Whole-Exome Sequencing Suggests <i>LAMB3</i> as a Susceptibility Gene for Morbid Obesity

Jiao, Hong; Kulyté, Agné; Näslund, Erik; Thorell, Anders; Gerdhem, Paul; Kere, Juha; Arner, Peter; Dahlman, Ingrid

doi:10.2337/db16-0522

Cited by 20 publications

(11 citation statements)

References 29 publications

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“…hASCs were reverse transfected 24 h before induction of adipogenesis using ON-TARGETplus SMARTpool siRNAs targeting SCAMP3 or nontargeting siRNA control #1 (Dharmacon) as previously described 33 . The RNA and medium were collected at days 2, 6 and 9 after the induction of differentiation.…”

Section: Methodsmentioning

confidence: 99%

MicroRNA-27a/b-3p and PPARG regulate SCAMP3 through a feed- forward loop during adipogenesis

Kulyté

Kwok

Hoon

et al. 2019

Sci Rep

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MicroRNAs (miRNA) modulate gene expression through feed-back and forward loops. Previous studies identified miRNAs that regulate transcription factors, including Peroxisome Proliferator Activated Receptor Gamma (PPARG), in adipocytes, but whether they influence adipogenesis via such regulatory loops remain elusive. Here we predicted and validated a novel feed-forward loop regulating adipogenesis and involved miR-27a/b-3p, PPARG and Secretory Carrier Membrane Protein 3 (SCAMP3). In this loop, expression of both PPARG and SCAMP3 was independently suppressed by miR-27a/b-3p overexpression. Knockdown of PPARG downregulated SCAMP3 expression at the late phase of adipogenesis, whereas reduction of SCAMP3 mRNA levels increased PPARG expression at early phase in differentiation. The latter was accompanied with upregulation of adipocyte-enriched genes, including ADIPOQ and FABP4, suggesting an anti-adipogenic role for SCAMP3. PPARG and SCAMP3 exhibited opposite behaviors regarding correlations with clinical phenotypes, including body mass index, body fat mass, adipocyte size, lipolytic and lipogenic capacity, and secretion of pro-inflammatory cytokines. While adipose PPARG expression was associated with more favorable metabolic phenotypes, SCAMP3 expression was linked to increased fat mass and insulin resistance. Together, we identified a feed-forward loop through which miR-27a/b-3p, PPARG and SCAMP3 cooperatively fine tune the regulation of adipogenesis, which potentially may impact whole body metabolism.

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Section: Methodsmentioning

confidence: 99%

MicroRNA-27a/b-3p and PPARG regulate SCAMP3 through a feed- forward loop during adipogenesis

Kulyté

Kwok

Hoon

et al. 2019

Sci Rep

Self Cite

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“…The cells were cultured until day 7 or 12 of differentiation, at which time the medium and RNA were collected. hMSCs were also reverse transfected 24 h before induction of adipogenesis using ON-TARGETplus SMARTpool siRNAs targeting FAM13A or non-targeting siRNA pool (Dharmacon) as previously described [ 24 ].…”

Section: Methodsmentioning

confidence: 99%

FAM13A and POM121C are candidate genes for fasting insulin: functional follow-up analysis of a genome-wide association study

et al. 2018

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Aims/hypothesis By genome-wide association meta-analysis, 17 genetic loci associated with fasting serum insulin (FSI), a marker of systemic insulin resistance, have been identified. To define potential culprit genes in these loci, in a cross-sectional study we analysed white adipose tissue (WAT) expression of 120 genes in these loci in relation to systemic and adipose tissue variables, and functionally evaluated genes demonstrating genotype-specific expression in WAT (eQTLs). Methods Abdominal subcutaneous adipose tissue biopsies were obtained from 114 women. Basal lipolytic activity was measured as glycerol release from adipose tissue explants. Adipocytes were isolated and insulin-stimulated incorporation of radiolabelled glucose into lipids was used to quantify adipocyte insulin sensitivity. Small interfering RNA-mediated knockout in human mesenchymal stem cells was used for functional evaluation of genes. Results Adipose expression of 48 of the studied candidate genes associated significantly with FSI, whereas expression of 24, 17 and 2 genes, respectively, associated with adipocyte insulin sensitivity, lipolysis and/or WAT morphology (i.e. fat cell size relative to total body fat mass). Four genetic loci contained eQTLs. In one chromosome 4 locus (rs3822072), the FSI-increasing allele associated with lower FAM13A expression and FAM13A expression associated with a beneficial metabolic profile including decreased WAT lipolysis (regression coefficient, R = −0.50, p = 5.6 × 10 −7). Knockdown of FAM13A increased lipolysis by~1.5-fold and the expression of LIPE (encoding hormone-sensitive lipase, a rate-limiting enzyme in lipolysis). At the chromosome 7 locus (rs1167800), the FSI-increasing allele associated with lower POM121C expression. Consistent with an insulin-sensitising function, POM121C expression associated with systemic insulin sensitivity (R = −0.22, p = 2.0 × 10 ). POM121C knockdown decreased expression of all adipocyte-specific markers by 25-50%, suggesting that POM121C is necessary for adipogenesis. Conclusions/interpretation Gene expression and adipocyte functional studies support the notion that FAM13A and POM121C control adipocyte lipolysis and adipogenesis, respectively, and might thereby be involved in genetic control of systemic insulin sensitivity.Keywords Genomics . Insulin sensitivity . Lipid metabolism Diabetologia (2018Diabetologia ( ) 61:1112Diabetologia ( -1123 https://doi.org/10.1007/s00125-018-4572-8Tweet The genes FAM13A and POM121C might be involved in genetic control of systemic insulin sensitivity in humans by controlling abdominal adipocyte function #genomics #GWAS Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00125-018-4572-8) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

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“…WES of pooled DNA from 100 individuals with morbid obesity and 100 controls of Swedish ancestry followed by targeted genotyping in up to 3,197 case–control subjects identified a low‐frequency variant (rs62623713) in the synaptophysin like 2 ( SYPL2 ) gene associated with morbid obesity and BMI . A similar study in the same population identified a low‐frequency variant (rs2076349) in the laminin subunit beta 3 ( LAMB3 ) gene associated with morbid obesity and BMI . A whole‐exome single‐variant association analysis in 1,205 Hispanic Americans (78 families) identified a low‐frequency variant (rs11554137) in the isocitrate dehydrogenase 1 ( IDH1 ) gene associated with BMI at the conventional genome‐wide level of significance .…”

Section: Established Strategiesmentioning

confidence: 96%

Established and emerging strategies to crack the genetic code of obesity

2018

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Tremendous progress has been made in the genetic elucidation of obesity over the past two decades, driven largely by technological, methodological and organizational innovations. Current strategies for identifying obesity-predisposing loci/genes, including cytogenetics, linkage analysis, homozygosity mapping, admixture mapping, candidate gene studies, genome-wide association studies, custom genotyping arrays, whole-exome sequencing and targeted exome sequencing, have achieved differing levels of success, and the identified loci in aggregate explain only a modest fraction of the estimated heritability of obesity. This review outlines the successes and limitations of these approaches and proposes novel strategies, including the use of exceptionally large sample sizes, the study of diverse ethnic groups and deep phenotypes and the application of innovative methods and study designs, to identify the remaining obesity-predisposing genes. The use of both established and emerging strategies has the potential to crack the genetic code of obesity in the not-too-distant future. The resulting knowledge is likely to yield improvements in obesity prediction, prevention and care.

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Whole-Exome Sequencing Suggests LAMB3 as a Susceptibility Gene for Morbid Obesity

Cited by 20 publications

References 29 publications

MicroRNA-27a/b-3p and PPARG regulate SCAMP3 through a feed- forward loop during adipogenesis

MicroRNA-27a/b-3p and PPARG regulate SCAMP3 through a feed- forward loop during adipogenesis

FAM13A and POM121C are candidate genes for fasting insulin: functional follow-up analysis of a genome-wide association study

Established and emerging strategies to crack the genetic code of obesity

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