PAPPA-mediated adipose tissue remodeling mitigates insulin resistance and protects against gestational diabetes in mice and humans.
PAPPA-mediated adipose tissue remodeling mitigates insulin resistance and protects against gestational diabetes in mice and humans.
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DOI：
10.1126/scitranslmed.aay4145
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发表时间：
2020-11-25
影响因子：
17.1
通讯作者：
Corvera S
中科院分区：
文献类型：
--
作者：
Rojas-Rodriguez R;Ziegler R;DeSouza T;Majid S;Madore AS;Amir N;Pace VA;Nachreiner D;Alfego D;Mathew J;Leung K;Moore Simas TA;Corvera S
妊娠是一种持续适应母体和胎儿营养需求变化的生理状态，包括母体胰岛素敏感性降低，从而适当提高胎儿的葡萄糖可用性。然而，过度的胰岛素抵抗与胰岛素分泌不足一起导致妊娠期糖尿病（GDM），大大增加了妊娠并发症的风险，并使母亲和后代将来易患代谢疾病。在这里，我们报告了妊娠相关血浆蛋白A（PAPPA）与妊娠期脂肪组织扩张的信号通路。脂肪组织在胰岛素敏感性的调节中起着核心作用，我们发现，在小鼠和人类中，妊娠引起脂肪组织重塑，脂肪细胞大小改变，血管化和体外扩张能力。已知PAPPA是由人胎盘分泌的金属蛋白酶，其通过胰岛素样生长因子（IGF）结合蛋白（IGFBP）的蛋白水解调节IGF生物利用度2、4和5。我们证明，重组PAPPA可以刺激离体人体脂肪组织扩张的IGFBP-5和IGF-1依赖的方式。此外，缺乏PAPPA的小鼠表现出受损的脂肪组织重塑、妊娠诱导的胰岛素抵抗和肝脂肪变性，再现了人类GDM的多个方面。在6361名孕妇的队列中，循环PAPPA浓度与妊娠期糖尿病的发生率和几率呈负相关。这些数据确定PAPPA和IGF信号通路是调节母体脂肪组织生理学和全身葡萄糖稳态所必需的，具有长期代谢风险和治疗用途的潜力。
Pregnancy is a physiological state of continuous adaptation to changing maternal and fetal nutritional needs, including a reduction of maternal insulin sensitivity allowing for appropriately enhanced glucose availability to the fetus. However, excessive insulin resistance in conjunction with insufficient insulin secretion results in gestational diabetes mellitus (GDM), greatly increasing the risk for pregnancy complications and predisposing both mothers and offspring to future metabolic disease. Here, we report a signaling pathway connecting pregnancy-associated plasma protein A (PAPPA) with adipose tissue expansion in pregnancy. Adipose tissue plays a central role in the regulation of insulin sensitivity, and we show that, in both mice and humans, pregnancy caused remodeling of adipose tissue evidenced by altered adipocyte size, vascularization, and in vitro expansion capacity. PAPPA is known to be a metalloprotease secreted by human placenta that modulates insulin-like growth factor (IGF) bioavailability through prolteolysis of IGF binding proteins (IGFBPs) 2, 4, and 5. We demonstrate that recombinant PAPPA can stimulate ex vivo human adipose tissue expansion in an IGFBP-5– and IGF-1–dependent manner. Moreover, mice lacking PAPPA displayed impaired adipose tissue remodeling, pregnancy-induced insulin resistance, and hepatic steatosis, recapitulating multiple aspects of human GDM. In a cohort of 6361 pregnant women, concentrations of circulating PAPPA are inversely correlated with glycemia and odds of developing GDM. These data identify PAPPA and the IGF signaling pathway as necessary for the regulation of maternal adipose tissue physiology and systemic glucose homeostasis, with consequences for long-term metabolic risk and potential for therapeutic use.
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影响因子：
29
作者：
Cortés VA;Curtis DE;Sukumaran S;Shao X;Parameswara V;Rashid S;Smith AR;Ren J;Esser V;Hammer RE;Agarwal AK;Horton JD;Garg A
通讯作者：
Garg A
影响因子：
3.6
作者：
Eriksson, Britt;Lof, Marie;Forsum, Elisabet
通讯作者：
Forsum, Elisabet
影响因子：
16.6
作者：
通讯作者：
--
DOI：
10.1111/j.1471-0528.1993.tb12973.x
发表时间：
1993-04-01
期刊：
BRITISH JOURNAL OF OBSTETRICS AND GYNAECOLOGY
影响因子：
--
作者：
BRAMBATI, B;MACINTOSH, MCM;GRUDZINSKAS, JG
通讯作者：
GRUDZINSKAS, JG
影响因子：
2
作者：
BISCHOF, P
通讯作者：
BISCHOF, P