Abstract
Polymorphic variants of the FTO (fat mass and obesity) gene associate with body mass index in humans, but the underlying molecular mechanisms have not been firmly determined. FTO is linked to energy homeostasis via amino acid sensing and is thought to activate the mammalian target of rapamycin complex 1, a negative regulator of autophagy. FTO localises both to the nucleus and the cytoplasm, and in this study we identify a functional nuclear localisation signal (NLS) in the N-terminus of FTO, as well as nuclear localization information in its very C-terminus. Inhibition of FTO nuclear transport has no effect on autophagy and in contrast to a previously proposed role of FTO in autophagy, we find no difference in starvation-induced autophagy in control cells compared to a panel of cell types depleted of FTO. Future studies that further characterise the cellular functions of FTO will be important to understand why variants in FTO are associated with body weight.
Highlights
Obesity is becoming an increasing threat to the public health, growing into epidemic proportions [1]
In contrast to a previously proposed role of Fat mass-and obesity-associated gene (FTO) in autophagy, we find no effect on autophagy in several assays using control cells compared to siRNA-mediated knockdown of FTO and Fto-/- mouse embryonic fibroblasts (MEFs)
We show that FTO is expressed in a range of different human cancer cell lines, which may be related to a proposed role for FTO in regulation of genes related to cancer [26]
Summary
Obesity is becoming an increasing threat to the public health, growing into epidemic proportions [1]. Genome-wide association studies (GWAS) have robustly linked single nucleotide polymorphisms (SNPs) within introns of Fat mass-and obesity-associated gene (FTO) with obesity and type 2 diabetes [3,4,5]. Adding to the controversy around FTO, a recent report [9] clearly showed that the obesity associated SNPs in FTO function as a long-range promoter for the downstream IRX3 (Iroquois Homeobox 3) gene, but not for FTO. Several reports suggest that FTO has a direct role in regulation of food intake and preference [10], as well as fat development, maintenance and metabolism [11,12,13,14]. FTO has been linked to the activity of mammalian target of rapamycin complex 1 (mTORC1) and lack of FTO has been suggested to induce degradation or recycling of cellular components through autophagy [15]
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