Association of Morbid Obesity With FTO and INSIG2 Allelic Variants

Chu, Xin; Erdman, Robert; Susek, Meghan; Gerst, Heather; Derr, Kimberly; AlAgha, Mouna; Wood, G. Craig; Hartman, Christina; Yeager, Stephanie; Blosky, Mary Ann; Krum, Wanda; Stewart, Walter F.; Carey, David J.; Benotti, Peter N.; Still, Christopher D.; Gerhard, Glenn S.

doi:10.1001/archsurg.2007.77

Cited by 40 publications

(46 citation statements)

References 36 publications

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Section: Discussioncontrasting

confidence: 41%

“…However, even this association was not supported by our findings. Chu et al [2008] found the strongest association with BMI, when both genes were affected and proposed interactions between FTO and INSIG2 . In another study, the INSIG2 CC genotype was found negatively associated with weight loss in a lifestyle intervention program in overweight children and adolescents.…”

Section: Discussionmentioning

confidence: 98%

“…1 a) [Dina et al, 2007;Chu et al, 2008]. In our patients, the AA genotype was even more frequent (32.3 vs. 21%) and the TT genotype less frequent (19.4 vs. 31%) than in the Pennsylvanian cohort of 707 morbidly obese subjects, whereas the AT genotype was observed at a similar frequency (48%) [Chu et al, 2008]. However, we consider these differences in frequencies as marginal because they likely reflect minor differences in age (mean age 38.7 vs. 45.9 years), gender (62 vs. 81% females), ethnicity (this study comprised only Caucasians), and/or eating habits between the samples.…”

Section: Discussionmentioning

confidence: 99%

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FTO and INSIG2 Genotyping Combined with Metabolic and Anthropometric Phenotyping of Morbidly Obese Patients

Burgdörfer

Korenkov²,

Jonas³

et al. 2013

Mol Syndromol

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termediate-risk AT genotype was found in patients and controls at similar frequencies (48.4 vs. 48.6%, OR = 0.99). The low-risk TT genotype for rs9939609 was found in 19.4% of patients (35.5% of controls; p = 0.0013) and was associated with a decreased risk for morbid obesity (OR = 0.43, CI = 0.26-0.73). In contrast, INSIG2 rs7566605 showed no association with obesity in our patients. Evaluation of metabolic data indicated associations between the high-risk FTO genotype (rs9939609_AA) and increased levels of serum glutamic oxaloacetic transaminase (GOT) and between the high-risk INSIG2 genotype (rs7566605_CC) and lower waist-to-hip ratio and lower hemoglobin A1c (HbA1c) levels. Our results confirm an association of the FTO SNP with extreme obesity. However, we found no association of the potential obesity risk allele of INSIG2 in our sample and thus cannot confirm an association of the INSIG2 CC genotype with obesity. We identified an association between the high-risk FTO genotype (rs9939609_AA) and higher GOT levels, which could possibly reflect the increased frequency of nonalcoholic steatohepatitis with obesity. We also detected associations of the high-risk INSIG2 genotype (rs7566605_CC) with lower waist-to-hip ratios and lower HbA1c levels, which may indicate amelioration of impaired glucose tolerance and type 2 diabetes for patients with this genotype after bariatric surgery. AbstractObesity is a major health problem worldwide. Associations of obesity with common variants of the fat mass-and obesityassociated gene (FTO) and insulin-induced gene 2 (INSIG2) have been reported in various studies. We aimed to further investigate the association of 2 single nucleotide polymorphisms (SNPs), rs9939609 in FTO and rs7566605 in INSIG2 , with body mass index (BMI) and other anthropometric and metabolic parameters in subjects with morbid obesity (BMI ≥ 40). SNPs rs9939609 and rs7566605 were genotyped in 124 unrelated morbidly obese patients (mean BMI = 50, range 40.1-77.1) from Mainz, Germany, and in 253 normal controls without a history of morbid obesity. Metabolic and anthropometric parameters were analyzed in 109 of the 124 patients, and associations with the genotype data were examined. The high-risk AA genotype for FTO rs9939609 was observed in 32.3% of patients versus 15.8% of controls (p = 0.0004) and was associated with an increased obesity risk [odds ratio (OR) = 2.54, 95% confidence interval (CI) = 1.53-4.21]. The in-

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Section: Discussioncontrasting

confidence: 41%

Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

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FTO and INSIG2 Genotyping Combined with Metabolic and Anthropometric Phenotyping of Morbidly Obese Patients

Burgdörfer

Korenkov²,

Jonas³

et al. 2013

Mol Syndromol

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“…FTO/INSIG2 double homozygotes and homozygote/heterozygote pairs had significantly higher BMI than other genotypes. Independent analyses of each gene do not show relationship with BMI [40].…”

Section: Discussionmentioning

confidence: 82%

The FTO Obesity Gene. Genotyping and Gene Expression Analysis in Morbidly Obese Patients

et al. 2008

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Our results show: (1) A strong association between rs9939609 SNP of the FTO gene variant and obesity in Spanish morbidly obese adult patients; (2) positive correlations between FTO mRNA and leptin, perilipin, and visfatin gene expressions in subcutaneous adipose tissue; (3) FTO and perilipin gene expressions were positively correlated in visceral fat depot. Overall these results may suggest a role of FTO in the regulation of lipolysis as well as in total body fat rather in fat distribution patterns.

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“…All patients who were enrolled in the Bariatric Surgery Program of the Geisinger Center for Nutrition and Weight Management between October 2004 and October 2010 were offered the opportunity to participate in the study (41). Over 90% of patients consented to participate.…”

Section: Methodsmentioning

confidence: 99%

Cellular mechanism of insulin resistance in nonalcoholic fatty liver disease

Kumashiro

Erion

Zhang

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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500

409

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Insulin resistance is associated with nonalcoholic fatty liver disease (NAFLD) and is a major factor in the pathogenesis of type 2 diabetes. The development of hepatic insulin resistance has been ascribed to multiple causes, including inflammation, endoplasmic reticulum (ER) stress, and accumulation of hepatocellular lipids in animal models of NAFLD. However, it is unknown whether these same cellular mechanisms link insulin resistance to hepatic steatosis in humans. To examine the cellular mechanisms that link hepatic steatosis to insulin resistance, we comprehensively assessed each of these pathways by using flash-frozen liver biopsies obtained from 37 obese, nondiabetic individuals and correlating key hepatic and plasma markers of inflammation, ER stress, and lipids with the homeostatic model assessment of insulin resistance index. We found that hepatic diacylglycerol (DAG) content in cytoplasmic lipid droplets was the best predictor of insulin resistance (R = 0.80, P < 0.001), and it was responsible for 64% of the variability in insulin sensitivity. Hepatic DAG content was also strongly correlated with activation of hepatic PKCε (R = 0.67, P < 0.001), which impairs insulin signaling. In contrast, there was no significant association between insulin resistance and other putative lipid metabolites or plasma or hepatic markers of inflammation. ER stress markers were only partly correlated with insulin resistance. In conclusion, these data show that hepatic DAG content in lipid droplets is the best predictor of insulin resistance in humans, and they support the hypothesis that NAFLD-associated hepatic insulin resistance is caused by an increase in hepatic DAG content, which results in activation of PKCε.

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Association of Morbid Obesity With FTO and INSIG2 Allelic Variants

Abstract: Increased BMI in morbid obesity is associated with a combination of FTO and INSIG2 SNPs.

Cited by 40 publications

References 36 publications

FTO and INSIG2 Genotyping Combined with Metabolic and Anthropometric Phenotyping of Morbidly Obese Patients

FTO and INSIG2 Genotyping Combined with Metabolic and Anthropometric Phenotyping of Morbidly Obese Patients

The FTO Obesity Gene. Genotyping and Gene Expression Analysis in Morbidly Obese Patients

Cellular mechanism of insulin resistance in nonalcoholic fatty liver disease

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