Elevated Norepinephrine Stimulates Adipocyte Hyperplasia in Ovine Fetuses With Placental Insufficiency and IUGR

Abstract

Prevailing hypoxemia and hypoglycemia in near-term fetuses with placental insufficiency-induced intrauterine growth restriction (IUGR) chronically increases norepinephrine concentrations, which lower adrenergic sensitivity and lipid mobilization postnatally, indicating a predisposition for adiposity. To determine adrenergic-induced responses, we examined the perirenal adipose tissue transcriptome from IUGR fetuses with or without hypercatecholaminemia. IUGR was induced in sheep with maternal hyperthermia, and hypercatecholaminemia in IUGR was prevented with bilateral adrenal demedullation. Adipose tissue was collected from sham-operated control (CON) and IUGR fetuses and adrenal-demedullated control (CAD) and IUGR (IAD) fetuses. Norepinephrine concentrations were lower in IAD fetuses than in IUGR fetuses despite both being hypoxemic and hypoglycemic. In IUGR fetuses, perirenal adipose tissue mass relative to body mass was greater compared with the CON, adrenal-demedullated control, and IAD groups. Transcriptomic analysis identified 581 differentially expressed genes (DEGs) in CON vs IUGR adipose tissue and 193 DEGs in IUGR vs IAD adipose tissue. Integrated functional analysis of these 2 comparisons showed enrichment for proliferator-activated receptor signaling and metabolic pathways and identified adrenergic responsive genes. Within the adrenergic-regulated DEGs, we identified transcripts that regulate adipocyte proliferation and differentiation: adipogenesis regulatory factor, C/CCAAT/enhancer binding protein α, and sterol carrier protein 2. DEGs associated with the metabolic pathway included pyruvate dehydrogenase kinase 4, 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 4, IGF-binding proteins (IGFBP-5 and IGFBP-7). Sex-specific expression differences were also found for adipogenesis regulatory factor, pyruvate dehydrogenase kinase 4, IGFBP5, and IGFBP7. These findings indicate that sustained adrenergic stimulation during IUGR leads to adipocyte hyperplasia with alterations in metabolism, proliferation, and preadipocyte differentiation pathways.

Keywords: PPAR signaling; RNAseq; adipogenesis regulatory factor; adrenergic regulation; catecholamines; fetal growth restriction.