The identification of the novel obesity susceptibility loci has instigated new studies exploring through which arm of the energy balance, i.e. food intake or energy expenditure, these loci lead to obesity.
In particular for the FTO locus, which was discovered as the first obesity susceptibility locus, new insights have begun to accumulate. Some studies have provided evidence for a role of the FTO locus in food intake. For example, two studies in a total of >8000 British children consistently showed that the BMI-increasing allele of the FTO locus was associated with increased energy intake, independent of body size (Cecil et al, 2008; Timpson et al, 2008). A third study in 3337 children showed that homozygotes for the FTO risk allele had a significantly reduced satiety responsiveness score (Wardle et al, 2008). This observation was confirmed in a smaller study of 131 children with careful registration of the children's consumption of palatable food presented after having eaten a meal (Wardle et al, 2009). Homozygotes for the BMI-lowering FTO-allele ate significantly less than the heterozygotes or homozygotes of the BMI-increasing allele, suggesting that those with BMI-lowering allele are protected against overeating by promoting responsiveness to internal satiety signals (Wardle et al, 2009). However, not all studies have been able to support a role for the FTO locus in energy intake (Bauer et al, 2009; Hakanen et al, 2009; Johnson et al, 2009). While data from /to-deficient mice have suggested that /to might induce obesity through an effect on energy expenditure (Fischer et al, 2009), there is no evidence to support such role in humans (Berentzen et al, 2008; Cecil et al, 2008; Goossens et al, 2009; Hakanen et al, 2009; Haupt et al, 2009; Rampersaud et al, 2008; Speakman et al, 2008; Wardle et al, 2008).
For the locus identified in the second wave on genome-wide association studies (Chambers et al, 2008; Loos et al, 2008), the MC4R gene is the nearest and most obvious candidate gene. Mutations in the MC4R gene are known to result in extreme obesity through hyperphagia (Farooqi et al, 2003). However, it is still unclear whether the near MC4R locus indeed reflects the functions of MC4R. A few studies, which were performed even before the genome-wide association era, have examined the potential role of genetic variation near MC4R gene in contributing to the physical activity energy expenditure based on evidence from studies of Mc4r knockout mice (Butler et al, 2001; Ste Marie et al, 2000). A study in 669 individuals showed that homozygotes for a variant located downstream of the MC4R gene had the lowest moderate-to-strenuous activity scores (p= 0.005) and the highest inactivity scores (Loos et al, 2005). The same locus was found to be linked to physical activity levels in a genome-wide linkage study in 1030 siblings from 319 Hispanic families (Cai et al, 2006).
Little is known about the more recently discovered loci and genes. The neuron-specific over-expression of SH2B1 has been shown to be protective against high-fat diet-induced obesity in mice (Ren et al, 2007), whereas the BDNF variant has been shown to be associated with eating behaviour in humans (Bauer et al, 2009; Shugart et al, 2009). A recent study in 1700 Dutch women (Bauer et al, 2009) examined the majority of the newly discovered obesity loci found that the SH2B1, KCTD15, MTCH2, NEGR1, and BDNF loci were associated with dietary macronutrient intake.
Although the above-mentioned studies provide some first evidence of association with energy intake and expenditure, replication of these observations in larger cohorts will be required to confirm the reported findings.
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