SUN-669 - Building Baby Fat: Early Nutrition Shapes Immune Development in Adipose Tissue

Adipose tissue (AT) is a critical endocrine organ whose development is coordinated by immune cells programmed during early life. Adipose tissue macrophages (ATMs) play key roles in tissue development, lipid metabolism, and immune regulation, but become dysregulated in adult obesity. Elevated pro-inflammatory omega-6 (n6) fatty acids (FA) relative to pro-resolving omega-3 (n3) FA are associated with increased adiposity and obesity risk later in life; however, the impact of early developmental FA exposure on ATM phenotypes remains unclear. We hypothesized that exposure to a high n6/n3 FA environment during development predisposes offspring AT to inflammation by priming ATM responses and shifting ATMs away from pro-resolving phenotypes.
C57BL/6J female mice were randomized to an n6-rich or balanced n6/n3 control diet from mating through lactation. Inguinal AT was collected from offspring at postnatal day (PND) 12 for flow cytometry and ATM proteomics, and from a separate cohort at PND14 for global gene expression analysis of subcutaneous AT. Litters were pooled for analysis such that each biological replicate represented one dam, with mixed-sex offspring reflecting natural variation in sex distribution.
Global gene expression analysis demonstrated significant enrichment of fibrosis, macrophage activation, and cytokine signaling pathways, resembling transcriptional patterns observed in obese adults. Flow cytometry revealed increased MHCIIhi dendritic cells (p=0.0002) and an uncharacterized macrophage population (p=0.0002), alongside reductions in classical monocytes (p=0.0253), vascular-associated ATMs (p=0.0024), and double-positive ATMs (p=0.0238), with a strong trend toward decreased patrolling monocytes (p=0.0541). Proteomic analysis of F4/80+ ATMs showed enrichment of cytokine signaling, apoptosis, and cellular stress response pathways.
Collectively, these findings indicate that developmental exposure to a high n6/n3 FA environment shifts offspring ATMs away from pro-resolving states toward immune activation, potentially predisposing adipose tissue to exaggerated inflammatory responses. Ongoing studies will define immune cell transcriptional diversity, mechanisms regulating immunometabolism during developmental FA exposure, and the contribution of ATMs to adipogenesis and later-life metabolic dysfunction.

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