Research finds new genetic link to severe obesity
Almost everyone knows that maintaining a healthy weight is important. To determine whether your body weight is healthy, you can calculate your body mass index (BMI), which is reported as weight in kilograms (kg) divided by height in meters squared (m2). Generally, a BMI lower than 18.5 is defined as underweight; a BMI of 18.5 to 24.9 is defined as normal weight; a BMI of 25 to 29.9 is defined as overweight; and a BMI of 30 or greater is defined as obesity. Individuals with a BMI of 40 or more are considered extremely obese and are much more susceptible to negative effects of obesity.
Despite increased attention, overweight/obesity is escalating in prevalence worldwide. The World Health Organization estimates that the worldwide prevalence of obesity has nearly doubled in the past several decades. In addition, the prevalence of overweight and obesity varies between different regions and countries. In some regions, almost a quarter of all people are obese.
Obesity is a silent killer that causes more harm than one can imagine. Multiple lines of evidence support the detrimental effects of obesity on human health. Obesity increases a person's chance of developing diabetes, high blood pressure, heart disease, stroke, cancer, gallstones, and many other diseases and conditions. Each year, millions of people die from complications of overweight and obesity.
Due to its high prevalence and remarkable impact on health, obesity has gained increasing attention in the academic world. Scientists have been trying to decipher what causes obesity. But it turns out that obesity is a rather complex condition and no single cause exists. Many things appear to contribute to the development of obesity, including eating too much, living a sedentary lifestyle, not sleeping enough, exposure to substances that disrupt the endocrine system, taking specific medications, and genetics.
Nearly all diseases result from a complex interaction between a person's genetic makeup and the environmental agents. Genes that have been associated with obesity include ADIPOQ, FTO, LEP, LEPR, INSIG2, MC4R, PCSK1, PPARG, etc. These genes regulate energy expenditure, food intake, appetite, cholesterol production, insulin biosynthesis, or fat formation. Individuals with certain variants of these genes are more likely to become obese.
Now, a new study identifies loss-of-function mutations in a gene called ADCY3, which contribute to severe obesity. The discovery suggests ADCY3 as a therapeutic target for treatment of obesity. This work is carried out by researchers from the University of Lahore in Pakistan, the University of Lille in France, Imperial College London in the UK, Katholieke Universiteit Leuven in Belgium, Radboud University Medical Center in the Netherlands, and several other research institutes.
You can read the full paper (Loss-of-function mutations in ADCY3 cause monogenic severe obesity) in the journal Nature Genetics.
A previous study by the same team has shown that recessive mutations in known obesity-related genes explain ~30% of cases with severe obesity in a consanguineous population in Pakistan, suggesting the presence of other genetic risk factors for obesity in this population. In the current study, the team employed gene sequencing technique to find that mutations in the ADCY3 gene are also associated with severe obesity in this population.
ADCY3 codes for an enzyme called adenylyl cyclase type 3, which is widely expressed in various human tissues and involved in various physiological and pathophysiological metabolic processes. Genetic studies have shown that ADCY3 genetic polymorphisms are associated with obesity in European and Chinese populations. Moreover, some studies carried out in animal models have revealed that ADCY3 dysfunction leads to increased body weight and fat mass.
Combined with other studies, the new study suggests that ADCY3 is a key mediator of energy homeostasis and represents a potential therapeutic target to treat obesity and reduce the risk of obesity-related complications.