Body and mind

Genetic needle found in obesity’s enormous haystack

For decades, researchers have been combing the haystack of human genes for reasons that can explain the global obesity epidemic. By examining the total gene pool of the world’s large populations, researchers have discovered more than 700 genetic variants, each explaining a small part of the link between gene mutations and obesity. A Danish research group has trawled through the genes of isolated populations and has discovered one gene that has resulted in new knowledge about obesity that may lead to new treatment.

Knowing what causes a disease is essential to cure it. Not knowing often means only treating the symptoms. This is largely the situation with obesity. Obesity is expressed among people who are genetically predisposed if they are exposed to an unhealthy lifestyle, such as eating too much food or exercising too little. Nevertheless, researchers have had incredible difficulty in identifying the underlying genetic imbalance that leads to people’s altered appetite regulation and changed energy balance. Danish researchers have now successfully used a new method to reveal the genetic basis for obesity.

“Researchers previously compared genetic data from large populations and discovered multiple variants that each only explained small changes in weight, whereas we chose to examine small populations that have lived in tough and isolated conditions. Random changes in genetic susceptibility and selection have led to unusual genetic variants with large effect sizes in such populations. We could therefore see strong genetic variants among people who were predisposed to obesity. Thus, we got very clear indications of which genes we need to try to upregulate or downregulate to treat obesity,” explains Torben Hansen, Professor, Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen.

Whole segments of the genome

The Danish studies have focused on the Inuit population in Greenland. These people are especially interesting because they lived under extreme conditions while migrating from Siberia and then across northern Canada and because they have lived in isolation, in unusually cold conditions and on a very-low-carbohydrate diet for centuries.

“These conditions have left clear genetic marks in the genome of Greenlanders, so their genes differ vastly from those of Europeans. We have therefore been able to discover very clear genetic associations to type 2 diabetes and obesity in their genome.”

Chip genotyping has enabled this new research, allowing researchers to rapidly and efficiently examine specific segments of the genome. Researchers can screen for gene mutations in selected areas of the genetic material and associate the specific changes with physical characteristics of an individual, for example the degree of obesity.

“Comparing gene variants and health data among more than 5000 Greenlandic Inuit showed that 4% have a special variant of the ADCY3 (encoding adenylate cyclase 3) gene and that these people had a very strong inherited tendency towards obesity associated with the genetic mutation. We found seven Greenlanders who lacked both copies of the gene. All were very obese.

Resistance to obesity

The study of ADCY3 is the latest in a series attempting to uncover the potential causes of metabolic diseases such as obesity and diabetes. In 2014, Torben Hansen and colleagues published an article in Nature, in which they discovered a serious mutation in the TBC1D4 gene in one out of six Greenlanders.

“The protein encoded by TBC1D4 ensures glucose uptake in muscle. The mutation prevents this from happening. This may have been an advantage in the past, when the Inuit population ate very little carbohydrate. They could thus benefit from being able to retain glucose in their blood. Today, the genetic mutation leads to a vastly increased risk of developing diabetes. A person with two copies of the gene variant has a 60% risk of developing type 2 diabetes before turning 60 years old.”

The researchers are already searching for a cure for people with the TBC1D4 variant, and preliminary research indicates that exercise is the cure. Exercise vastly increases the ability of people with the TBC1D4 variant to remove glucose from the blood. Inuit people are not the only ones to benefit from this new knowledge. Studies of small and isolated populations enable researchers to get a general understanding of human metabolism.

“Our studies of the Inuit population show what happens if we completely switch off the expression of a specific gene. This provides clear answers on the role of individual genes and proteins in relation to understanding the development of obesity and diabetes. Such answers can be used to develop novel treatments for other population groups.”

The new study of ADCY3 and obesity is a good example of this. The researchers have attempted to increase the activity of the ADCY3 gene in mice, and this makes the mice completely resistant to obesity. The hope is therefore to understand how ADCY3 works and then activate the expression of the gene in people with obesity.

“Something similar happened when researchers studied families with low concentrations of serum cholesterol. The studies revealed that all these families had a mutation in the PCSK9 gene. This led to the development of an extremely effective drug – not just for the affected families – but for everyone with high cholesterol. Similarly, we hope that investigating sufficiently many mutations in the Inuit population will enable us to find new genes and methods for regulating them so we can help obese people for example.”

Genetic architecture of obesity and related metabolic traits — recent insights from isolated populations” was published in 2018 in Current Opinion in Genetics & Development. Several of the article’s authors are employed at the Novo Nordisk Foundation Center for Basic Metabolic Research at the University of Copenhagen. “Loss-of-function variants in ADCY3 increase risk of obesity and type 2 diabetes” was published in Nature Genetics in 2018. “A common Greenlandic TBC1D4 variant confers muscle insulin resistance and type 2 diabetes” was published in Nature in 2014.

Torben Hansen
We perform genetic, microbiome and metabolome studies in monogenic diabetes, childhood obesity, Inuit in Greenland and large-scale genetic epidemiology studies. We use national registers to identify families and cases with extreme phenotypes, and have initiated whole exome sequencing and large-scale studies of the oral microbiome in relation to cardiometabolic health and disease. Our major aims are: 1) to define subsets of cases with cardiometabolic disease and define optimal preventive and curative strategies 2) to define health associated genetics and microbiomics 3) to obtain a deeper understanding of cardiometabolic dysfunction at the molecular, organ and whole body level applying deep phenotyping, various imaging technologies and omics profiling methods.