Work

The effects of diet-induced obesity on glucose metabolism in the mouse endometrium

Year: 2026

Type: article

Abstract: Background Embryo transfer studies in women with high BMI show lower implantation rates, indicating impaired uterine function. Most mouse studies using diet-induced obesity (DIO) do not characterize the metabolomic phenotype in their models. Additionally, studies usually focus on implantation sites, ignoring the role of the epithelium in supporting embryo development. At proestrus, the uterine epithelium metabolizes glucose for its own needs and stores glycogen to support embryo development after mating. Our objectives were to (1) thoroughly characterize systemic metabolism in a long-term DIO mouse model, and (2) determine how DIO affects glucose metabolism in the uterine epithelium at proestrus. Methods and results Mice were randomly assigned to one of three experimental diets (10%, 45%, or 60% kcal from fat) and fed ad libitum. Both high-fat diet (HFD) groups progressively increased in body mass and glucose intolerance during the course of the experiment. After 18 weeks, the mice were sacrificed at proestrus. In serum, gas chromatography-mass spectrometry (GC–MS) showed that HFDs altered the levels of 23 metabolites ( P <0.05). Analysis of these metabolites showed enrichment in pathways related to lipids, glucose, and energy metabolism. Confirming that the HFD mice were insulin-resistant, liver glycogen stores decreased, while hepatic triglyceride levels were increased in the 60% fat group, in agreement with observations in obese people. In contrast, effects on the uterus were minimal. There was no difference in immunostaining in the uterus for the glycolytic enzymes PKM2 and PFKM. There was no difference in the glycogen levels or immunostaining for glycogen-metabolizing enzymes in the endometrium. Additionally, immunostaining for phospho-IRS and phospho-AKT in the uterine epithelium was similar across groups, indicating no change in AKT signaling in fasted mice. GC–MS analysis of the uterus found alterations in only 10 metabolites in the 60% fat group relative to the 10% fat group ( P <0.05). Analysis of those metabolites found 4 pathways to be significantly enriched—glycosaminoglycan biosynthesis, mannose type O-glycan biosynthesis, linoleic acid metabolism, and purine metabolism. Conclusion Our DIO model resulted in systemic traits indicative of insulin resistance. However, obesity had a minimal effect on glucose metabolism in the endometrium at proestrus.

Source: Uterine Research

DOI: 10.1186/s44494-026-00008-8