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

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.

First-Trimester Screening for Gestational Diabetes Mellitus in Twin Pregnancies

“…PAPPA is a metalloprotease secreted by the human placenta that modulates insulin-like growth factor (IGF) bioavailability through proteolysis of IGF-binding proteins (IGFBPs) 2, 4, and 5. There is evidence that low concentrations of PAPPA result in impaired proteolysis of adipose tissue IGFBPs, which are up-regulated in adipose depots during pregnancy [30]. In turn, IGF signaling decreases, impairing pregnancy-induced increases in adipocyte number and size as well as tissue vascularization.…”

Placenta-Derived Exosomes as a Modulator in Maternal Immune Tolerance During Pregnancy

“…Without treatment, it may lead to preterm birth, fetal death and other pregnancy complications due to poor placentation induced by hyperglycemia. Although GDM is usually preventable and manageable, infants of mothers with GDM are at increased risk for heart disease, obesity or type 2 diabetes (205)(206)(207).…”

“…Maternal body mass index (BMI) has a strong association with the risk of GDM, indicating excessive adipocytes are a potential stressor for placentation ( 213 ). Adiponectin and leptin, mainly produced by the placenta during pregnancy, have a wide range of functions in adipose tissue such as vascularization, adipocyte enlargement and expansion ( 207 ). Exosomes from adipose tissue of GDM patients altered placental glucose metabolism by increasing gene expression of the glycolysis and gluconeogenesis pathways ( 214 ).…”

Research Advances in the Roles of Circular RNAs in Pathophysiology and Early Diagnosis of Gestational Diabetes Mellitus

“…In vitro, recombinant PAPPA has been shown to stimulate human adipose tissue to expand in an IGFBP-5 and IGF-1-dependent manner (Gyrup and Oxvig, 2007). Rojas-Rodriguez et al (Rojas-Rodriguez et al, 2020) reported that insulin resistance is closely associated with endothelial dysfunction (Aziz et al, 2018), and hsa_circ_0010283 is involved in vascular smooth muscle cell dysfunction by regulating the miR-133a-3p/pregnancyassociated plasma protein A (PAPPA) pathway (Feng et al, 2020). PAPPA-deficient mice develop insulin resistance in pregnancy.…”