☆ 4.5 Article

FGF15/FGF19 alleviates insulin resistance and upregulates placental IRS1/GLUT expression in pregnant mice fed a high-fat diet

PLACENTA (2021)

Journal

PLACENTA

Volume 112, Issue -, Pages 81-88

Publisher

W B SAUNDERS CO LTD

DOI: 10.1016/j.placenta.2021.07.286

Keywords

Fibroblast growth factor 15/19; Insulin resistance; Gestational diabetes mellitus; Insulin receptor substrate 1; Glucose transporters

Funding

Natural Science Foundation of Guangdong Province and Sun Yat-Sen University

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Abstract

The study found that FGF19 can alleviate insulin resistance in pregnant high-fat diet mice by regulating the expression of IRS1/GLUTs in the placenta. This effect leads to improvements in glycolipid metabolism.

Introduction: This study aimed to evaluate whether FGF19 can alleviate insulin resistance and change the expression of placental IRS1/GLUTs. Methods: Mice transgenic for Fgf15 (the murine homologue of human FGF19) were constructed, and human recombinant FGF19 was administered to pregnant high-fat diet mice. Then, glycolipid metabolism parameters and the weight of foetus and placenta were observed. The expression levels of key molecules of the insulin signalling pathway and glucose transporters in placentae were detected by qRT-PCR and western blotting. Primary trophoblasts and JAR cells were cultured in high-glucose medium, and FGF19 was added to observe its regulatory effects on IRS1/GLUTs. Results: Overexpressing FGF15 or exogenously administering FGF19 reduced the levels of fasting blood glucose, HOMA-IR, triglycerides, and free fatty acids in pregnant high-fat diet mice compared to control mice (P < 0.05). FGF15/FGF19 did not significantly affect placental weight, foetal weight or litter size (P > 0.05). In addition, FGF15/FGF19 upregulated the expression of p-IRS1 and GLUT4 in the placentae of high-fat diet mice and upregulated GLUT1 levels in the placentae of normal diet-fed mice (P < 0.05), while it did not significantly alter total IRS1 and GLUT3 levels (P > 0.05). Consistent with the results of the animal experiments, FGF19 increased the expression of p-IRS1 and GLUT4 in trophoblast cells cultured in high-glucose medium (P < 0.05). Discussion: Overexpressing FGF15 or administering FGF19 to pregnant high-fat diet mice can improve glycolipid metabolism and alleviate systemic and local insulin resistance. The possible underlying mechanism may involve upregulation of placental expression of p-IRS1 and GLUT4.

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Fibroblast Growth Factor 19 in Gestational Diabetes Mellitus and Fetal Growth

Meng-Nan Yang, Rong Huang, Xin Liu, Ya-Jie Xu, Wen-Juan Wang, Hua He, Guang-Hui Zhang, Tao Zheng, Fang Fang, Jian-Gao Fan, Fei Li, Jun Zhang, Jiong Li, Fengxiu Ouyang, Zhong-Cheng Luo

Summary: This study found that FGF19 is not associated with glucose homeostasis in newborns of GDM mothers. However, cord plasma FGF19 concentrations were positively correlated with birth weight and length in females, suggesting a sex-dimorphic role of FGF19 in fetal growth. Further studies are needed to validate these findings and explore the underlying mechanisms.

FRONTIERS IN ENDOCRINOLOGY (2022)