New Gene Mutations Linked to Severe Obesity in Children

Marlene Busko

October 30, 2013

Researchers have identified a number of rare mutations in a gene that appear to be associated with having a slow metabolism and may help explain why some young children become severely obese. The study was published online October 24 in Cell.

"We identified a new gene called [kinase suppressor of Ras 2] KSR2 that contributes to obesity from a young age and in particular is associated with a slow metabolic rate," lead author I. Sadaf Farooqi, PhD, from the University of Cambridge, United Kingdom, told Medscape Medical News. "This gene is an important regulator of appetite, metabolic rate, and how we burn both carbohydrates and fat," she explained.

While mutations in this gene are present in only about 2% of people with severe obesity, the findings add to a growing body of evidence regarding the important role that genetics can play in some forms of obesity, she notes.

Clinicians treating obese patients "still have to advise [them] about diet and physical activity, [but] for patients with severe obesity, particularly when it begins in early childhood [before age 10 years], it is worth looking into potential genetic causes," she said.

And it's possible that, one day, pharmacological approaches "based on the modulation of KSR2 activity could represent a novel potential therapeutic strategy for the treatment of obesity and type 2 diabetes," she and her colleagues write.

Understanding Childhood Obesity

Dr. Farooqi and colleagues established the Genetics of Obesity Study (GOOS) to investigate specific genes that may lead to severe and early weight gain in an attempt to help explain why some young children are constantly hungry and severely obese, whereas others, including their siblings, remain thin. They have so far published work on about 10 genes.

The current study follows previous research in mice lacking the KSR2 gene; such animals are obese and have high insulin levels and impaired glucose tolerance.

Dr. Farooqi and colleagues sequenced KSR2 in 2101 individuals with severe early-onset obesity who were enrolled in GOOS, and in 1536 control individuals from the large population-based Ely study in the United Kingdom.

They found multiple rare variants in KSR2 that were associated with impaired cellular fatty-acid oxidation and glucose oxidation. Significantly more rare variants of KSR2 were identified in individuals who were severely obese (45/2101) than in normal-weight controls (14/1353) (P = .0021).

"These findings suggest that KSR2 variants predispose to obesity against a background of other genetic and environmental factors," the authors write.

In animal studies, Dr. Farooqi and colleagues confirmed that mice lacking the KSR2 gene had an increased appetite and rapidly gained weight, especially fat mass.

And in vitro, they found that metformin countered impaired cellular fatty-acid oxidation and glucose oxidation. Thus, "very preliminary work in cells has suggested that metformin might work for this subgroup of patients," Dr. Farooqi said, although she stressed that more work will be needed to confirm this.

Hope on Horizon for Treatments for Genetic Causes of Obesity

Dr. Farooqi notes that research such as this is providing a better understanding of the genetics involved in severe obesity. Ultimately, therapies could be developed to treat obesity and diabetes by targeting these genes and pathways, she predicts.

"One of the genetic causes [of obesity] is [already] treatable, and that's leptin deficiency, but there may be a treatment for others like [melanocortin-4-receptor] MC4R in the near future," she said.

Currently MC4R mutations are the most common genetic cause of obesity, with about 5% of patients with severe obesity and about 1% of obese people generally having such mutations.

One US pharmaceutical company, Rhythm (Boston, Massachusetts), recently announced that it is beginning phase 1 trials to investigate a novel MC4R agonist for the treatment of obesity caused by such mutations.

In the meantime, discovering a genetic explanation for obesity "is actually quite important for the patients," she said. "It often helps them in knowing why they struggle with their weight and often helps to motivate them to try to see if they can do something about it."

The study was supported by the Wellcome Trust, the Medical Research Council, the NIHR Cambridge Biomedical Research Centre, and the European Research Council. The authors have reported no relevant financial relationships.

Cell. Published Oct. 24, 2013. Article

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