PAPPA-mediated adipose tissue remodeling mitigates insulin resistance and protects against gestational diabetes in mice and humans
Authors
Rojas-Rodriguez, RazielZiegler, Rachel
DeSouza, Tiffany
Majid, Sana
Madore, Aylin S.
Amir, Nili S.
Pace, Veronica A.
Nachreiner, Daniel
Alfego, David
Mathew, Jomol
Leung, Katherine
Moore Simas, Tiffany A.
Corvera, Silvia
Faculty Advisor
Silvia Corvera, MDUMass Chan Affiliations
Division of Data Sciences and Technology, ITDepartment of Obstetrics and Gynecology
Clinical Translational Research Pathway
Graduate School of Biomedical Sciences
Senior Scholars Program
School of Medicine
Program in Molecular Medicine
Document Type
Journal ArticlePublication Date
2020-11-25Keywords
Cellular and Molecular PhysiologyEndocrine System Diseases
Female Urogenital Diseases and Pregnancy Complications
Medical Education
Nutritional and Metabolic Diseases
Reproductive and Urinary Physiology
UMCCTS funding
Metadata
Show full item recordAbstract
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.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
DOI
10.1126/scitranslmed.aay4145Permanent Link to this Item
http://hdl.handle.net/20.500.14038/49368PubMed ID
33239385Notes
Sana Majid participated in this study as a medical student in the Senior Scholars research program at the University of Massachusetts Medical School.
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10.1126/scitranslmed.aay4145