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Diet and lifestyle

Genetic variant regulates how well the body converts belly fat

New research shows that variants of a specific gene on chromosome 19 determine whether your body is good at getting rid of belly fat or piling it up around the waist. This discovery can potentially be used to develop medicine for obesity.

Belly fat can be dangerous and lead to a variety of diseases from type 2 diabetes to cardiovascular disease.

New Swedish research shows that variants of a specific gene play a major role in the body’s ability to convert belly fat so it can be metabolized (lipolysis).

Some people have genetic variants that dispose to accumulating belly fat, while others have variants that reduce belly fat, almost without effort.

“In a previous study, we showed that differences in how people convert belly fat are associated with differences in the risk of becoming overweight and developing diabetes. In this study, we wanted to enhance our understanding and find out what might cause defects in lipolysis in fat depots,” explains an author, Ingrid Dahlman, Adjunct Professor, Karolinska Institutet, Stockholm, Sweden.

The study has been published in Molecular Metabolism.

Interesting study, says a colleague

Nils J. Færgeman, Professor, Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense says that the new study is interesting because it identifies several genes and gene variants that regulate functions that are associated with increased risk of developing type 2 diabetes, a major problem globally.

Nils J. Færgeman did not participate in the research but has read it and thinks that it has exciting perspectives.

“The researchers found several variants in a gene that controls a very basic mechanism for converting the fat in our cells: lipolysis. By isolating some mutations that appear to affect the transcription of genes encoding the proteins involved in lipolysis, they have identified some very basic processes for how lipolysis is regulated,” says Nils J. Færgeman.

Fat biopsies from nearly 1000 people

The researchers examined the levels of lipolysis among 939 people from whom the researchers had extracted a biopsy of their belly fat.

The individuals spanned a wide range of ages and body types, but more participants were overweight than normal weight and underweight.

Then the researchers linked the levels of lipolysis with whole-genome sequencing of the participants’ DNA.

The researchers were thus able to search for genetic variants in the DNA and determine whether some genetic variants were associated with poorly functioning lipolysis.

Genetic variants are differences in the genetic code of the same gene, and this may affect the function of the gene.

“We screened the DNA of all the trial participants for known genetic variants to determine whether some are overrepresented among people with more lipolysis than others. Being able to do this was quite unique because not many researchers have access to as many fat tissue biopsies as we had. Analysing fat tissue from nearly 1000 people is a huge task,” explains Ingrid Dahlman.

Genetic variant increases risk of poor lipolysis of belly fat

The results indicated several possible genes in which the variants might influence lipolysis, but one gene in particular caught the attention of the researchers.

Of 60 sites in the DNA that were more or less strongly associated with differences in lipolysis, the HIF3A gene on chromosome 19 was most strongly correlated.

Thus, the researchers found that HIF3A does not itself regulate lipolysis but instead regulates the expression of other genes that do.

When individuals have specific variants of HIF3A, this decreases the expression of the gene and leads to elevated lipolysis, which correlates with higher body mass index (BMI).

“To the best of my knowledge, this is the first genetic variant identified that influences lipolysis,” says Ingrid Dahlman.

Genetic variant may be a target for new medicine against obesity

Ingrid Dahlman explains that the discovery indicates a possible target in the fight against the exploding obesity epidemic, which has ravaged the world for years.

If the pharmaceutical industry can develop medicine that targets HIF3A and increases its expression, this could potentially lead to decreasing lipolysis, which could lead to weight loss and prevent related diseases.

However, this discovery is only the first step on a very long road towards developing medicine targeting obesity based on HIF3A.

“The discovery is also interesting in understanding why people differ. Two people who weigh the same may have different risks of developing type 2 diabetes or gaining weight. Variants in HIF3A may help to explain the difference between individuals,” says Ingrid Dahlman.

Genome-wide association study of adipocyte lipolysis in the GENetics of adipocyte lipolysis (GENiAL) cohort” has been published in Molecular Metabolism. In 2018, the Novo Nordisk Foundation awarded a grant to Ingrid Dahlman for the project The Role of Adipose Tissue in Cardiovascular Disease with or without Diabetes.

Ingrid Dahlman
Professor
Ingrid Dahlman is studying the role of the human abdominal subcutaneous adipose tissue depot in the development of insulin resistance. The amount and function of white adipose tissue is linked to insulin resistance and type 2 diabetes. Ingrid Dahlman applies global transcriptome and DNA methylome profiling, as well as genetic association analyses, to define gene regulatory pathways in adipocytes that contribute to adipose tissue dysfunction and insulin resistance. Ingrid Dahlman has recently reported a number of genes implicated in the regulation of body fat size and distribution, and adipose morphology, for example PLXND1 and LAMB3.