Department of Clinical Science, Intervention and Technology, Division of Paediatrics, Huddinge, Karolinska Institutet, Stockholm, Sweden.
Department of Medicine, Huddinge, Karolinska Institutet, C2:94, SE-141 86, Stockholm, Sweden.
Diabetologia. 2018 May;61(5):1112-1123. doi: 10.1007/s00125-018-4572-8. Epub 2018 Feb 27.
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).
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.
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). 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), adipocyte insulin sensitivity (R = 0.28, p = 3.4 × 10) and adipose hyperplasia (R = -0.29, p = 2.6 × 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.
目的/假设：通过全基因组关联荟萃分析，已经确定了 17 个与空腹血清胰岛素（FSI）相关的遗传位点，FSI 是全身胰岛素抵抗的标志物。为了确定这些位点中的潜在罪魁祸首基因，我们在一项横断面研究中，分析了这些位点中 120 个基因在与全身和脂肪组织变量相关的情况下在白色脂肪组织（WAT）中的表达，并对显示出 WAT 中基因型特异性表达的基因进行了功能评估（eQTLs）。
从 114 名女性中获得腹部皮下脂肪组织活检。通过从脂肪组织外植体中释放甘油来测量基础脂肪分解活性。分离脂肪细胞，并使用放射性标记的葡萄糖掺入脂质来量化脂肪细胞的胰岛素敏感性。使用人间充质干细胞中的小干扰 RNA 介导的敲除来评估基因的功能。
研究候选基因的 48 个在 WAT 中的表达与 FSI 显著相关，而 24、17 和 2 个基因的表达分别与脂肪细胞胰岛素敏感性、脂肪分解和/或 WAT 形态（即相对于全身脂肪质量的脂肪细胞大小）相关。四个遗传位点包含 eQTLs。在一个 4 号染色体位点（rs3822072）中，FSI 增加的等位基因与 FAM13A 表达降低相关，而 FAM13A 表达与包括降低 WAT 脂肪分解（回归系数，R=-0.50，p=5.6×10）在内的有益代谢特征相关。FAM13A 的敲低使脂肪分解增加了约 1.5 倍，并且 LIPE（编码激素敏感脂肪酶，脂肪分解的限速酶）的表达增加。在 7 号染色体位点（rs1167800）中，FSI 增加的等位基因与 POM121C 表达降低相关。与胰岛素增敏功能一致，POM121C 表达与全身胰岛素敏感性（R=-0.22，p=2.0×10）、脂肪细胞胰岛素敏感性（R=0.28，p=3.4×10）和脂肪增生（R=-0.29，p=2.6×10）相关。POM121C 的敲低使所有脂肪细胞特异性标志物的表达降低了 25-50%，表明 POM121C 是脂肪生成所必需的。
结论/解释：基因表达和脂肪细胞功能研究支持 FAM13A 和 POM121C 分别控制脂肪细胞脂肪分解和脂肪生成的观点，并且可能参与全身胰岛素敏感性的遗传控制。
