RSPO3 impacts body fat distribution and regulates adipose cell biology in vitro
RSPO3 impacts body fat distribution and regulates adipose cell biology in vitro
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DOI：
10.1038/s41467-020-16592-z
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发表时间：
2020-06-03
影响因子：
16.6
通讯作者：
Christodoulides, Constantinos
中科院分区：
文献类型：
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作者：
Loh, Nellie Y.;Minchin, James E. N.;Christodoulides, Constantinos
脂肪分布是心脏代谢的独立危险因素。然而，它的分子和细胞基础仍然不清楚。在这里，我们证明了RSP03上的两个独立的GWA信号，它们与体重指数调整的腰臀比增加相关，特异性地增加了皮下脂肪细胞中RSP03的表达。这些变异还与下半身脂肪减少、臀部脂肪细胞增大和胰岛素抵抗有关。基于人类细胞研究，RSPO_3可能通过抑制脂肪生成和增加臀部脂肪细胞对凋亡的敏感性来限制臀部股脂肪组织(AT)的扩张。RSPO_3还可能通过刺激腹部脂肪前体细胞(AP)的增殖来促进上体脂肪的分布。在体外，RSPO_3在腹部和臀部AP中引起的不同的生物反应与WNT信号的不同变化有关。携带无意义的rsp3突变的斑马鱼表现出脂肪分布的改变。我们的研究发现RSPO_3是外周AT存储容量的一个重要决定因素。RSP03基因座上的遗传变异与腰臀比(根据BMI进行了调整)有关。在这里，罗等人。描述与体脂分布相关的两个独立的RSP3信号，进行精细定位，并探讨RSP3在人类脂肪细胞生物学和斑马鱼体脂分布中的作用
Fat distribution is an independent cardiometabolic risk factor. However, its molecular and cellular underpinnings remain obscure. Here we demonstrate that two independent GWAS signals at RSPO3, which are associated with increased body mass index-adjusted waist-to-hip ratio, act to specifically increase RSPO3 expression in subcutaneous adipocytes. These variants are also associated with reduced lower-body fat, enlarged gluteal adipocytes and insulin resistance. Based on human cellular studies RSPO3 may limit gluteofemoral adipose tissue (AT) expansion by suppressing adipogenesis and increasing gluteal adipocyte susceptibility to apoptosis. RSPO3 may also promote upper-body fat distribution by stimulating abdominal adipose progenitor (AP) proliferation. The distinct biological responses elicited by RSPO3 in abdominal versus gluteal APs in vitro are associated with differential changes in WNT signalling. Zebrafish carrying a nonsense rspo3 mutation display altered fat distribution. Our study identifies RSPO3 as an important determinant of peripheral AT storage capacity. Genetic variants at the RSPO3 locus are associated with waist-to-hip ratio (adjusted for BMI). Here, Loh et al. describe two independent RSPO3 signals that associate with body fat distribution, perform fine-mapping and explore the function of RSPO3 in human adipocyte biology and body fat distribution in zebrafish