FTO Is Increased in Muscle During Type 2 Diabetes, and Its Overexpression in Myotubes Alters Insulin Signaling, Enhances Lipogenesis and ROS Production, and Induces Mitochondrial Dysfunction

Bravard, Amélie; Lefai, Étienne; Meugnier, Emmanuelle; Pesenti, Sandra; Disse, Emmanuel; Vouillarmet, Julien; Peretti, Noël; Rabasa‐Lhoret, Rémi; Laville, Martine; Vidal, Hubert; Rieusset, Jennifer

doi:10.2337/db10-0281

Cited by 102 publications

(80 citation statements)

References 42 publications

(75 reference statements)

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“…30 In type 2 diabetes, FTO was increased in the muscle, which altered insulin signaling, enhanced lipogenesis and reactive oxygen species production, and induced mitochondrial dysfunction in myotubes. 31 Intraperitoneal glucose injection reduced hepatic FTO mRNA levels in mice, but there were positive correlations between hepatic FTO mRNA expression and gluconeogenic gene expression. 32 This positive correlation was supported by another study, which also demonstrated that FTO mRNA was negatively associated with fat mass in skeletal muscle.…”

Section: Introductionmentioning

confidence: 90%

Variation in sequence and expression of the avian FTO, and association with glucose metabolism, body weight, fatness and body composition in chickens

et al. 2011

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OBJECTIVE:The fat mass and obesity-associated gene (FTO), a crucial gene that affects human obesity and metabolism, has been widely studied in mammals but remains poorly characterized in birds. We aimed to identify variant FTO transcripts in domestic avian species, and to characterize the expression and biological functions of FTO in chickens. METHODS: Variant FTO transcripts and their expression in birds were investigated using RACE and real-time quantitative reverse transcriptase-PCR technology. The effects of FTO on glucose metabolism, growth and body composition were determined by fasting and various diet treatments, as well as association analysis in a F 2 resource population. The function of cFTO1 was further studied by overexpression in chick embryo fibroblast (CEF) cells. RESULTS: Variant FTO transcripts were identified in chicken (cFTO1 to cFTO4), duck (dFTO1, dFTO2 and dFTO4) and goose (gFTO1, gFTO2 and gFTO5). In the chicken, the complete transcript (cFTO1) was predominantly expressed in the leg muscle, pituitary, hypothalamus and cerebellum. Fasting increased both cFTO1 and PGC1a gene expression in the cerebrum, liver, breast muscle and subcutaneous fat, but decreased expression in the pituitary and anterior hypothalamus. In all tested tissues in chickens, a high-glucose diet markedly increased cFTO1 and PGC1a expression. Feeding a high-fat diet increased both cFTO1 and PGC1a expression, except in the pituitary. Overexpression of cFTO1 in CEF cells significantly increased the expression of PGC1a (2.5-fold), STAT3 (2.2-fold) and HL (1.5-fold), a cluster of genes related to energy metabolism. A total of 65 single nucleotide polymorphisms (SNPs) were identified in chicken FTO, and 18 tested SNPs were significantly associated with traits of body weight, body composition and fatness. CONCLUSIONS: These data collectively indicate that FTO is related to glucose metabolism, body weight, fatness and body composition in birds, thus expanding knowledge of FTO function to non-mammalian species. INTRODUCTIONThe epidemic of human obesity, with its associated high risk for many metabolic diseases, has attracted much attention in recent years. The fat mass and obesity-associated gene (FTO) was recently identified as an obesity candidate gene by three largescale and independent genome-wide association studies, which strongly associated several single nucleotide polymorphisms (SNPs) of FTO with obesity-related traits, including body mass index, hip circumference and body weight. 1 --3 Significant associations between FTO and obesity were independently replicated in many other studies of different populations, including Korean, 4 Japanese, 5 18,20 --22 In mice, FTO deficiency caused postnatal growth retardation and a significant reduction in adipose tissue and lean body mass, 23 and FTO deletion resulted in lesser postnatal growth and lower serum IGF-1 levels. 24 Another mouse model with a missense mutation in FTO maintained linear growth but developed a lean phenotype. 25 Overexpression of FTO leads to a dose-depe...

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Section: Introductionmentioning

confidence: 90%

Variation in sequence and expression of the avian FTO, and association with glucose metabolism, body weight, fatness and body composition in chickens

et al. 2011

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“…These models include (a) excess ROS production by the mitochondria in experimental murine models of excess nutrient intake and T2D; 2,23,[28][29][30] (b) excess ROS production by NADPH oxidases due to the overactivity of the renin-angiotensin system and increased angiotensin II levels; 31 and more recently (c) excess ROS production by XO in experimental diabetes models. 32 The present review will focus only on excess ROS production according to model (a) above given the abundance of research that has focused on mitochondrial ROS as being implicated in skeletal muscle insulin resistance.…”

Section: Linking Mitochondrial Ros To Skeletal Muscle Insulin Resistancementioning

confidence: 99%

“…32,50,51 In contrast to these findings, Brinkmann et al 52 reported reduced levels of F2-isoprostanes in the skeletal muscle of people with T2D when compared with age and BMI-matched controls.…”

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confidence: 94%

Skeletal muscle reactive oxygen species: A target of good cop/bad cop for exercise and disease

Mason

Wadley

2014

Redox Report

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Metabolic stresses associated with disease, ageing, and exercise increase the levels of reactive oxygen species (ROS) in skeletal muscle. These ROS have been linked mechanistically to adaptations in skeletal muscle that can be favourable (i.e. in response to exercise) or detrimental (i.e. in response to disease). The magnitude, duration (acute versus chronic), and cellular origin of the ROS are important underlying factors in determining the metabolic perturbations associated with the ROS produced in skeletal muscle. In particular, insulin resistance has been linked to excess ROS production in skeletal muscle mitochondria. A chronic excess of mitochondrial ROS can impair normal insulin signalling pathways and glucose disposal in skeletal muscle. In contrast, ROS produced in skeletal muscle in response to exercise has been linked to beneficial metabolic adaptations including mitochondrial biogenesis and muscle hypertrophy. Moreover, unlike insulin resistance, exercise-induced ROS appears to be primarily of nonmitochondrial origin. The present review summarizes the diverse ROS-targeted metabolic outcomes associated with insulin resistance versus exercise in skeletal muscle, thus, presenting two contrasting perspectives of pathologically harmful versus physiologically beneficial ROS. Here, we discuss the key sites of ROS production during exercise and the effect of ROS in skeletal muscle of people with type 2 diabetes.

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“…FTO could act as a demethylase of both single-stranded DNA (3-meT) and RNA (3-meU) (35,36 overexpression of FTO in myotubes significantly altered the expression of several genes, particularly those of the mitochondria (23), suggesting that the demethylation activity of FTO on DNA might regulate the expression of metabolic genes, and that dysregulation of this process might participate to obesity and/or T2D phenotype. Interestingly, we observed a transient increase of FTO expression in the early phase of 3T3-L1 differentiation, which coincides with the induction of PPARc2 expression, a key transcription factor involved in adipocyte differentiation.…”

Section: Figure 4 Effect Of Fto Silencing On 3t3-l1 Differentiation mentioning

confidence: 99%

The expression of FTO in human adipose tissue is influenced by fat depot, adiposity, and insulin sensitivity

Bravard

Veilleux

Disse

et al. 2013

Obesity

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Objective: The fat mass and obesity associated (FTO) gene is related to obesity, but the regulation of FTO expression in adipose tissue is not fully understood. We investigated FTO expression in paired subcutaneous and omental adipose tissues (SAT and OAT) from healthy women undergoing gynecological surgeries, and its relation with adiposity and insulin sensitivity. Design and Methods: FTO expression in SAT of type 2 diabetic patients treated or not with Rosiglitazone was also compared. Results: Both the mRNA and protein levels of FTO were higher in OAT from women than in SAT. Only OAT FTO protein levels negatively correlated with BMI and body fat mass, whereas SAT FTO mRNA levels were negatively correlated with subcutaneous fat deposition. In addition, SAT FTO mRNA and protein levels were increased in insulin resistant women (high HOMA) compared to insulin sensitive women (low HOMA), whereas OAT FTO expression was not different between these two subgroups. Interestingly, FTO mRNA levels were increased in SAT of type 2 diabetic patients, and treatment of diabetics with Rosiglitazone improved insulin sensitivity and reduced SAT FTO mRNA levels. Lastly, FTO expression was transiently increased in the early phase of 3T3-L1 cell differentiation, which coincides with the induction of PPARc2 expression. However, partial reduction of FTO did not impact PPARc2 expression and adipocyte differentiation. Conclusion: Therefore, FTO gene expression is higher in OAT than in SAT in lean to moderately obese women. OAT FTO expression is associated with adiposity, whereas SAT FTO expression is associated with insulin sensitivity. These associations are independent of an effect of FTO on adipocyte differentiation.

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FTO Is Increased in Muscle During Type 2 Diabetes, and Its Overexpression in Myotubes Alters Insulin Signaling, Enhances Lipogenesis and ROS Production, and Induces Mitochondrial Dysfunction

Cited by 102 publications

References 42 publications

Variation in sequence and expression of the avian FTO, and association with glucose metabolism, body weight, fatness and body composition in chickens

Variation in sequence and expression of the avian FTO, and association with glucose metabolism, body weight, fatness and body composition in chickens

Skeletal muscle reactive oxygen species: A target of good cop/bad cop for exercise and disease

The expression of FTO in human adipose tissue is influenced by fat depot, adiposity, and insulin sensitivity

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