FTO expression is regulated by availability of essential amino acids

• Published in: International Journal of Obesity 2013-05, Vol.37 (5), p.744-747
• Main Authors: Cheung, M K, Gulati, P, O'Rahilly, S, Yeo, G S H
• Format: Article
• Language: English
• Subjects: 631/208/199; 631/208/200; 631/443/319/1642/393; Alpha-Ketoglutarate-Dependent Dioxygenase FTO; Amino acids; Amino Acids, Essential - metabolism; Animals; Arcuate Nucleus of Hypothalamus - metabolism; Biological and medical sciences; Blotting, Western; Body mass index; Cell Line; Diet, High-Fat; Down-Regulation; Epidemiology; Gene expression; Gene Expression Regulation; Genetic aspects; Genetic regulation; Genome-Wide Association Study; Glucose; Glucose - metabolism; Health Promotion and Disease Prevention; HEK293 Cells; Humans; Hypothalamus; Internal Medicine; Laboratories; Medical sciences; Medicine; Medicine & Public Health; Metabolic Diseases; Metabolism; Mice; Mixed Function Oxygenases - metabolism; Mortality; Nutrients; Nutritional status; Obesity; Obesity - genetics; Obesity - metabolism; Obesity - physiopathology; Oxo-Acid-Lyases - metabolism; Polymorphism, Single Nucleotide; Proteins; Proteins - metabolism; Public Health; RNA, Messenger - metabolism; short-communication; Time Factors
• ISSN: 0307-0565; 1476-5497
• DOI: 10.1038/ijo.2012.77

Genome-wide association studies have revealed that single nucleotide polymorphisms in fat mass and obesity-associated transcript (FTO) are robustly associated with body mass index and obesity. Expression of Fto in the hypothalamic arcuate nucleus is bidirectionally regulated as a function of nutritional status; decreasing following a 48-h fast and increasing after 10-week exposure to a high-fat diet. Here, we utilize an in vitro approach to determine which nutrients could regulate FTO levels at a cellular level. Using mouse and human cell lines, we find that FTO levels are not influenced by serum starvation. We demonstrate, however, that both glucose and total amino-acid deprivation regulates FTO expression. In particular, we have found that FTO mRNA and protein levels are dramatically downregulated by total amino-acid deprivation in mouse hypothalamic N46 cells, mouse embryonic fibroblasts and in human HEK293 cells. The drop rate of Fto mRNA is faster than its rate of natural degradation, pointing to regulation at the transcriptional level, which is reversible upon amino-acid replacement. Strikingly, this downregulation was seen only with essential amino-acid deficiency and not nonessential amino acids. These data suggest that FTO might have a role in the sensing of essential amino-acid availability.