Unraveling the role of salt-sensitivity genes in obesity with integrated network biology and co-expression analysis

Obesity is a multifactorial disease caused by complex interactions between genes and dietary factors. Salt-rich diet is related to the development and progression of several chronic diseases including obesity. However, the molecular basis of how salt sensitivity genes (SSG) contribute to adiposity in obesity patients remains unexplored. In this study, we used the microarray expression data of visceral adipose tissue samples and constructed a complex protein-interaction network of salt sensitivity genes and their co-expressed genes to trace the molecular pathways connected to obesity. The Salt Sensitivity Protein Interaction Network (SSPIN) of 2691 differentially expressed genes and their 15474 interactions has shown that adipose tissues are enriched with the expression of 23 SSGs, 16 hubs and 84 bottlenecks (p = 2.52 x 10–16) involved in diverse molecular pathways connected to adiposity. Fifteen of these 23 SSGs along with 8 other SSGs showed a co-expression with enriched obesity-related genes (r ≥ 0.8). These SSGs and their co-expression partners are involved in diverse metabolic pathways including adipogenesis, adipocytokine signaling pathway, renin-angiotensin system, etc. This study concludes that SSGs could act as molecular signatures for tracing the basis of adipogenesis among obese patients. Integrated network centered methods may accelerate the identification of new molecular targets from the complex obesity genomics data.

肥胖是一种多因素疾病，由基因与膳食因素之间的复杂相互作用所诱发。高盐饮食与包括肥胖在内的多种慢性疾病的发生、发展紧密相关。然而，盐敏感基因（Salt Sensitivity Genes，SSG）如何介导肥胖患者的脂肪蓄积，其背后的分子机制至今仍未明确。本研究通过获取内脏脂肪组织样本的微阵列表达数据，构建了盐敏感基因及其共表达基因的复杂蛋白质相互作用网络，以此追溯与肥胖相关的分子通路。包含2691个差异表达基因及15474条相互作用关系的盐敏感蛋白质相互作用网络（Salt Sensitivity Protein Interaction Network，SSPIN）分析结果显示，脂肪组织中富集了23个盐敏感基因、16个枢纽节点与84个瓶颈节点（p=2.52×10^-16），这些节点参与了诸多与脂肪蓄积相关的分子通路。该23个盐敏感基因中，有15个与另外8个盐敏感基因，均与富集的肥胖相关基因呈现出显著共表达特征（相关系数r≥0.8）。上述盐敏感基因及其共表达关联基因参与了多种代谢通路，涵盖脂肪生成、脂肪细胞因子信号通路、肾素-血管紧张素系统等。本研究最终得出结论：盐敏感基因可作为分子标志物，用于解析肥胖患者的脂肪生成机制。以整合网络为核心的研究策略，或可加速从复杂的肥胖基因组学数据中筛选新型分子靶点的进程。