In utero programming of later adiposity: the role of fetal growth restriction

Abstract

Intrauterine growth restriction (IUGR) is strongly associated with obesity in adult life. The mechanisms contributing to the onset of IUGR-associated adult obesity have been studied in animal models and humans, where changes in fetal adipose tissue development, hormone levels and epigenome have been identified as principal areas of alteration leading to later life obesity. Following an adverse in utero development, IUGR fetuses display increased lipogenic and adipogenic capacity in adipocytes, hypoleptinemia, altered glucocorticoid signalling, and chromatin remodelling, which subsequently all contribute to an increased later life obesity risk. Data suggest that many of these changes result from an enhanced activity of the adipose master transcription factor regulator, peroxisome proliferator-activated receptor-γ (PPARγ) and its coregulators, increased lipogenic fatty acid synthase (FAS) expression and activity, and upregulation of glycolysis in fetal adipose tissue. Increased expression of fetal hypothalamic neuropeptide Y (NPY), altered hypothalamic leptin receptor expression and partitioning, reduced adipose noradrenergic sympathetic innervations, enhanced adipose glucocorticoid action, and modifications in methylation status in the promoter of hepatic and adipose adipogenic and lipogenic genes in the fetus also contribute to obesity following IUGR. Therefore, interventions that inhibit these fetal developmental changes will be beneficial for modulation of adult body fat accumulation.

Figure 1

Developmental stages of adipose tissue (adapted from Brooks and Perosio, [17]). Phase 1: emergence of loose connective tissue composed of an amorphous ground substance and stellate cells (filed). Phase 2: aggregates of mesenchymal cells (filed) are condensed around proliferating primitive blood vessels (bold ovals). Phase 3: mesenchymal cells differentiating into stellate preadipocytes within a glomerulus. Phase 4: appearance of adipocytes with multiple small lipid droplets closely packed around the capillaries. Phase 5: fat lobule with many unilocular cells (clear circles) is evident. This developmental process (phase 1 to 5) occurs between the 14- and 23-week gestation period. From 23 to 29 weeks, the number of fat lobules is relatively constant. From the 23rd to 29th week and throughout postnatal life, the growth of adipose tissue is determined mainly by an increase in size of the fat lobules arising from adipocyte hypertrophy and enlargement of adipose capillaries.

Figure 2

Schematic overview depicting key postulated molecular changes in adipose tissue and in hormonal status in the fetus and that may be involved in the development of later obesity following intrauterine growth restriction. For full explanation and definitions, see (Section 5). TGF-α1 (transforming growth factor alpha-1), CTGF (connective tissue growth factor), CYR61 (cysteine-rich, angiogenic inducer, 61), dermatopontin, and chymase-1.