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The Obesity Gene, FTO, Is of Ancient Origin, Up-Regulated during Food Deprivation and Expressed in Neurons of Feeding-Related Nuclei of the Brain

Department of Neuroscience (R.F., M.H., P.K.O., O.S., J.A.J., A.M.O. J.L., H.B.S.), Functional Pharmacology, Uppsala University, Biomedical Center, SE 75124 Uppsala, Sweden; and Minnesota Obesity Center (P.K.O., A.S.L.), Department of Food Science and Nutrition (A.S.L.), St. Paul, Minnesota 55108

Address all correspondence and requests for reprints to: Robert Fredriksson, Department of Neuroscience, Biomedical Center, Box 593, SE 75124 Uppsala, Sweden. E-mail: robert.fredriksson{at}bmc.uu.se.

Gene variants of the FTO (fatso) gene have recently been strongly associated with body mass index and obesity. The FTO gene is well conserved and found in a single copy in vertebrate species including fish and chicken, suggesting that the ancestor of this gene was present 450 million years ago. Surprisingly, the FTO gene is present in two species of algae but not in any other invertebrate species. This could indicate that this gene has undergone a horizontal gene transfer. Quantitative real-time PCR showed that the gene is expressed in many peripheral and central rat tissues. Detailed in situ hybridization analysis in the mouse brain showed abundant expression in feeding-related nuclei of the brainstem and hypothalamus, such as the nucleus of the solitary tract, area postrema, and arcuate, paraventricular, and supraoptic nuclei as well as in the bed nucleus of the stria terminalis. Colabeling showed that the FTO gene is predominantly expressed in neurons, whereas it was virtually not found in astrocytes or glia cells. The FTO was significantly up-regulated (41%) in the hypothalamus of rats after 48-h food deprivation. We also found a strong negative correlation of the FTO expression level with the expression of orexigenic galanin-like peptide, which is mainly synthesized in the arcuate nucleus. These results are consistent with the hypothesis that FTO could participate in the central control of energy homeostasis.