.

Switching off ceramide synthase 6 in a precisely controlled way resulted in a clear effect: “The mice continue eating the high-fat diet, nevertheless their glucose metabolism improves," explains Hammerschmidt. "It's possible that inhibition of ceramide synthase 6, or the ceramide-binding mitochondrial proteins we found, could be used as a basis for therapies in humans, but there is still a long way to go.” 


Source: Max Planck Institute for Metabolism Research

02.06.2019

Read all latest stories

Related articles

Photo

Heat therapy

Soaking in a hot tub has unexpected benefits, researchers find

According to new research, obese women with polycystic ovary syndrome (PCOS) may be able to improve their health outlook with a particularly enjoyable form of therapy: regular sessions in a hot tub.…

Photo

Not so sweet after all

Could sugar be responsible for the obesity and diabetes epidemics?

The idea that sugar could be a fundamental cause of the global obesity and diabetes epidemics, with deleterious effects on the human body that go beyond just empty calories, should be considered…

The Norfolk Diabetes Prevention Study

UK -- Family doctors (GPs) in Norfolk are inviting patients aged over 40, with a Body Mass Index above 30 and a family history of diabetes, to take part in the Norfolk Diabetes Prevention Study…

Related products

Eppendorf - Mastercycler nexus X2

Research use only (RUO)

Eppendorf - Mastercycler nexus X2

Eppendorf AG
SARSTEDT - Low DNA Binding Micro Tubes

Research use only (RUO)

SARSTEDT - Low DNA Binding Micro Tubes

SARSTEDT AG & CO. KG
Shimadzu – CLAM-2030

Research Use Only (RUO)

Shimadzu – CLAM-2030

Shimadzu Europa GmbH