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

Abstract

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.

FAM13A affects body fat distribution and adipocyte function

“…Wardhana et al 37 and Tang et al 36 showed a negative correlation of adipose Fam13a expression with diet-induced obesity in mice, in agreement with our data. Lundbäck et al 38 and Tang et al 36 noted FAM13A as a negative regulator of adipogenesis by using different immortalized cell models and genetic manipulation approaches: Lundbäck et al 38 showed that siRNA knockdown of FAM13A during a specific differentiation window of human mesenchymal stem cells (from day 4 to day 7) induced genes indicative of adipogenesis (CEBPA, PPARG) 38 , while Tang et al 36 showed that overexpression of Fam13a in mouse 3T3-L1 cells led to apoptosis of preadipocyte and diminished its conversion to adipocytes. Regarding whole-body metabolism, Wardhana et al 37 .…”

Genetic variation in CADM2 as a link between psychological traits and obesity

“…With this in mind, neuronal remodelling is important for health and pathology and requires cell turnover, so levels of CADM2 likely influence plasticity of the brain. Similarly, to increase the fat that can be stored, adipocytes either increase in volume (metabolically detrimental) or in number (metabolically benign) 61 . CADM2 levels could be a part of the volume vs number fate determination.…”

Genome-Wide Association Study of Diabetogenic Adipose Morphology in the GENetics of Adipocyte Lipolysis (GENiAL) Cohort

“…The medium was collected at day 7 and 9 of differentiation of hMCSs for measuring glycerol release as an index of lipolysis, as described [27]. A standard curve ranging from 0 to 120 µM was used to calculate the concentrations of the samples.…”

“…Following electroporation of siRNA, hMSCs were collected for isolation of RNA at the day differentiation was induced (day 0), days 1, and 7 post-induction of differentiation. Extraction of total RNA, measurement of concentration and purity as well as reverse transcription were performed as described [27]. Quantitative RT-PCR of coding genes was performed using commercial TaqMan probes (Applied Biosystems, Foster City, US).…”