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A genetic approach to understanding obesity: genotype and behavioural phenotype in the maintenance of child obesity

Relationship between genotype and behavioural phenotype for obesity

Child obesity has become one of the most significant complex public health problems of this century. Globally, an estimated 42 million children below five years of age present with excess adipose tissue. Yet, not all children become overweight or obese in an ‘obesogenic environment’, suggesting that individual differences exist in susceptibility and resistance towards weight gain and obesity1. Genetic variation, environmental differences and variation in the response to the environment determine susceptibility and the expressed phenotype.

Evidence for a genetic role in obesity and eating behaviour?

The evidence supporting a genetic contribution to obesity is considerable. Twin, familial aggregation and family studies have been consistent in characterising a heritable association between the influence of genes and obesity. Notably, twin studies have shown heritability estimates as high as 75% for child BMI2 and similarly high estimates for body fat3. Heritability estimates for appetite and eating behavioural traits associated with susceptibility towards obesity have also been documented in children. For example, the genetic influence towards macronutrient preference, food preference, satiety and food enjoyment, eating in the absence of hunger, food fussiness and preference for fruit and vegetables have been shown to be highly heritable4.

Functional studies, which link candidate genes to an obese phenotype, provide additional robust evidence to support a genetic role in obesity and eating behaviour. Single gene mutations, for example in the leptin (LEP), leptin receptor (LEPR), melanocortin 4 receptor (MC4R), proopiomelanocortin (POMC) genes lead to extreme obesity in children and appear to disrupt appetite regulating mechanisms that control food intake leading to hyperphagia5. These monogenic obesities have yielded important insights into key pathways underlying the control of energy balance, but are population rare (5-7%) and don’t reflect the obesities commonly observed today. Instead, most obese phenotypes are thought to be polygenic and involve complex gene-gene and gene-environment interactions operating frequently with small effects.

Common gene polymorphisms: a role in obesity and eating behaviour

Extensive ‘genome-wide associations studies’ (GWAS), powered to detect small effects by testing in large populations, have transformed progress in identifying new obesity gene variants or single nucleotide polymorphisms (SNPS) for hypothesis driven research. To date, evidence for over 90 susceptibility loci regulating body weight have been identified6. Candidate common gene variants that predispose to polygenic obesity and contribute to variance in eating behaviours associated with child obesity include the fat mass and obesity-associated (FTO) gene, peroxisome proliferator-activated receptor (PPARG), melanocortin 4 receptor (MC4R), adrenergic receptors and reward related variants such as D2 dopamine receptor (DRD2) gene polymorphisms7.

Currently, the most robustly characterized gene model for polygenic obesity is the FTO gene, discovered from a multi-centre GWAS for type 2 diabetes8. FTO, residing on chromosome 16, encodes a protein with 2-oxoglutaratedependent nucleic acid demethylase activity9 and is expressed in greatest proportion in brain tissue, and elsewhere in pancreatic islet, adipose tissue and adrenal gland. FTO SNP rs9939609, located in the first intron and present at a high allelic frequency (approx. 39%), has been associated with increased BMI in children and adults8. In children, one copy of the minor (A) allele (risk allele) was associated with an increase in BMI of approx. 0.2 kg/m2 from ages 7-10 years, increasing to approx. 0.4 kg/m2 at age 11 years8. Multiple studies have since confirmed a role for FTO gene variants in influencing BMI and fat mass in children10,11. It is possible that SNPs in intron 1 of FTO are involved in the expression of other genes nearby (e.g. RPGRIP1 and IRX3) and might therefore mediate an influence on obesity via these neighbouring genes, illustrating a more complex understanding FTO than originally envisaged12.

FTO related susceptibility to polygenic obesity is thought to be primarily mediated via a central role in the control of food via alterations in appetitive pathways, rather than via energy expenditure. Experimental studies in rodents have shown that expression of the gene is concentrated in brain regions known to be responsible for regulating feeding9,13. In support of functional evidence, studies conducted in children have shown that FTO variants predispose to obesity risk though increased energy intake10,14 a preference for energy dense foods10,14 reduced satiety responsiveness15 and loss of control over eating16. Thus, FTO appears to represent a gene model that predisposes towards obesogenic eating behaviours.

Molecular genetics has contributed valuable information about the genetic architecture of common complex disease such as obesity. The knowledge that polygenic obesity, like monogenic obesity, appears to be driven principally by disruption of appetite regulation can potentially be used in development of novel therapeutic targets and behavioural strategies which may have implications for diagnosis, prevention and management of obesity.

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