Human obesity: FTO, IRX3, or both?a

Until recently, evidence was lacking for an enhanced gene expression of the fat mass and obesity (FTO) gene in humans who carry obesitysusceptible genetic variants in FTO. By using a data set of 153 cerebellar brain samples from individuals of European ancestry, Smemo and colleagues have now demonstrated that carriers of common single nucleotide polymorphisms in the FTO gene exhibit a higher cerebellar expression of the homeobox gene IRX3 [1]. They further demonstrated that the obesity-associated noncoding sequences within FTO are functionally connected, at megabase distances, with IRX3. In contrast, in this study of cerebellar samples, FTO gene expression did not differ between FTO genotypes. Additional genetic experiments revealed that global Irx3 deficiency led to a w30% body weight reduction in mice [1]. At first glance, these findings argue against a contribution of increased central nervous system FTO expression to obesity in carriers of common obesity susceptible single nucleotide polymorphisms (SNPs) within FTO, as previously suggested by findings from genetic animal studies (systematically reviewed in Ref. [2]). Instead, these results suggest that overexpression of IRX3 as a functional long-range target of obesityassociated variants within FTO might drive weight gain and the development of overweight and obesity in carriers of common single nucleotide polymorphisms in the FTO gene. However, some important points require more detailed discussion. It should be borne in mind that the studied brain regione the cerebellume is not primarily involved in food intake or appetite regulation. This is however certainly the case for the brainstem and the hypothalamus, and it was in this latter region that Smemo and colleagues found Irx3 expression to play a role for the metabolic parameters regulated by this gene [1]. Fto is however also highly expressed in especially the hypothalamus and its arcuate, paraventricular, dorsomedial and ventromedial nuclei [3], all of which are recognized to be much more highly involved in the regulation of appetite and energy metabolism than the cerebellum. It is possible that FTO expression in humans in e.g. these regions of the hypothalamus, and/or brainstem e regions in which Fto expression in animal models furthermore has been shown to be implicated in feeding condition and regulation of energy expenditure (systematically reviewed in Ref. [2])e could be differentially regulated depending on FTO genotype. These data suggest that the function of Fto expression may function in a site dependently manner, as global overexpression of Fto has been shown to cause hyperphagia [4]. Other studies however suggest that Fto protein and gene expression in the brain at least in mice is uniform