Objectives

Lipolysis, hydrolysis of triglycerides to fatty acids in adipocytes, is tightly regulated, poorly understood, and, if perturbed, can lead to metabolic diseases including obesity and type 2 diabetes. The goal of this study was to identify the genetic regulators of lipolysis and elucidate their molecular mechanisms.

Methods

Adipocytes from abdominal subcutaneous adipose tissue biopsies were isolated and were incubated without (spontaneous lipolysis) or with a catecholamine (stimulated lipolysis) to analyze lipolysis. DNA was extracted and genome-wide genotyping and imputation conducted. After quality control, 939 samples with genetic and lipolysis data were available. Genome-wide association studies of spontaneous and stimulated lipolysis were conducted. Subsequent in vitro gene expression analyses were used to identify candidate genes and explore their regulation of adipose tissue biology.

Results

One locus on chromosome 19 demonstrated genome-wide significance with spontaneous lipolysis. 60 loci showed suggestive associations with spontaneous or stimulated lipolysis, of which many influenced both traits. In the chromosome 19 locus, only HIF3A was expressed in the adipocytes and displayed genotype-dependent gene expression. HIF3A knockdown in vitro increased lipolysis and the expression of key lipolysis-regulating genes.

Conclusions

In conclusion, we identified a genetic regulator of spontaneous lipolysis and provided evidence of HIF3A as a novel key regulator of lipolysis in subcutaneous adipocytes as the mechanism through which the locus influences adipose tissue biology.

中文翻译：

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脂肪细胞脂肪分解（GENiAL）队列研究中的脂肪细胞脂肪分解的全基因组关联研究。

目标

脂肪分解，甘油三酸酯水解为脂肪细胞中的脂肪酸，受到严格调节，了解甚少，如果受到干扰，会导致代谢性疾病，包括肥胖症和2型糖尿病。这项研究的目的是确定脂解的遗传调控因子，并阐明其分子机制。

方法

分离来自腹部皮下脂肪组织活检组织的脂肪细胞，并在不（自发性脂解）或儿茶酚胺（刺激性脂解）的情况下进行温育以分析脂解。提取DNA，进行全基因组基因分型和估算。经过质量控制后，可获得939个具有遗传和脂解数据的样品。进行了自发性和刺激性脂解的全基因组关联研究。随后的体外基因表达分析用于鉴定候选基因并探索其对脂肪组织生物学的调控。

结果

19号染色体上的一个基因座表现出自发脂解作用的全基因组意义。60个基因座显示出与自发或刺激性脂解的暗示性关联，其中许多都影响了这两种性状。在19号染色体基因座中，仅HIF3A在脂肪细胞中表达，并显示出基因型依赖性基因表达。HIF3A敲低体外增加脂解和关键的脂解调控基因的表达。

结论

总之，我们确定了自发性脂解的遗传调节剂，并提供了HIF3A作为皮下脂肪细胞中脂解的新型关键调节剂的证据，这是该基因位点影响脂肪组织生物学的机制。