The Developmental Origins of Obesity

Pregestational obesity (PGO, BMI ≥30) is a significant independent risk factor for the development of obesity in childhood and adolescence. Notably, elevated levels of IL-6 and leptin have been found in the cord blood of offspring born to women with PGO, along with increased body fat. Both our research and that of others have shown an upregulation of pro-inflammatory genes in cord blood monocytes and alterations in innate immune function, including a blunted response to pro-inflammatory stimuli. However, it remains unclear whether these effects are due to an altered immune response in differentiated immune cells or if they are programmed earlier in gestation, during the progenitor cell stage. Long-chain polyunsaturated fatty acids (LCPUFAs) are crucial for cellular function, acting as precursors to membrane components and signaling molecules involved in cardiovascular, metabolic, and immune processes. Modern dietary patterns have led to a relative deficiency in n-3 LCPUFAs, such as Docosahexaenoic acid (DHA) and Eicosapentaenoic acid (EPA). As a result, international health guidelines recommend LCPUFA supplementation during pregnancy. Studies have shown that increased intake of n-3 LCPUFAs during pregnancy exerts effective anti-inflammatory effects in the maternal circulation, adipose tissue, and placenta. The recently completed MIGHT study (NCT02574767), which involved 1005 women with overweight or PGO, investigated the effects of DHA supplementation during pregnancy (200 mg vs. 800 mg/day). A subgroup of the newborns from this cohort also participated in the EpiFat study (NCT04249635), conducted by our team (2017-2021). The findings demonstrated that maternal DHA supplementation (800 mg/day) significantly reduced body fat and improved adipose metabolic markers in offspring at birth, with these effects persisting until 4 months of age. Additionally, the cord blood monocytes of PGO offspring exhibited increased expression of pro-inflammatory genes (IL-6, MCP-1, TNF-α, IL-8), but these effects were completely reversed in the offspring of DHA-supplemented women. These results provide strong evidence of pro-inflammatory programming in innate immune cells and adiposity in offspring of women with PGO, and show that maternal PUFA supplementation during pregnancy can reverse these early obesity biomarkers. However, it remains unclear whether these effects persist into early childhood (5 years of age), particularly in high-risk populations such as those born to women with PGO. Moreover, we hypothesize that maternal obesogenic signals during early embryonic development may affect the progenitor cells of adipocytes (mesenchymal stem cells, MSC) and monocytes (hematopoietic stem cells, HSC), potentially leading to long-term effects on the offspring. This study hypothesizes that: "Maternal obesity increases the risk of childhood obesity by programming adipose and immune progenitor cells, an effect that may be mitigated by maternal supplementation with polyunsaturated fatty acids during pregnancy." To test this hypothesis, we propose: A pilot clinical study to examine whether maternal PGO affects the lineage commitment, number, TLR4 signaling, and epigenetic markers (ChIP-seq) of monocyte (HSC) and adipocyte (MSC) progenitor cells, and whether maternal supplementation with PUFAs during pregnancy can modify these effects. The OMEGA Stem study will invite 160 healthy women (80 with normal weight and 80 with pregestational obesity) with singleton pregnancies to participate. Participants will receive either 600 mg/day of EPA/DHA (1 capsule) or standard antenatal care. A trained midwife will enroll the women \<16 weeks of pregnancy, with data collection (sociodemographic information, clinical data and blood samples) at study initiation, 26-28 weeks, and at delivery. Neonatal body composition will be assessed by a trained midwife (24-48 hours after delivery) through anthropometric measurements and skinfold thickness, calculated using Catalano's formula.