Title

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

UMMS Affiliation

Program in Molecular Medicine; School of Medicine; Senior Scholars Program; Graduate School of Biomedical Sciences; Clinical Translational Research Pathway; Department of Obstetrics and Gynecology; Division of Data Sciences and Technology, IT

Faculty Mentor

Silvia Corvera, MD

Publication Date

2020-11-25

Document Type

Article

Disciplines

Cellular and Molecular Physiology | Endocrine System Diseases | Female Urogenital Diseases and Pregnancy Complications | Medical Education | Nutritional and Metabolic Diseases | Reproductive and Urinary Physiology

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.

DOI of Published Version

10.1126/scitranslmed.aay4145

Source

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. PAPPA-mediated adipose tissue remodeling mitigates insulin resistance and protects against gestational diabetes in mice and humans. Sci Transl Med. 2020 Nov 25;12(571):eaay4145. doi: 10.1126/scitranslmed.aay4145. PMID: 33239385; PMCID: PMC8375243. Link to article on publisher's site

Journal/Book/Conference Title

Science translational medicine

Comments

Sana Majid participated in this study as a medical student in the Senior Scholars research program at the University of Massachusetts Medical School.

Related Resources

Link to Article in PubMed

PubMed ID

33239385

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