Research ArticleMetabolism

PAPPA-mediated adipose tissue remodeling mitigates insulin resistance and protects against gestational diabetes in mice and humans

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Science Translational Medicine  25 Nov 2020:
Vol. 12, Issue 571, eaay4145
DOI: 10.1126/scitranslmed.aay4145

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Placenta—adipose tissue cross-talk

Hyperglycemia occurs in some women during pregnancy, predisposing both them and their offspring to metabolic disease later in life. Rojas-Rodriguez et al. report that a metalloprotease secreted by the placenta, pregnancy-associated plasma protein A (PAPPA), increased adipose tissue remodeling in pregnant mice and human adipose tissue explants by modulating insulin-like growth factor 1 signaling. Knocking out PAPPA in mice reduced adipose tissue remodeling. Reduced PAPPA is associated with insulin resistance and gestational diabetes in both the knockout mice and a cohort of pregnant women, suggesting that PAPPA plays a role in healthy metabolic adaptation to pregnancy.

Abstract

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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