Inactivation of the Fto gene protects from obesity

Fischer, Julia; Koch, Linda; Emmerling, Christian; Vierkotten, Jeanette; Peters, Thomas; Brüning, Jens C.; Rüther, Ulrich

doi:10.1038/nature07848

Cited by 853 publications

(875 citation statements)

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“…17,19 FTO-deficient and dominant-negative mutant FTO mice have shown reduced fat mass and increased energy expenditure. 20,21 These reports indicate that FTO has an important role in energy homeostasis by regulating energy expenditure. Although the effects of the SNPs rs1558902 and rs1421085 on gene expression need to be elucidated, variations in FTO probably affect subcutaneous and visceral fat accumulation.…”

Section: Discussionmentioning

confidence: 98%

Polymorphisms in NRXN3, TFAP2B, MSRA, LYPLAL1, FTO and MC4R and their effect on visceral fat area in the Japanese population

Hotta

Nakamura

et al. 2010

J Hum Genet

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The predominant risk factor of metabolic syndrome is intra-abdominal fat accumulation, which is determined by waist circumference and waist-hip ratio measurements and visceral fat area (VFA) that is measured by computed tomography (CT). There is evidence that waist circumference and waist-hip ratio in the Caucasian population are associated with variations in several genes, including neurexin 3 (NRXN3), transcription factor AP-2b (TFAP2B), methionine sulfoxide reductase A (MSRA), lysophospholipase-like-1 (LYPLAL1), fat mass and obesity associated (FTO) and melanocortin 4 receptor (MC4R) genes. To investigate the relationship between VFA and subcutaneous fat area (SFA) and these genes in the recruited Japanese population, we genotyped 8 single-nucleotide polymorphisms (SNPs) in these 6 genes from 1228 subjects. Multiple regression analysis revealed that gender, age, and rs1558902 and rs1421085 genotypes (additive model) in FTO were significantly associated with body mass index (BMI; P¼0.0039 and 0.0039, respectively), SFA (P¼0.0027 and 0.0023, respectively) and VFA (P¼0.045 and 0.040, respectively). However, SNPs in other genes, namely, NRXN3, TFAP2B, MSRA, LYPLAL1 and MC4R were not significantly associated with BMI, SFA or VFA. Our data suggest that some SNPs, which were identified in genome-wide studies in the Caucasians, also confer susceptibility to fat distribution in the Japanese subjects.

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Section: Discussionmentioning

confidence: 98%

Polymorphisms in NRXN3, TFAP2B, MSRA, LYPLAL1, FTO and MC4R and their effect on visceral fat area in the Japanese population

Hotta

Nakamura

et al. 2010

J Hum Genet

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“…This may not be too surprising, because overexpression of FTO in mice affects body weight only, whereas loss-of-function mutations in mice 8,9 and humans 6 did not only result in reduced body weight but also other defects. We found significant changes in the GO subcategory: 'cellular response to starvation' .…”

Section: Discussionmentioning

confidence: 99%

“…Homozygous loss-of-function of FTO was reported to cause severe growth retardation and multiple malformations, 6 whereas a duplication of FTO was found to be associated with morbid obesity. 7 Fto-knockout mice 8 and mice with a missense mutation in exon 6 9 showed leanness, postnatal growth retardation and a higher metabolic rate. Mice with one or two additional copies of Fto had a gene-dosage-dependent increase in body weight.…”

Section: Introductionmentioning

confidence: 99%

FTO levels affect RNA modification and the transcriptome

et al. 2012

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A block of single-nucleotide polymorphisms within intron 1 of the FTO (fat mass and obesity associated) gene is associated with variation in body weight. Previous works suggest that increased expression of FTO, which encodes a 2-oxoglutaratedependent nucleic acid demethylase, leads to increased body weight, although the underlying mechanism has remained unclear. To elucidate the function of FTO, we examined the consequences of altered FTO levels in cultured cells and murine brain. Here we show that a knockdown of FTO in HEK293 cells affects the transcripts levels of genes involved in the response to starvation, whereas overexpression of FTO affects the transcript levels of genes related to RNA processing and metabolism. Subcellular localization of FTO further strengthens the latter notion. Using immunocytochemistry and confocal laser scanning microscopy, we detected FTO in nuclear speckles and -to a lesser and varying extent -in the nucleoplasm and nucleoli of HEK293, HeLa and MCF-7 cells. Moreover, RNA modification analyses revealed that loss of Fto affects the 3-methyluridine/ uridine and pseudouridine/uridine ratios in total brain RNA. We conclude that altered levels of FTO have multiple and diverse consequences on RNA modifications and the transcriptome. Keywords: FTO; RNA modifications; nuclear speckles; transcriptome INTRODUCTION Genome-wide association studies have revealed a strong association between a block of single-nucleotide polymorphisms (SNPs) in intron 1 of the fat mass and obesity-associated (FTO) gene, body mass index and other obesity-related traits in children and adults of different populations. 1-3 Stratigopoulos et al 4 have suggested that one of the SNPs (rs8050136) affects binding of the transcriptional regulator CUX1. By studying allelic expression levels in heterozygous individuals, we have found that the risk allele of the FTO gene makes more transcripts and have proposed that increased expression of the FTO gene leads to increased body weight. 5 This hypothesis is supported by the clinical findings in rare patients and in mouse models with an FTO/Fto mutation. Homozygous loss-of-function of FTO was reported to cause severe growth retardation and multiple malformations, 6 whereas a duplication of FTO was found to be associated with morbid obesity. 7 Fto-knockout mice 8 and mice with a missense mutation in exon 6 9 showed leanness, postnatal growth retardation and a higher metabolic rate. Mice with one or two additional copies of Fto had a gene-dosage-dependent increase in body weight. 10 FTO is a member of non-heme Fe(II)-and a-ketoglutaratedependent oxygenase superfamily and is found in vertebrates and green algea, but not in invertebrate animals, fungi and green plants. 11 By in vitro studies, FTO was shown to function as a demethylase with a strong preference for 3meU and 3meT in single-stranded RNA and DNA, respectively. 12,13 Han et al 14 have provided structural evidence for understanding the substrate specificity of FTO and have suggested

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“…Interestingly, the weight gain was found to be independent of alterations in energy expenditure typically associated with hypothalamic abnormalities and was unlike any other eating behavior previously reported in the general population Haupt et al 2009;Jonassaint et al 2011). At the same time, studies performed using two different Fto mouse models characterized by complete inactivation and a dominant point mutation of the Fto gene revealed a complex and contradictory phenotype compared to humans possessing the common FTO gene variant (Church et al 2009;Fischer et al 2009). In brief, these Fto mouse models were shown to be lean and protected from obesity despite being fed a basal or high-fat diet and having consumed increased amounts of these diets after adjustment for body weight.…”

Section: Obesity Susceptibility Genes That Interact With Dietary Fatsmentioning

confidence: 53%

The genetics of childhood obesity and interaction with dietary macronutrients

et al. 2013

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The genes contributing to childhood obesity are categorized into three different types based on distinct genetic and phenotypic characteristics. These types of childhood obesity are represented by rare monogenic forms of syndromic or non-syndromic childhood obesity, and common polygenic childhood obesity. In some cases, genetic susceptibility to these forms of childhood obesity may result from different variations of the same gene. Although the prevalence for rare monogenic forms of childhood obesity has not increased in recent times, the prevalence of common childhood obesity has increased in the United States and developing countries throughout the world during the past few decades. A number of recent genome-wide association studies and mouse model studies have established the identification of susceptibility genes contributing to common childhood obesity. Accumulating evidence suggests that this type of childhood obesity represents a complex metabolic disease resulting from an interaction with environmental factors, including dietary macronutrients. The objective of this article is to provide a review on the origins, mechanisms, and health consequences of obesity susceptibility genes and interaction with dietary macronutrients that predispose to childhood obesity. It is proposed that increased knowledge of these obesity susceptibility genes and interaction with dietary macronutrients will provide valuable insight for individual, family, and community preventative lifestyle intervention, and eventually targeted nutritional and medicinal therapies.

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Inactivation of the Fto gene protects from obesity

Cited by 853 publications

References 30 publications

Polymorphisms in NRXN3, TFAP2B, MSRA, LYPLAL1, FTO and MC4R and their effect on visceral fat area in the Japanese population

Polymorphisms in NRXN3, TFAP2B, MSRA, LYPLAL1, FTO and MC4R and their effect on visceral fat area in the Japanese population

FTO levels affect RNA modification and the transcriptome

The genetics of childhood obesity and interaction with dietary macronutrients

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