FTO is a transcriptional repressor to auto-regulate its own gene and potentially associated with homeostasis of body weight

Abstract

Fat mass and obesity-associated (FTO) protein is a ferrous ion (Fe2+)/2-oxoglutarate (2-OG)-dependent demethylase preferentially catalyzing m6A sites in RNA. The FTO gene is highly expressed in the hypothalamus with fluctuation in response to various nutritional conditions, which is believed to be involved in the control of whole body metabolism. However, the underlying mechanism in response to different nutritional cues remains poorly understood. Here we show that ketogenic diet-derived ketone body β-hydroxybutyrate (BHB) transiently increases FTO expression in both mouse hypothalamus and cultured cells. Interestingly, The FTO protein represses Fto promoter activity, which can be offset by BHB. We then demonstrate that FTO binds to its own gene promoter, and Fe2+, but not 2-OG, impedes this binding and increases FTO expression. The BHB-induced occupancy of the promoter by FTO influences the assembly of the basal transcriptional machinery. Importantly, a loss-of-function FTO mutant (I367F), which induces a lean phenotype in FTOI367F mice, exhibits augmented binding to, and elevated potency to repress the promoter. Furthermore, FTO fails to bind to its own promoter that promotes FTO expression in the hypothalamus of high-fat diet-induced obese and 48-h fasting mice, suggesting a disruption of the stable expression of this gene. Taken together, this study uncovers a new function of FTO as a Fe2+-sensitive transcriptional repressor dictating its own gene switch to form an auto-regulatory loop that may link with the hypothalamic control of body weight.

Methylation and Expression of FTO and PLAG1 Genes in Childhood Obesity: Insight into Anthropometric Parameters and Glucose–Lipid Metabolism

“…This mechanism is based on the principle of negative feedback loop. A properly functioning mechanism allows to control the weight and maintain it at an appropriate level [ 50 ]. It is possible that the increased level of methylation of this region prevents FTO protein from binding to the promoter.…”

Fat mass and obesity-associated (FTO) gene epigenetic modifications in gestational diabetes: new insights and possible pathophysiological connections

“…FTO influences the posttranscriptional regulation of gene expression promoting m6A demethylation on mRNA transcripts [ 58 , 59 ], but its function is still largely unknown. A significant role of the hypothalamic FTO expression [ 60 ] as well as a relationship between FTO and weight gain [ 59 , 61 ] due to several mRNA transcripts dynamically altered in response to diverse availabilities of energy and nutrient has been suggested [ 62 , 63 ]. In addition, FTO overexpression leads to obesity and increased appetite [ 64 ], while loss protein evolves in lean phenotypes [ 65 ].…”

Soy Products Ameliorate Obesity-Related Anthropometric Indicators in Overweight or Obese Asian and Non-Menopausal Women: A Meta-Analysis of Randomized Controlled Trials

“…It is worth mentioning that since Frayling first proposed in 2007 that fat mass and obesity associated (FTO) gene is associated with obesity [45], a large number of studies have been carried out around the world to confirm the relationship between FTO gene and BMI [46,47,48,49]. However, there are few studies on the differences of FTO gene polymorphism in different countries and regions.…”