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Diet and lifestyle

Genes that make you fat but keep you fit

You might think that obesity is always linked to poor health. Although this may often be true, new research suggests that obesity does not always make people unhealthy. Genetic epidemiologist Ruth Loos has discovered a set of genes that protects people from developing cardiovascular disease and diabetes, even though it predisposes them to gaining weight.

Globally, 39% of people are overweight or obese, and an estimated 2.8% of the world’s economic resources is used to treat obese people. Recent research shows that the obesity epidemic may need to be approached differently, since it has no single cause and does not always lead to poor health. Ruth Loos from the Icahn School of Medicine in New York is one of the researchers whose results confirm this.

“We have identified one of the first genes that increases body fat mass but protects against type 2 diabetes and cardiovascular disease. Examining this observation, we found that the gene, called IRS1, determines not only the amount of fat stored in the body but also where exactly it is stored.”

IRS1 promotes subcutaneous fat storage, which is where fat ideally should be stored, and prevents intra-abdominal fat storage, which is metabolically harmful. After discovering IRS1, Ruth Loos and her colleague Tuomas Kilpelainen from the Novo Nordisk Foundation Center for Basic Metabolic Research at the University of Copenhagen have continued searching the human genome for more genes associated with healthy obesity.

“Using a genome-wide screen, we identified 90 additional healthy obesity genes and are working hard to gain insight into the underlying biology. Preliminary analyses suggest that these healthy obesity genes may act in the adrenal cortex, the liver and the adipocytes. More work is needed to get to the bottom of this, but I think these genes will help us to better understand the link between obesity and cardiometabolic diseases.”

Less is more

Besides Ruth Loos’ specific interest in healthy obesity genes, her team has worked for many years to identify genes that affect body weight in general, regardless of how they affect other diseases.

“We have found more than 300 genomic regions that are associated with obesity. The genes in these genomic regions collectively point towards the brain being a key organ for controlling body weight. The main challenge, however, is to pinpoint the obesity-causing genes in each of these chromosomal regions, which often harbour multiple genes.”

To overcome this challenge, she has started to focus on genetic variants located in the exons – the coding parts of genes.

“These coding variants are typically very rare, but when present, they may change the function of the gene. Thus, if we find an association between such a coding variant and obesity, we can be fairly certain that the gene is causal.”

Small pieces of the obesity puzzle

In ongoing work with the GIANT (Genetic Investigation of Anthropometric Traits) Consortium, Ruth Loos has identified 14 coding variants associated with body mass index, one of which is a coding variant in MC4R, a gene that acts in the brain to control food intake.

“Only one in 5000 people carries this coding variant, but among those who do, MC4R is not functional and they weigh on average 7 kg more than others with a functional MC4R gene.”

Ruth Loos emphasizes that a healthy lifestyle remains key in preventing weight gain.

“We know that our propensity to gain weight depends not only on environmental and lifestyle factors, such as diet and physical activity, but also on genetic factors that determine how people respond to certain lifestyles.”

Developing personalized treatment is challenging

According to Ruth Loos, some people gain weight quickly on a high-fat diet because they are more genetically susceptible than those who can eat anything without putting on weight. A differentiated approach is therefore necessary.

“Interest in personalized medicine has increased in recent years. In the context of obesity, this might mean that a person’s genetic characteristics could help a healthcare professional customize weight loss treatment for optimal results.”

In fact, a weight loss medication is already being developed that does exactly that. However, since most of the genetic mutations are very rare, drugs will only be effective for a few individuals. This makes developing personalized treatment challenging.

“This, however, should not discount the importance of genetic research. The main reason we search for obesity genes is to gain insight into the biology of body weight regulation. Once we understand the biology, we may identify new drug targets,” Ruth Loos says.

Ruth Loos gave a presentation at the Copenhagen Bioscience Conferences, a Novo Nordisk Foundation initiative, in October 2017. Ruth Loos co-authored “Obesity”, published in Nature Reviews in June 2017.

Ruth Loos
Professor
Genetic Epidemiology Our primary research interests focus on the identification of genes and genetic loci contributing to the risk of obesity and related metabolic traits. We have been involved in gene - discovery since 2005, when ‘genome - wide association’ was introduced and have since actively contributed to many consortia that use this approach to identify genetic loci for a large number of metabolic traits. By identifying genes that influence the risk of obesity and related metabolic traits, we aim to provide new insights in the mechanisms that regulate body weight and risk of metabolic disease. Eventually, such biological insights might results in a better tailored treatment or prevention. Increasingly, our gene - discovery work also focuses on the identification of low - frequency variants through the implementation exome - chip genotyping and sequencing projects, not only in individuals of white European descent, but also in those of African and Hispanic decent. We have established consortia to study the genetics of body fat percentage, circulating leptin levels, physical activity and heart rate and continue to invited studies for participation to study common and low-frequency variants. We are actively involved in the GIANT (Genetic Investigation of ANthropometric Traits) Consortium, lead by Prof. Joel Hirschhorn, with whom we have discovered more than 90 common variants associated with body mass index (BMI; assesses overall body sizes), over 40 common variants for waist-to-hip ratio (WHR; assesses body fat distribution), and hundreds for height. The GIANT Consortium is currently inviting studies to participate in their ExomeChip efforts.