FTO-genotype affects postprandial neuronal responses to visual food cues

Abstract

Until now, genetic approaches to unravel the pathophysiology of human obesity have shown only moderate success. One of the most promising obesity susceptibility loci identified by large genome wide association studies (GWAS) in humans is the fat mass and obesity associated gene (FTO). Single nucleotide polymorphisms (SNP) in the FTO gene are robustly associated with the regulation of body weight [1] and can account for a maximum of an additional 3 kg weight gain in homozygous individuals, which is largely due to the increased food intake [2,3]. Moreover, studies in rodents established a bidirectional relationship between food intake and the levels of FTO protein in the brain. In the rodent hypothalamic arcuate nucleus (ARC), FTO-protein levels decrease after fasting [4] and increase after high fat diet feeding [5]. Conversely, knock-down and overexpression of FTO protein in this area increase and decrease food intake respectively [5]. In line with these findings, in humans the FTO-genotype appears to be associated not only with the amount of food intake but also with specific macronutrient preferences [6]. Overall, these data suggest a causal role for FTO-genotype role in regulating both food related brain activity and ingestive behavior. Recent data by Karra et al. further suggest, that homozygosity in an FTO-risk allele alters responses to food images in brain regions associated with the regulation of energy homeostasis and food reward [7]. In this issue of “Molecular Metabolism” Heni et al. demonstrate that metabolic state and FTO genotype interact to modulate cerebral processing of food images in the prefrontal cortex. The authors employed functional magnetic resonance imaging (fMRI) to assess the blood oxygenation level dependent (BOLD) response to high vs. low calorie food images in normal weight subjects following an oral glucose preload vs. drinking a glass of water [8]. This study is of significant relevance implicating that the brain reward system is mediating FTO's effect on food intake and related cerebral responses. Although subtle effects may have gone unnoticed due to the rather small sample size – in particular of homozygous subjects, these data clearly raise important questions. In particular, this relates to asking how FTO impacts on hedonic food intake and food related cerebral activity in humans. In an important study, Karra et al. demonstrated that FTO genotype is associated with the degree of postprandial suppression of the major orexigenic hormone acyl-ghrelin [7]. Next to its role in homeostatic ingestive behavior, ghrelin has further been shown in rodents to affect mesolimbic dopaminergic (DA) reward circuitry and subsequently food intake [9]. Thus the observed attenuated suppression of circulating ghrelin levels in subjects with homozygosity for FTO risk alleles provides a plausible link between FTO-genotype and altered food related cerebral responses and ingestive behavior. nterestingly, in mice with DA neuron-specific deletion of FTO, activation of type 2 and type 3 dopamine receptors (D2/D3-R), that are both involved in food reward signaling in midbrain dopamine reward circuits, is reduced [10]. In a next step, it would be important to tease apart a possible direct influence of FTO genotype on reward-related brain activity and hedonic food intake from a ghrelin dependent effect, e.g., by combining brain imaging with pharmacological manipulation of mesolimbic, dopaminergic reward circuits. This experimental approach, may yield exciting new insights on the role of FTO in regulating food intake and body weight. In conclusion, the findings of Heni et al. add further support to the suggested role of FTO in the reward-related regulation of appetite control and in a more general perspective underscore the importance of gene polymorphisms in shaping human ingestive behavior and body weight. Combining GWAS with subsequent functional testing represents a promising approach to tailor medical therapy to individual patient genotypes in the future.