肥胖使个体容易患多种心脏代谢紊乱,包括2型糖尿病(T2D)。由于体重指数(BMI)无法可靠地区分脂肪和瘦体重,使用腰臀比(WHR)评估了代谢有害的腹部肥胖.根据体重指数(WHRadjBMI)调整的腰臀比反过来又是确定的腹部脂肪和肥胖的性别特异性标记,以及不良代谢结果的预测因子,比如T2D。然而,协调人类肥胖和体脂分布的性别差异的潜在基因和调节机制尚不清楚。
我们通过对来自WHRadjBMIGWAS队列和英国生物库(UKB)的人类皮下脂肪RNA测序(RNA-seq)数据(n〜1400)和WHRadjBMIGWAS数据(n〜700,000)的整合基因组学方法,搜索了WHRadjBMI的遗传主调节因子。使用共表达网络,全转录组关联研究(TWAS),和多基因风险评分(PRS)方法。最后,我们在对脂肪组织功能至关重要的人原代细胞类型中使用基因敲除实验从功能上验证了我们的基因组结果.
这里,我们确定了一个包含35个肥胖GWAS基因的脂肪基因共表达网络,并以性别依赖性方式解释了UKB(n=392,551)中腹部肥胖和T2D的大量多基因风险.我们表明,该网络保留在芬兰Kuopio肥胖研究和墨西哥肥胖研究的脂肪组织数据中。该网络由一种新型的脂肪主转录因子(TF)控制,TBX15,一种WHRadjBMIGWAS基因,反式调节网络。在人原代前脂肪细胞中敲低TBX15导致130个网络基因表达的变化,包括关键的脂肪TF,PPARG和KLF15受到显著影响(FDR<0.05),从而在功能上验证TBX15对WHRadjBMI共表达网络的反式调节作用。
我们的研究发现了TBX15TF在反式调节347脂肪的脂肪共表达网络中的一种新的关键功能,线粒体,和代谢重要的基因,包括PPARG,KLF15,PPARA,ADIPOQ,和35个肥胖GWAS基因。因此,基于我们融合的基因组,转录,和功能性证据,我们解释了TBX15在脂肪组织中的主要转录调节因子的作用,并发现其在人类腹型肥胖中的重要性。
Obesity predisposes individuals to multiple cardiometabolic disorders, including type 2 diabetes (T2D). As body mass index (BMI) cannot reliably differentiate fat from lean mass, the metabolically detrimental abdominal obesity has been estimated using waist-hip ratio (WHR). Waist-hip ratio adjusted for body mass index (WHRadjBMI) in turn is a well-established sex-specific marker for abdominal fat and adiposity, and a predictor of adverse metabolic outcomes, such as T2D. However, the underlying genes and regulatory mechanisms orchestrating the sex differences in obesity and body fat distribution in humans are not well understood.
We searched for genetic master regulators of WHRadjBMI by employing integrative genomics approaches on human subcutaneous adipose RNA sequencing (RNA-seq) data (n ~ 1400) and WHRadjBMI GWAS data (n ~ 700,000) from the WHRadjBMI GWAS cohorts and the UK Biobank (UKB), using co-expression network, transcriptome-wide association study (TWAS), and polygenic risk score (PRS) approaches. Finally, we functionally verified our genomic results using gene knockdown experiments in a human primary cell type that is critical for adipose tissue function.
Here, we identified an adipose gene co-expression network that contains 35 obesity GWAS genes and explains a significant amount of polygenic risk for abdominal obesity and T2D in the UKB (n = 392,551) in a sex-dependent way. We showed that this network is preserved in the adipose tissue data from the Finnish Kuopio Obesity Study and Mexican Obesity Study. The network is controlled by a novel adipose master transcription factor (TF), TBX15, a WHRadjBMI GWAS gene that regulates the network in trans. Knockdown of TBX15 in human primary preadipocytes resulted in changes in expression of 130 network genes, including the key adipose TFs, PPARG and KLF15, which were significantly impacted (FDR < 0.05), thus functionally verifying the trans regulatory effect of TBX15 on the WHRadjBMI co-expression network.
Our study discovers a novel key function for the TBX15 TF in trans regulating an adipose co-expression network of 347 adipose, mitochondrial, and metabolically important genes, including PPARG, KLF15, PPARA, ADIPOQ, and 35 obesity GWAS genes. Thus, based on our converging genomic, transcriptional, and functional evidence, we interpret the role of TBX15 to be a main transcriptional regulator in the adipose tissue and discover its importance in human abdominal obesity.