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Do I Look Fat in these Genes?

Rare Genetic Disorders Offer Insight to Obesity   

Studies of twins, adopted children and their families have provided strong evidence of the heritability of obesity. In particular, a 1990 study of identical twins raised apart found that their adult BMI was strongly correlated to each other (despite being separated at birth) rather than to the families in which they were adopted ( Stunkard, N Engl J Med ). 

While estimates vary widely as to what share of an individual’s BMI is attributable to genetics (30% to 70%, depending on the study), most studies suggest that severe early onset obesity in children is likely to be associated with a genetic disorder. 

Pediatric endocrinologist Andrea Haqq of the University of Alberta studies childhood obesity and its genetic roots. Of the single-gene causes of childhood obesity, the most common is a mutation in the melanocortin 4 receptor (MC4R).  A University of Cambridge study by O’Rahilly and Farooqi ( Intl J Obes, 2008 ) found that 3% to 5% of children with early onset obesity harbour this mutation.
“Children with this genetic deficiency are usually tall and obese and are prone to de­veloping hyperinsulinemia,” Dr. Haqq explains. Behaviourally, these children are distinguished by hypherphagia and excessive food seeking. 

Children with Prader-Willi Syndrome dis­play even more extreme food-seeking behaviours. “This condition is very challenging for families and limiting for the children, as they can never have unsupervised access to food,” says Dr Haqq, who follows some 40 chil­dren with the syndrome. As they mature, most individuals with Prader-Willi must live in group homes where food is kept under lock and key. 

Approximately one in 10,000 people — about 3,000 Canadians — are affected by this syn­drome. Dr. Haqq hypothesizes that the obsessive hunger seen in these children is at least partly driven by ghrelin, a gastrointestinal hormone that increases appetite. She has demonstrated that children with Prader-Willi Syndrome exhibit four to five times increased fasting circulating ghrelin levels compared to obese children without this syndrome. She is currently studying whether a high-protein diet will improve satiety in these children, as there is some evidence that protein may impact ghrelin. 

The benefits of this research will extend beyond the few thousand patients affected by these rare genetic disorders.  “Just as re­search into leptin deficiency led to the understanding of leptin as an appetitive regu­latory hormone, work done in Prader-Willi Syndrome and MC4R-deficiency may give us insights to the complex neuroendocrine reg­ulation of body weight in the general population,” suggests Dr. Haqq.  

For example, of the single-gene defects that cause obesity (including the above two conditions), all those discovered to date are primarily involved in disrupting satiety. 

This builds on previous research suggest­ing that hereditary factors primarily affect the efficiency with which nutrients are stored or disposed. Such discoveries will guide future treat­ment paths. 

“As we better understand the pathophysiology of obesity, we will probably find that subsets of individuals will respond differently to different therapies. As a result, we will be able to target treatments more ef­fectively,” says Dr. Haqq.  

Researchers are now working on small molecule agonists to the MC4 receptor, a potential treatment that could have a significant impact on curbing the obesity epidemic, as MC4R-deficiency may be present in as many as one in 1,000 people ( Hum Mutat, 2007 ). 

Regardless of one’s genetic inheritance, Dr. Haqq and others stress that the environ­ment still plays a crucial role in determining what and how much individuals eat. 

“These conditions remind us that there are definite biologic drivers to appetite, but we cannot forget the importance of the environment acting on those genes,” says. Dr. Haqq.