Abstract
Single-nucleotide polymorphisms in the first intron of the ubiquitously expressed FTO gene are associated with obesity. Although the physiological functions of FTO remain unclear, food intake is often altered when Fto expression levels are manipulated. Furthermore, deletion of FTO from neurones alone has a similar effect on food intake to deletion of FTO in all tissues. These results indicate that FTO expression in the brain is particularly important. Considerable focus has been placed on the dynamic regulation of Fto mRNA expression in the hypothalamus after short-term (16–48 hour) fasting, but results have been controversial. There are no studies that quantify FTO protein levels across the brain, and assess its alteration following short-term fasting. Using immunohistochemistry, we found that FTO protein is widely expressed in mouse brain, and present in the majority of neurones. Using quantitative Western blotting and RT-qPCR we show that FTO protein and mRNA levels in the hypothalamus, cerebellum and rostral brain are relatively uniform, and levels in the brain are higher than in skeletal muscles of the lower limbs. Fasting for 18 hours does not alter the expression pattern, or levels, of FTO protein and mRNA. We further show that the majority of POMC neurones, which are critically involved in food intake regulation, also express FTO, but that the percentage of FTO-positive POMC neurones is not altered by fasting. In summary, we find no evidence that Fto/FTO expression is regulated by short-term (18-hour) fasting. Thus, it is unlikely that the hunger and increased post-fasting food intake caused by such food deprivation is driven by alterations in Fto/FTO expression. The widespread expression of FTO in neurones also suggests that physiological studies of this protein should not be limited to the hypothalamus.
Highlights
Obesity is a major public health issue
In another study where food intake was measured, FTO genotype was not associated with total energy intake, but rather with altered food preference; individuals with the A allele consumed a greater proportion of calories from fat [9]
FTO protein is widely expressed across the brain Immunohistochemical experiments on brains of free-fed mice revealed that FTO protein is not limited to specific brain regions but is expressed relatively uniformly throughout the brain, including the hypothalamus (Figure 1A), hippocampus and neocortex (Figure 1B), and the cerebellum (Figures 1C and 1D)
Summary
Obesity is a major public health issue. It predisposes to numerous diseases, including heart disease, type 2 diabetes and cancer, and it imposes a significant economic burden on Western societies. Genes associated with more common, less severe forms of obesity have recently begun to be revealed by genome wide association studies In this way, single nucleotide polymorphisms (SNPs) in the first intron of the fat mass and obesity-associated (FTO) gene were found to be associated with obesity in numerous human populations [2,3,4]. In another study where food intake was measured, FTO genotype was not associated with total energy intake, but rather with altered food preference; individuals with the A allele consumed a greater proportion of calories from fat [9] These results suggest that FTO may affect body weight by influencing food intake and dietary composition
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