Genetic factors in obesity: the role of energy intake over metabolism

19 December 2008

New publications have shed light on some of the genetic factors involved in obesity, (defined as a body mass index or BMI greater than 30 kg/m2). Two papers in Nature Genetics report the association of specific genetic variants with obesity. The first presents the results of a genome-wide association (GWA) study with more than 300,000 single nucleotide polymorphisms (SNPs) typed in around 31,000 individuals. Most of these were Icelandic, along with around 3,000 Dutch, 2,000 European Americans and 1,000 African American subjects; results were combined with previously published results in over 5,500 Danish individuals. A total of 29 genetic variants in 11 chromosomal regions were found to be significantly associated with obesity, including previously identified variants close to or in the FTO, MC4R, BDNF and SH2B1 genes, and variants at seven loci not previously connected with obesity [Thorleifsson G et al. Nat. Genet. 2008 14 December | doi:10.1038/ng.274].

Many of the variants identified are near genes highly expressed or known to act in the brain and central nervous system (CNS), and may therefore be involved in the neuronal control of weight regulation. The authors note that this “underscores the importance of genes that regulate food intake over those involved in metabolism”. They also observe that the variants they report are all relatively common in the sampled populations (because the analysis is biased towards identification of these more common variants) and collectively explain only a small proportion of genetic variation in BMI and weight, whilst more rare mutations in the same loci might be involved in the rarer and more extreme cases of genetically-determined obesity.
The second paper is a meta-analysis of fifteen previously published GWAs with a combined total of more than 32,000 individuals looking for genetic variants associated with BMI; the fourteen most promising candidate variants were analysed in an additional fourteen groups with a combined total of more than 59,000 individuals. The results presented by the researchers confirm the involvement previously reported variants in the FTO and MC4R gene loci, along with a further six loci in the TMEM18, KCTD15, GNPDA2, SH2B1, MTCH2 and NEGR1 genes [Willer CJ et al. Nat. Genet.2008 14 December | doi:10.1038/ng.287].

The researchers acknowledge that the identified loci, their precise positions and the mechanisms by which they influence BMI and obesity will require further analysis. However, as with the first paper, they too note the high representation of genes involved in the central nervous system (CNS) that may be involved in the neuronal control of weight regulation. They also observe that many more genetic variants that influence BMI may well remain as yet undetected, particularly those that are less common or exert smaller individual effects, some of these might lie within the previously identified loci.

A third paper in the New England Journal of Medicine focused on the fat mass and obesity–associated (FTO) gene in Scottish children. The common rs9939609 (A allele) FTO genevariant was found to be associated with increased weight and body-mass index (BMI) in a sample of around 3,000 children, as expected. However, the researchers then focused on a much smaller sub-sample of 76 children to examine links between the variant and adiposity, energy expenditure, and food intake. Itwas found to be associated with increased fat (but not lean) mass, and with increased energy intake independently of body weight [Cecil JE et al. (2008) N Engl J Med. 359(24):2558-66].

Children were given one of three pre-meal snacks providing no energy, a low total energy value, or a high total energy value. Children with the A allele showed significantly greater energy intake at the subsequent test meals than those without it, especially if they had received the zero or low-energy pre-meal snacks, although the mass of food consumed by the A allele children was not increased compared with that of other children. Resting energy expenditure was equivalent for both groups of children, leading the authors to propose that the variant is not linked with any defect in metabolic adaptation to obesity, but rather that it may be involved in the regulation of food choice and intake, such that children with the variant eat more high-calorie foods than those without it. Researcher Professor Colin Palmer reportedly said that these findings “reinforced the idea that soaring obesity rates were closely linked to the widespread availability of cheap, calorie-packed foods” (see BBC news article).

Comment: Obesity is a serious public health concern in the UK and many other countries, where rising levels of obesity are predicted to lead to a huge surge in associated diseases such as metabolic syndrome, type 2 diabetes and cardiovascular disease. England’s Chief Medical Officer Sir Liam Donaldson has spoken of an "obesity timebomb" in the UK (see BBC news article). Whilst the environmental causes of obesity are relatively straightforward, being essentially excess dietary energy intake and inadequate physical activity, the genetic factors that influence it are more complex, although known to exert a significant effect on the risk of obesity. An improved understanding of the underlying genetics of obesity is an important goal for the development and targeting of effective interventions; Willer et al. correctly observe that the discovery of additional genetic variants that influence BMI will slowly increase predictive power”, but that insight into the underlying biological mechanisms involved in obesity and the design of therapeutic interventions may be more significant in terms of health impact.


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