Liraglutide-Driven Weight Loss Modulates Placental Remodeling in Obese Pregnancies in Mice.

BACKGROUND

The placenta stands at the maternal-fetal interface and is a key organ regulating the intrauterine environment. In pregnancies exposed to obesity, placental function, signaling, and nutrient handling are adversely altered. Pre-conception weight loss is a potential intervention to alter an obesogenic milieu of pregnancy, which we investigated in a mouse model of maternal obesity using diet or administration of the glucagon-like peptide-1 (GLP-1) receptor agonist liraglutide.

METHODS

Pre-pregnancy weight loss in C57BL/6 high-fat diet (HFD)-fed dams was induced in the pre-pregnancy period by switching diet from HFD to chow diet or administering liraglutide (0.3 mg/kg/day subcutaneously for 4 weeks) whilst continuing HFD. In addition, a group of HFD-fed dams were switched to chow diet post-conception. The metabolomic profile and gene expression within the placenta was compared at day 18-20 of gestation.

RESULTS

1H NMR spectroscopy metabolomic analysis of placenta of HFD mice showed an altered amino acid metabolomic profile, with lower aspartate, glutamate, and glutamine levels compared to the placenta of chow-fed mice (p < 0.05). Meanwhile, gene expression analysis identified both oxidative stress and inflammation in the placentas of HFD-fed dams. Whilst dietary modification alone was sufficient to reduce markers of oxidative stress and inflammation, liraglutide treatment modulated pathological changes, including placental metabolic stress but not inflammation.

CONCLUSIONS

These findings highlight the importance of dietary or pharmacological interventions in the pre- or immediate post-conception period, with pre-conception offering a critical window to reduce aberrant placental changes induced by obesity.