Agouti Signaling Protein Promotes Trophoblast Cell Proliferation,Invasion,and Tube Formation Through PPARγ Under High-Glucose Conditions

doi:10.3870/j.issn.1672-8009.2026.03.003

Journal of Medical Molecular Biology ›› 2026, Vol. 23 ›› Issue (3): 250-257.doi: 10.3870/j.issn.1672-8009.2026.03.003

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Agouti Signaling Protein Promotes Trophoblast Cell Proliferation,Invasion,and Tube Formation Through PPARγ Under High-Glucose Conditions

WEI Xue^1#, GONG Hao^1#, ZHANG Qian¹, DONG Shuqin¹, WEI Jing², LU Yu¹

¹Department of Endocrinology,²Department of Obstetrics and Gynecology,the Affiliated Taizhou People’s Hospital of Nanjing Medical University,Taizhou School of Clinical Medicine,Nanjing Medical University,Taizhou,Jiangsu,225300,China

Received:2025-12-24 Published:2026-06-01
Contact: LU Yu(E-mail:luyu_666@126.com)
About author:#:These authors contributed equally as first author.
Supported by:
Six Talent Peaks Project in Jiangsu Province(No.WSN-336),Scientific Research Project of Health Commission in Jiangsu Province(No.LGY2020067),Scientific Research Project of Taizhou School of Clinical Medicine of Nanjing Medical University(No.TZKY20220110)

Abstract

Abstract: Objective To investigate the expression of agouti signaling protein(ASIP)in the placenta of pregnant women with different glucose tolerance,as well as its effect,under high-glucose conditions,on trophoblast cell proliferation,invasion,and tube formation. Methods Placental tissues were collected from pregnant women with gestational diabetes mellitus(GDM,n=20)and without GDM(non-GDM,n=20).ASIP expression and localization were detected by immunohistochemistry and immunofluorescence.The human trophoblast cell line HTR-8/SVneo was cultured under high-glucose conditions and treated with recombinant ASIP or the peroxisome proliferator-activated receptor γ(PPARγ)antagonist GW9662.Cell proliferation,invasion,and tube formation were assessed using MTT,Transwell,and Matrigel assays,respectively.Western blotting assay and RT-qPCR were performed to analyze protein and mRNA expression. Results Placental weight was significantly higher in the GDM group than in the non-GDM group(570 g vs 490 g,P=0.019).ASIP mRNA and protein levels were significantly upregulated in GDM placental villous trophoblasts,and immunohistochemistry and immunofluorescence further confirmed significantly increased ASIP protein expression in the placental villous trophoblasts.Under high-glucose conditions,the expression levels of ASIP mRNA and protein in HTR-8/SVneo cells were significantly increased.Subsequently,recombinant ASIP(50-200 ng/mL)promoted cell proliferation and induced the phosphorylation of PPARγ,signal transducer and activator of transcription 1(STAT1),and STAT3 in a dose-dependent manner.Furthermore,treatment of HTR-8/SVneo cells with ASIP(200 ng/mL)for 24 h significantly enhanced trophoblast proliferation,invasion,and tube formation.The promoting effects of ASIP were partially reversed by co-treatment with the PPARγ antagonist GW9662(20 μmol/L). Conclusion ASIP expression is elevated in trophoblast cells under both GDM and high-glucose conditions.ASIP promotes excessive proliferation,invasion,and tube formation of trophoblast cells via a PPARγ-dependent mechanism under high-glucose conditions,thereby contributing to the placental remodeling of GDM.

Key words: agouti signaling protein, trophoblast, placenta, gestational diabetes mellitus, peroxisome proliferator-activated receptor γ

CLC Number:

R714.256

WEI Xue, GONG Hao, ZHANG Qian, DONG Shuqin, WEI Jing, LU Yu. Agouti Signaling Protein Promotes Trophoblast Cell Proliferation,Invasion,and Tube Formation Through PPARγ Under High-Glucose Conditions[J]. Journal of Medical Molecular Biology, 2026, 23(3): 250-257.

References

[1] UGWUDIKE B,KWOK M.Update on gestational diabetes and adverse pregnancy outcomes[J].Curr Opin Obstet Gynecol,2023,35(5):453-459.
[2] SWEETING A,HANNAH W,BACKMAN H,et al.Epidemiology and management of gestational diabetes[J].Lancet,2024,404(10448):175-192.
[3] CARRASCO-WONG I,MOLLER A,GIACHINI F R,et al.Placental structure in gestational diabetes mellitus[J].Biochim Biophys Acta Mol Basis Dis,2020,1866(2):165535.
[4] MOLITIERNO R,IMPARATO A,IAVAZZO N,et al.Microscopic changes and gross morphology of placenta in women affected by gestational diabetes mellitus in dietary treatment:A systematic review[J].Open Med(Wars),2025,20(1):20251142.
[5] ARCOT A,WALKER R E,GALLAGHER K,et al.Gestational diabetes mellitus and vascular malperfusion lesions in the placenta:A systematic review and meta-analysis[J].Int J Gynaecol Obstet,2025,170(3):1071-1083.
[6] PRABAHARAN E,ARMANT D R,DREWLO S.Human placentation:Foundations and implications for reproductive endocrinology and infertility[J].Syst Biol Reprod Med,2025,71(1):279-306.
[7] XIAO B,ZHANG W,JI N,et al.Knockdown of CCNB1 alleviates high glucose-triggered trophoblast dysfunction during gestational diabetes via Wnt/β-catenin signaling pathway[J].Open Med(Wars),2025,20(1):20241119.
[8] KEMPF E,LANDGRAF K,STEIN R,et al.Aberrant expression of Agouti signaling protein(ASIP)as a cause of monogenic severe childhood obesity[J].Nat Metab,2022,4(12):1697-1712.
[9] 孙晓燕,宋昱龙,蒋婧,等.ASIP基因及其重组蛋白对山羊脂肪细胞脂肪沉积的效应[J].核农学报,2025,39(1):38-46.
SUN X Y,SONG Y L,JIANG J,et al.Effect of ASIP gene and recombinant ASIP protein on lipid deposition in goat adipocytes in vitro[J].J Nucl Agric Sci,2025,39(1):38-46.
[10] SMITH S R,GAWRONSKA-KOZAK B,JANDEROVÁ L,et al.Agouti expression in human adipose tissue:Functional consequences and increased expression in type 2 diabetes[J].Diabetes,2003,52(12):2914-2922.
[11] KLEBIG M L,WILKINSON J E,GEISLER J G,et al.Ectopic expression of the Agouti gene in transgenic mice causes obesity,features of type II diabetes,and yellow fur[J].Proc Natl Acad Sci U S A,1995,92(11):4728-4732.
[12] 中华医学会妇产科学分会产科学组,中华医学会围产医学分会,中国妇幼保健协会妊娠合并糖尿病专业委员会.妊娠期高血糖诊治指南(2022)[第二部分][J].中华妇产科杂志,2022,57(2):81-90.
Obstetrics Subgroup,Chinese Society of Obstetrics and Gynecology,Chinese Medical Association;Chinese Society of Perinatal Medicine,Chinese Medical Association;Committee of Pregnancy with Diabetes Mellitus,China Maternal and Child Health Association.Guideline of diagnosis and treatment of hyperglycemia in pregnancy(2022)[Part two][J].Chin J Obstet Gynecol,2022,57(2):81-90.
[13] CHAI O,TANG N,GUO R,et al.Downregulation of BRD4 attenuates high glucose-induced damage of trophoblast cells by inhibiting activation of AKT/mTOR pathway[J].Reprod Biol,2023,23(2):100751.
[14] XUE B Z,WILKISON W O,MYNATT R L,et al.The Agouti gene product stimulates pancreatic[beta]-cell Ca²⁺ signaling and insulin release[J].Physiol Genomics,1999,1(1):11-19.
[15] KIM J H,KIEFER L L,WOYCHIK R P,et al.Agouti regulation of intracellular calcium:Role of melanocortin receptors[J].Am J Physiol Endocrinol Metab,1997,272(3):E379-E384.
[16] RUMER K K,SEHGAL S,KRAMER A,et al.The effects of leptin on human cytotrophoblast invasion are gestational age and dose-dependent[J].Front Endocrinol,2024,15:1386309.
[17] CAI J X,LE A W,HAN X Y,et al.Chemerin sustains the growth of spongiotrophoblast and sinusoidal trophoblast giant cells through fatty acid oxidation[J].BMC Biol,2025,23(1):199.
[18] LIU Y,ALBRECHT E,SCHERING L,et al.Agouti Signaling protein and its receptors as potential molecular markers for intramuscular and body fat deposition in cattle[J].Front Physiol,2018,9:172.
[19] QIN Y,BILY D,AGUIRRE M,et al.Understanding PPARγ and its agonists on trophoblast differentiation and invasion:Potential therapeutic targets for gestational diabetes mellitus and preeclampsia[J].Nutrients,2023,15(11):2459.
[20] XIE T,LIU Y,LU H,et al.The knockout of the ASIP gene altered the lipid composition in bovine mammary epithelial cells via the expression of genes in the lipid metabolism pathway[J].Animals,2022,12(11):1389.
[21] XUE L,CAO C.Octanoic acid-rich enteral nutrition regulates intestinal M1/M2 macrophage polarization via the PPARγ/STAT-1/STAT-6 pathway to alleviate inflammatory bowel disease[J].Food Sci Nutr,2025,13(11):e71234.
[22] WANG L H,YANG X Y,ZHANG X,et al.Transcriptional inactivation of STAT3 by PPARgamma suppresses IL-6-responsive multiple myeloma cells[J].Immunity,2004,20(2):205-218.
[23] MYNATT R L,STEPHENS J M.Agouti regulates adipocyte transcription factors[J].Am J Physiol Cell Physiol,2001,280(4):C954-C961.

Agouti Signaling Protein Promotes Trophoblast Cell Proliferation,Invasion,and Tube Formation Through PPARγ Under High-Glucose Conditions

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