Knocking out a protein kinase prevents weight gain in mice

Breaking new ground 24. sep 2023 4 min Associate Professor Lykke Sylow, PhD fellow Tang Cam Phung Pham Written by Kristian Sjøgren

New research shows that mice lacking the obesity- and type 2 diabetes–associated gene for the Traf2- and NCK-interacting protein kinase (TNIK) cannot gain weight, regardless of how much they eat and how unhealthy the diet is. They are also more active and protected against many obesity-related side-effects. The researchers say that this gene probably has the same role in humans and could become an important target for obesity treatment.

Imagine not gaining weight – no matter how much food you eat.

No build-up of fat around your internal organs either, and you are therefore well protected against all sorts of problems related to metabolism and overweight.

In addition, you have a constant drive to be physically active.

This might sound like powers more suited to a comic book superhero than the real world, but that is what might result from knocking out a specific gene.

In experiments with mice, researchers eliminated the gene for TNIK, and this turned the mice into anti-fat supermice that did not gain weight, no matter how much high-fat food the researchers fed them.

The researchers also showed that TNIK is present in humans and probably has a similar role. TNIK can therefore become an extremely promising target for new types of treatment for people with obesity.

“The particularly interesting thing about knocking out the TNIK gene is that it does not negatively affect the muscle tissue to the same extent as some of the new weight-loss treatments. This enables a new type of treatment to be developed that does not necessarily make people with obesity eat less and thereby lose both fat tissue and muscle mass but instead simply ensures that the body does not store fat,” explains a researcher behind the study, Lykke Sylow, Associate Professor, Department of Nutrition, Exercise and Sports, University of Copenhagen.

The research has been published in Science Advances and was carried out in collaboration with researchers from the Department of Biomedical Sciences and the Department of Nutrition, Exercise and Sports, University of Copenhagen, Bispebjerg and Frederiksberg Hospital, Copenhagen and researchers from Germany and Finland.

Slim mice piqued researchers’ interest

The research originated in a random observation by one of Lykke Sylow’s colleagues that mice with the gene for TNIK knocked out looked very slim.

Lykke Sylow’s research group seeks to understand the molecular biological background for developing overweight, and the researchers therefore decided to investigate the possible link between the missing TNIK gene and the apparent difficulty in gaining weight.

The researchers used special cages equipped with precision lasers to monitor TNIK-knockout mice to determine how much the mice move, how much they eat and how much they drink.

The researchers also monitored how much weight the mice gained if they fed them a normal diet or a high-fat diet – the latter equivalent to eating a hamburger every day.

“These studies of the TNIK knockout mice started as a side project, but this developed quickly because the findings were so exciting,” says Lykke Sylow.

Fat-resistant mice

The initial results showed that the mice could not gain weight – even if they ate a high-fat diet.

The researchers also observed that the mice were much more mobile than the mice that had an intact TNIK gene.

In the further studies, the researchers examined the tissues and organs of the mice to determine how losing this gene could so strongly affect the health-related effects of unhealthy food.

These studies showed that the knockout mice lacked the ability to convert dietary fat and sugar into body fat.

The researchers also examined this in Drosophilia (fruit flies) and arrived at the same result.

“The ability to convert dietary fat and glucose into body fat is crucial to whether or not you gain weight: if you lack this ability, you cannot gain weight. Further, the knockout mice were also much more mobile, which also meant that they ate more – but without gaining weight,” explains lead author, Tang Cam Phung Pham, Postdoctoral Fellow, Department of Biomedical Sciences, University of Copenhagen.

Organs not harmed by high-fat diet

The researchers then examined how lacking the TNIK gene affects various organs.

Although the mice were fed a very-high-fat diet, this did not negatively affect their liver, which usually very precisely reflects how healthy or unhealthy something is. The more fat people eat, the more fat is deposited in their liver – but not in the TNIK knockout mice.

The mice were thus protected from developing the early stages of nonalcoholic fatty liver disease, which is often associated with an unhealthy lifestyle and overweight.

The researchers also examined the mice’s insulin sensitivity in the muscles and found that those with the missing TNIK gene became more insulin sensitive.

Higher insulin sensitivity means that the insulin secreted into the blood in connection with the consumption of a meal has a much stronger effect than in normal mice and thereby rapidly and effectively reduces blood glucose.

In fact, the mice were so insulin sensitive that the researchers had to stop several experiments involving exposure to very high doses of insulin. The mice’s blood glucose dropped so far that they could die.

The fat tissue also became more insulin sensitive.

All of this may sound very interesting in mice, but…

“After carrying out the experiments on mice and characterising the effect of the missing TNIK gene, we used large databases of human genomes to investigate whether variation in the gene for TNIK is also associated with long-term blood glucose, body mass index, fat percentage and food intake. These studies showed that the gene probably has a similar role among people, who will also react similarly if they lack the TNIK gene,” says Tang Cam Phung Pham.

Possible drug target

Lykke Sylow imagines that TNIK could become a promising drug target in the future.

A drug that effectively blocks the effect of TNIK could potentially reduce the storage of body fat and avoid the negative effects of a high-fat diet while making people want to be more mobile.

Many of the current weight-loss drugs are associated with loss of both fat tissue and muscle tissue. However, inhibiting TNIK seems to not suppress appetite and therefore affect skeletal muscle building, so this will probably only affect fat tissue and the associated comorbidities associated with overweight.

“I hope that others will pick up on these findings and take the discovery further to develop drugs to inhibit TNIK. Perhaps TNIK once protected us from the effects of long periods of fasting, but it seems that in a modern society we can do without TNIK, so investigating what happens to people if TNIK is disabled will be very interesting,” concludes Lykke Sylow.

However, she also emphasises that a few more studies are required to map the exact function of TNIK and whether losing it produces side-effects.

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