Genomic insights into early-onset obesity

Choquet and Meyre Genome Medicine 2010, 2:36 http://genomemedicine.com/content/2/6/36 REVIEW Genomic insights into early-onset obesity Hélène Choquet* and David Meyre* Abstract The biological causes of childhood obesity are complex. Environmental factors, such as massive marketing campaigns for food leading to over-nutrition and snacking and the decline in physical activity, have undoubtedly contributed to the increased prevalence of overweight and obesity in children, but these cannot be considered as the only causes. Susceptibility to obesity is also determined to a great extent by genetic factors. Furthermore, molecular mechanisms involved in the regulation of gene expression, such as epigenetic mechanisms, can increase the risk of developing early-onset obesity. There is evidence that early-onset obesity is a heritable disorder, and a range of genetic factors have recently been shown to cause monogenic, syndromic and polygenic forms of obesity, in some cases interacting with environmental exposures. Modifications of the transcriptome can lead to increased adiposity, and the gut microbiome has recently been shown to be key to the genesis of obesity. These new genomic discoveries complement previous knowledge on the development of earlyonset obesity and provide new perspectives for research on the complex molecular and physiological mechanisms involved in this disease. Personalized preventive strategies and genomic medicine may become possible in the near future. Epidemiology of early-onset obesity Childhood obesity is one of the most serious public health challenges of the 21st century. This global health problem is gradually affecting both developed and developing countries, particularly in urban settings. In the United States, childhood overweight and childhood obesity are defined as a body mass index (BMI; (Weight in kg)/(Height in m)²) greater than or equal to the 85th and 95th percentile for gender and age, respectively [1]. *Correspondence: , CNRS UMR8199, Institute of Biology, Pasteur Institute, 1 Pr Calmette Street, 59000 Lille, France © 2010 BioMed Central Ltd © 2010 BioMed Central Ltd In Europe, the European Children Obesity Group defined childhood overweight and childhood obesity as a BMI greater than or equal to 90th percentile to 97th percentile for gender and age [2]. A reference population has been established to propose an international standard definition for childhood overweight and childhood obesity [3]. The prevalence of overweight and obesity in childhood is increasing worldwide at an alarming rate: today, about one in three children and adolescents is overweight or obese in the United States; over the past three decades, the prevalence of obesity has tripled for children 2 to 5 years old and youths 12 to 19 years old, and has quadrupled for children 6 to 11 years old [4]. According to the World Health Organization and to the International Obesity Task Force, more than 155 million children and adolescents worldwide are overweight and 40 million are clearly obese. Early-onset obesity is associated with an increased incidence of adult obesity [5], type 2 diabetes [6], nonalcoholic fatty liver disease [7] and cardiovascular risk factors [8]. Obese children have an increased risk of developing obesity-related co-morbidities, such as orthopedic, ophthalmologic and renal complications [9], respiratory diseases such as obstructive sleep apnea [10], and psychosocial impairment [11]. Obesity-associated complications are now believed to be leading, for the first time in modern history, to a decrease in life expectancy of 2 to 5 years for the US generation that is currently young [12]. Today, medical and behavioral interventions as treatment for obesity in childhood remain scarce and largely ineffective. There are currently three main treatment modalities for obesity: lifestyle modifications, pharmacotherapy and bariatric surgery. The cornerstone of lifestyle modifications includes changes to dietary and exercise habits [13]. However, less than 5% of the obese people who follow these recommendations effectively lose weight and maintain that weight loss [14]. The longterm safety and efficacy of the anti-obesity drugs (orlistat and sibutramine) have not been determined in children or adolescents, mainly because pharmacotherapy is not routinely proposed as a treatment for childhood obesity [15]. Bariatric surgery is a new treatment for morbid obesity in children but the relevance of an invasive surgery procedure in childhood or adolescence is still Choquet and Meyre Genome Medicine 2010, 2:36 http://genomemedicine.com/content/2/6/36 under debate [16]. A recent study [17] reported the first case of laparoscopic sleeve gastrectomy successfully performed in a 6-year-old morbidly obese child. Because of the lack of efficiency of the current approaches to reverse childhood obesity, prevention was proposed as the first line of treatment in 2003 by the American Academy of Pediatrics [18]. In its policy statement, the Academy promoted breastfeeding, healthy eating habits and physical activity and encouraged limitation of television viewing. However, current prevention pro grams have had little success and have proven ineffective in reversing the rising rates of childhood obesity [19]. These disappointing observations reveal the urgent need to better understand the complex molecular and physiologic mechanisms involved in human obesity in order to propose better disease prevention and care. Early-onset obesity is a heritable disorder The epidemic of obesity is attributed to recent environ mental changes. Easy access to high-energy palatable food, combined with decreased physical activity levels, have undoubtedly had a major role in the global increase in the prevalence of early-onset obesity [20]. Beyond ‘the big two’, other putative environmental contributors to the recent obesity epidemic have been proposed, such as an obesity-prone intrauterine environment, assortative mating among obese individuals, decreasing sleep dura tion, infections and low-grade inflammation or the increasingly controlled ambient temperature [21]. How ever, if these factors are responsible for the global shift in BMI distribution, genetic factors must explain most of the inter-individual differences in obesity risk observed in populations (in other words, where each individual sits on the BMI distribution) [22]. In fact, the risk of obesity in a child is ten times higher if both parents are obese than if both parents are of normal weight [23]. Heritability represents the proportion of phenotypic variation in a population that is attributable to genetic variation among individuals. According to twin and family studies, heritability estimates for BMI during childhood or adolescence are between 0.20 and 0.86 [22,24-29]. Longitudinal studies have demonstrated that heritability estimates tend to increase from childhood to pre-adolescence [26,29] and from pre-adolescence to adolescence (...truncated)