Fetal programming of adipose tissue: effects of intrauterine growth restriction and maternal obesity/high-fat diet

Abstract

A newly recognized primary cause of obesity epidemic is the developmental programming effects of (1) intrauterine growth-restricted (IUGR) newborns exposed in utero to undernutrition, and (2) normal or excessive weight newborns exposed to maternal obesity and high-fat (HF) diets. The mechanisms contributing to offspring obesity have been extensively studied in animal models with adipose tissue identified as one of the principal targets of programming. IUGR and HF offspring exhibit programmed adipocytes, such that an intrinsic enhanced lipogenesis and adipocyte proliferation contribute to the development of obesity. This is attributed to early induction of adipogenic transcription factor peroxisome proliferator-activated receptor (PPAR)γ, whose activity is enhanced under limited or excess nutrient availability. Nonetheless, this occurs via different mechanisms involving PPARγ coregulators: In IUGR, it is upregulation of coactivators, whereas in HF newborns, it is downregulation of corepressors. Thus preventive therapeutic interventions will require target-specific modalities that depend on the primary etiology.

Figure 1. Sequential Regulation of Adipogenesis and Lipogenesis

(1) C/EBPδ and C/EBPβ upregulate PPARγ and C/EBPα; (2) PPARγ₂ upregulates C/EBPα and vice versa, resulting in adipocyte differentiation; (3) PPARγ₂ upregulates lipogenic transcription factor, SREBP1c; (4) SREBP1c upregulates extracellular lipolytic enzyme, lipoprotein lipase facilitating fatty acid uptake by adipocytes; (5) SREBP1c upregulates lipogenic enzyme, fatty acid synthase facilitating lipogenesis within adipocytes; (6) Intracellular lipolytic enzyme, hormone sensitive lipase acts on triglyceride to release fatty acid from adipocyte.

Figure 2. Adipose Tissue as an Endocrine Organ

Adipocytes secrete adipokines that regulate energy homeostasis, appetite regulation, insulin sensitivity, inflammatory response, and blood pressure. Imbalanced secretion of some of these adipokines is associated with obesity and metabolic syndrome. Tumor Necrosis Factor alpha (TNF-α), Interleukin 6 (IL-6), Monocyte chemotactic protein-1 (MCP-1), Angiotensinogen (AGT) and Plasminogen Activator Inhibitor (PAI).