Genetic Association and Gene Expression Analysis Identify<i>FGFR1</i>as a New Susceptibility Gene for Human Obesity

Jiao, Hong; Arner, Peter; Dickson, Suzanne L.; Vidal, Hubert; Mejhert, Niklas; Hénégar, Corneliu; Taube, Magdalena; Hansson, Caroline; Hinney, Anke; Galán, Pilar; Simon, Chantal; Silveira, Angela; Benrick, Anna; Jansson, John‐Olov; Bouloumié, Anne; Langin, Dominique; Laville, Martine; Debard, Cyrille; Axelsson, Tomas; Rydén, Mikael; Kere, Juha; Dahlman-Wright, Karin; Hamsten, Anders; Clément, Karine; Dahlman, Ingrid

doi:10.1210/jc.2010-2639

Cited by 27 publications

(28 citation statements)

References 18 publications

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“…Since PDX1 involves in the development and functions of β cells [14], the normalization of FGFR1 after metformin treatment may indicate the improved functions of β cells. Besides, gen analysis suggested that FGFR1 may be a regulator of adipogenesis by increasing fat cell numbers [27]. Moreover, our results confirmed the former hypothesis that the expression of FGFR1 was mediated by FGF21 circulating levels [28].…”

Section: Discussionsupporting

confidence: 86%

The effects of metformin on fibroblast growth factor 19, 21 and fibroblast growth factor receptor 1 in high-fat diet and streptozotocin induced diabetic rats

et al. 2017

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TYPE 2 DIABETES MELLITUS (T2DM) is associated with obesity and insulin resistance and has severe complications. As an effective and safe oral drug, metformin has been used to treat T2DM for almost fifty years. Possible mechanisms of metformin in improving glucose homeostasis are partially depended on the activation of adenosine monophosphate-activated protein kinase (AMPK) which then inhibits glucose output and increases insulin sensitivity in peripheral tissues [1].Fibroblast growth factor-19 (FGF19) and FGF21 belong to beta-klotho family, and recent studies showedThe effects of metformin on fibroblast growth factor 19, 21 and fibroblast growth factor receptor 1 in high-fat diet and streptozotocin induced diabetic rats Yan Wang 1), 2) , Ningning Dang 3) , Pei Sun 2) , Jin Xia 2), 4) , Chunxue Zhang 2), 4) and Shuguang Pang 1), 2), 4) Abstract. To understand metformin's effects on fibroblast growth factors (FGFs) and fibroblast growth factor receptor 1 (FGFR1), we investigated circulating fibroblast growth factor-19 (FGF19), FGF21 levels, and FGFR1 in type 2 diabetes mellitus (T2DM). In addition, protein kinase B (Akt) signaling pathway was detected to explain the possible mechanisms. T2DM was induced by feeding rats with high-fat diet for 11 weeks, followed by a low dose of streptozotocin (STZ, 30-35 mg/kg, intraperitoneally). Control rats (Con) were fed on a normal chow; diabetic rats (DM) were fed on high-fat diet supplemented with or without metformin (METF) for 12 weeks (500 mg·kg -1 ·d -1 ). Biochemical parameters were detected at the end of 24th weeks. FGFR1 expression and protein kinase B (Akt) phosphorylation in the pancreas and visceral adipose tissues were detected using either Western blot (WB) or immunohistochemistry (IHC). Serum FGF19 and FGF21 were measured using enzyme-linked immune sorbent assay (ELISA). Metformin treated DM rats showed improved glucose, lipid and bile acid metabolism. Besides, significantly decreased FGF19 and increased FGF21 were observed in DM+METF rats. DM rats showed significantly increased FGFR1 both in the pancreas and visceral adipose tissues. While in DM+METF rats, FGFR1 was almost remained at a normal level in the pancreas and increased in the visceral adipose tissue compared to that in DM rats. Besides, metformin treatment restores Akt phosphorylation in both tissues. The altered glucose and lipid profiles by metformin treatment may be associated with the increased circulating FGF21 and tissue-specific expressions of FGFR1.Key words: Diabetes, FGF21, FGFR1, β cell, Visceral adipose that they were produced by the activation of Farnesoid X Receptor (FXR) in the ileum and liver, respectively [2,3]. FGF19 and FGF21 are emerging as endocrine hormones since they showed novel roles in bile acid, lipid, and glucose metabolism [4][5][6]. In obese or diabetic animal models, administration of FGF19 and FGF21 led to beneficial effects on metabolism through increasing insulin sensitivity, energy expenditure and white adipose browning [7][8][9][10].FGFs exert their roles by binding...

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Section: Discussionsupporting

confidence: 86%

The effects of metformin on fibroblast growth factor 19, 21 and fibroblast growth factor receptor 1 in high-fat diet and streptozotocin induced diabetic rats

et al. 2017

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“…As argued by Price et al [39], part of this variation may be may be due secular trends in gene-environment interactions which have the effect of simulating recessive inheritance in multi-generational studies. The use of extreme obesity phenotypes would also tend to favour a recessive pattern if the true mode is additive and the heterozygous phenotype is either obscured by definition [40] or is indistinguishable in the data [41], [42]. Finally, very large sample sizes are required to reliably detect dominance effects and some recessive findings are likely to be due to lack of power to detect other modes of inheritance [43].…”

Section: Discussionmentioning

confidence: 99%

Segregation of a Latent High Adiposity Phenotype in Families with a History of Type 2 Diabetes Mellitus Implicates Rare Obesity-Susceptibility Genetic Variants with Large Effects in Diabetes-Related Obesity

et al. 2013

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BackgroundWe recently reported significantly greater weight gain in non-diabetic healthy subjects with a 1st degree family history (FH+) of type 2 diabetes mellitus (T2DM) than in a matched control group without such history (FH−) during voluntary overfeeding, implying co-inheritance of susceptibilities to T2DM and obesity. We have estimated the extent and mode of inheritance of susceptibility to increased adiposity in FH+.MethodsNormoglycaemic participants were categorised either FH+ (≥1 1st degree relative with T2DM, 50F/30M, age 45±14 (SD) yr) or FH− (71F/51M, age 43±14 yr). Log-transformed anthropometric measurements (height, hip and waist circumferences) and lean, bone and fat mass (Dual Energy X-ray Absorptiometry) data were analysed by rotated Factor Analysis. The age- and gender-adjusted distributions of indices of adiposity in FH+ were assessed by fits to a bimodal model and by relative risk ratios (RR, FH+/FH−) and interpreted in a purely genetic model of FH effects.ResultsThe two orthogonal factors extracted, interpretable as Frame and Adiposity accounted for 80% of the variance in the input data. FH+ was associated with significantly higher Adiposity scores (p<0.01) without affecting Frame scores. Adiposity scores in FH+ conformed to a bimodal normal distribution, consistent with dominant expression of major susceptibility genes with 59% (95% CI 40%, 74%) of individuals under the higher mode. Calculated risk allele frequencies were 0.09 (0.02, 0.23) in FH−, 0.36 (0.22, 0.48) in FH+ and 0.62 (0.36, 0.88) in unobserved T2DM-affected family members.ConclusionsThe segregation of Adiposity in T2DM-affected families is consistent with dominant expression of rare risk variants with major effects, which are expressed in over half of FH+ and which can account for most T2DM-associated obesity in our population. The calculated risk allele frequency in FH− suggests that rare genetic variants could also account for a substantial fraction of the prevalent obesity in this society.

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“…Amino acid substitutions may disrupt protein binding sites or ligand-binding pockets that are critical in protein function and may leads to alterations in the protein structure, folding or stability. In recent years, there has been considerable interest in understanding the genetic basis of FGFR1 associated with human disorder (Jiao et al, 2011, Rodriguez-Otero et al, 2011, Hitosugi et al, 2011). FGFR1 is one of the most commonly amplified gene involved in cancer which regulates cell proliferation, migration and differentiation (Ford et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

Screening of mutations affecting protein stability and dynamics of FGFR1—A simulation analysis

Rajith

Garwasis

et al. 2012

Applied & Translational Genomics

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Single amino acid substitutions in Fibroblast Growth Factor Receptor 1 (FGFR1) destabilize protein and have been implicated in several genetic disorders like various forms of cancer, Kallamann syndrome, Pfeiffer syndrome, Jackson Weiss syndrome, etc. In order to gain functional insight into mutation caused by amino acid substitution to protein function and expression, special emphasis was laid on molecular dynamics simulation techniques in combination with in silico tools such as SIFT, PolyPhen 2.0, I-Mutant 3.0 and SNAP. It has been estimated that 68% nsSNPs were predicted to be deleterious by I-Mutant, slightly higher than SIFT (37%), PolyPhen 2.0 (61%) and SNAP (58%). From the observed results, P722S mutation was found to be most deleterious by comparing results of all in silico tools. By molecular dynamics approach, we have shown that P722S mutation leads to increase in flexibility, and deviated more from the native structure which was supported by the decrease in the number of hydrogen bonds. In addition, biophysical analysis revealed a clear insight of stability loss due to P722S mutation in FGFR1 protein. Majority of mutations predicted by these in silico tools were in good concordance with the experimental results.

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Genetic Association and Gene Expression Analysis IdentifyFGFR1as a New Susceptibility Gene for Human Obesity

Abstract: FGFR1 is a novel obesity gene that may promote obesity by influencing adipose tissue and the hypothalamic control of appetite.

Cited by 27 publications

References 18 publications

The effects of metformin on fibroblast growth factor 19, 21 and fibroblast growth factor receptor 1 in high-fat diet and streptozotocin induced diabetic rats

The effects of metformin on fibroblast growth factor 19, 21 and fibroblast growth factor receptor 1 in high-fat diet and streptozotocin induced diabetic rats

Segregation of a Latent High Adiposity Phenotype in Families with a History of Type 2 Diabetes Mellitus Implicates Rare Obesity-Susceptibility Genetic Variants with Large Effects in Diabetes-Related Obesity

Screening of mutations affecting protein stability and dynamics of FGFR1—A simulation analysis

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