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Session: From the Womb to the World: Impact of Prenatal and Perinatal Exposures on Offspring Outcomes (Oral 21)

(OR21-04-23) Lipidomics in Human Umbilical Cord-Derived MSC Are Associated With Gestational Fatty-Free Acids and Triacylglycerols and Child Adiposity: The Healthy Start Study

Monday, July 24, 2023
4:36 PM – 4:48 PM ET
Location:  Constitution B
PRAC ELPC
Disclosure(s):
Manoel Lixandrao, PhD: No relevant financial relationship(s) with ineligible companies to disclose.
Leanne Redman, PhD: Abbott Nutrition: Grant/Research Support (Ongoing)
Advocare International, LP: Advisory Committee/Board Member (Ongoing)
Bobbie Labs: Advisory Committee/Board Member (Ongoing)
Everly Health: Consultant (Ongoing)
Willow Innovations, Inc: Consultant (Ongoing)
Kristen E. Boyle, PhD: No relevant financial relationship(s) with ineligible companies to disclose.
Objectives: During gestation, circulating metabolites contribute to child obesity and metabolic disease risk. Lipid metabolism of human infant umbilical cord-derived mesenchymal stem cells (MSCs) is disrupted in infants exposed to intrauterine obesity, though this is moderated by the circulating milieu (e.g., glucose, free fatty acids [FFA]). Hypothesis: lipid profile of MSCs differentiated to myocytes
in vitro is associated with intrauterine metabolic exposures and child adiposity in vivo.

Methods: We differentiated MSCs from 70 infants to myocytes for 21d (pre-pregnancy BMI: 24.9 ± 4.7 kg/m2; maternal age: 29.1 ± 6.2 y, gestational age at delivery: 39.4 ± 1.3 w; birthweight: 3.3 ± 0.4 kg). We analyzed quantitative MSC lipidomics by LC-MS/MS, serum cholesterols, triacylglycerols (TAG), FFA, insulin, and glucose in early (10-24w) and later (21-32w) gestation, and child adiposity by whole-body air plethysmography at birth and 4-6 years. We used principal component analysis and k-means clustering to analyze lipid species. We tested differences between clusters by differential expression for single lipids (DE, FDR < 0.05) and by t-test for sum of lipids and child outcomes. We used linear regression adjusted for adjusted for maternal age, gestational age at the serum measure, and infant sex to test associations.

Results: We identified 2 MSC clusters with low- (n = 39) and high- (n = 31) total lipid content (193 ± 75nM vs. 247 ± 93nM, respectively;
P = 0.01). DE showed 36 species up-regulated in the high-MSC cluster (e.g., 1,2-diacylglycerols (DAG) and phospholipids) and 42 down-regulated (e.g., 1,3-DAGs, ceramides, ceramide precursors, phospholipids, and TAGs). Child adiposity at 4-6y was lower in low- vs. high-MSC lipid content clusters (16.8 ± 5.2% vs. 22.9 ± 7.5%, respectively; P  < 0.001). MSC lipid content was associated with early gestation TAGs (ß = 0.07 ± 0.03, P = 0.05) and early (ß = 0.17 ± 0.05, P  < 0.001) and later gestation FFA (ß = 0.09 ± 0.04, P = 0.05).

Conclusions: MSC lipid profiles are associated with gestational TG and FFA and child adiposity. Differences in DAGs, which are linked to ectopic lipid storage and insulin resistance, may explain higher childhood adiposity. Deeper interrogation of lipid species in MSCs will help establish the molecular underpinnings contributing to childhood obesity.

Funding Sources: This work is supported by NIH, AHA, NIDDK and NIH/NCATS.