Prepregnancy GLP‐1RA use improves maternal lipid metabolism via liver‐secreted FGF21 during pregnancy in HFD‐fed dams

Jul 10, 2025Obesity (Silver Spring, Md.)

Using GLP-1RA before pregnancy improves fat metabolism during pregnancy through a liver hormone in high-fat diet mothers

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Abstract

Prepregnancy glucagon-like peptide-1 receptor agonist (GLP-1RA) use is associated with reduced triglyceride levels and improved lipid metabolism during pregnancy in women with obesity.

Prepregnancy GLP-1RA use led to a reduction in prepregnancy body mass index (BMI) and gestational weight gain.
There was a decrease in the incidence of metabolic dysfunction-associated liver disease during the first trimester among participants using GLP-1RA.
In an animal study, GLP-1RA improved levels of plasma fibroblast growth factor 21 (FGF21), adiponectin, and leptin during midgestation.
During late gestation, GLP-1RA groups showed improved liver lipid deposition and increased fatty acid oxidation.
GLP-1RA use was linked to changes in gene expression related to lipolysis and lipogenesis in both liver and visceral adipose tissue.

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OBJECTIVE: Obesity in women of childbearing age disrupts lipid metabolism in pregnancy. This study aims to evaluate the impact of prepregnancy glucagon-like peptide-1 receptor agonist (GLP-1RA) use on lipid metabolism during pregnancy.

METHODS: A retrospective case-control study with 42 participants was employed to analyze the impact of prepregnancy GLP-1RA use on lipid metabolism during pregnancy in women with obesity. An animal study involved 60 virgin female Sprague Dawley rats fed a normal diet or a high-fat diet (HFD) for 8 weeks, with the latter diet divided into HFD + saline, HFD + liraglutide, and HFD + semaglutide for 4 weeks. Rats were mated and then sacrificed on gestational day 21.

RESULTS: Clinically, prepregnancy GLP-1RA use reduced prepregnancy BMI, gestational weight gain, ratio with first-trimester metabolic dysfunction-associated steatotic liver disease, and triglyceride levels during pregnancy. In animals, GLP-1RA improved plasma fibroblast growth factor 21 (FGF21), adiponectin, triglyceride levels, and leptin in midgestation. During late gestation, compared with the HFD group, the GLP-1RA groups exhibited improved liver lipid deposition, increased fatty acid oxidation and lipolysis genes, decreased lipogenesis genes, and increased extracellular signal-regulated kinase (ERK)/peroxisome proliferator-activated receptor γ (PPAR-γ) and AMP-activated protein kinase (AMPK)/NAD-dependent protein deacetylase sirtuin-1 (SIRT1) pathways in liver; in the visceral adipose, the GLP-1RA groups showed increased lipolysis genes, decreased lipogenesis genes, and increased phosphorylated to total fibroblast growth factor receptor 1 (FGFR1) with activated ERK/PPAR-γ pathways.

CONCLUSIONS: Prepregnancy GLP-1RA use improves maternal lipid metabolism during pregnancy, potentially involving elevated liver-secreted FGF21. This study offers a new strategy for treating lipid metabolic disorders in pregnancy.

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Prepregnancy GLP‐1RA use improves maternal lipid metabolism via liver‐secreted FGF21 during pregnancy in HFD‐fed dams

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