Programmed upregulation of adipogenic transcription factors in intrauterine growth-restricted offspring

Abstract

As enhanced adipogenesis contributes to programmed obesity, adipogenic and lipogenic signaling pathways in intrauterine growth restricted (IUGR) offspring were examined. From 10 days to term gestation, rats received ad libitum food (control) or were 50% food-restricted (IUGR). Pups were nursed and weaned to ad libitum diet. mRNA and protein levels of adipogenic transcription factors and lipid enzymes (1 day and 9 month) and adipocyte cell size (3 weeks and 9 months) were determined. One day-old IUGR males showed upregulation of peroxisome proliferator-activated receptor (PPAR gamma(2)), including upstream factors regulating PPAR gamma, and RXR alpha, with which PPAR gamma heterodimerizes. Intracellular lipolytic enzyme (hormone-sensitive lipase) was downregulated. Nine-month-old IUGR males showed upregulation of adipogenic and lipogenic (SREBP1c) transcription factors with upregulation of enzymes facilitating fatty acid uptake (lipoprotein lipase) and synthesis (fatty acid synthase), leading to hypertrophic adipocytes. Paradoxical upregulation of adipogenesis signaling cascade prior to the development of obesity in IUGR males suggests early changes in signaling mechanisms.

Figure 1

mRNA and protein levels of PPARγ in newborn and adult male offspring from control (■) and IUGR (□) groups. Data are normalized to β-actin and presented as fold difference. β-Actin was comparable between IUGR and control offspring at both ages. Number of animals studied per group per age was 6 males from 6 litters for mRNA and 4 males from 4 litters for protein. *P < .001 versus control offspring.

Figure 2

mRNA levels of C/EBPβ, C/EBPδ, C/EBPα, and RXRα in newborn and adult male offspring from control (■) and IUGR (□) groups. Data are normalized to β-actin and presented as fold difference. β-Actin was comparable between IUGR and control offspring at both ages. Number of animals studied per group per age was 6 males from 6 litters. *P < .001 versus control offspring.

Figure 3

Protein levels of C/EBPβ, C/EBPδ, C/EBPα, and RXRα in newborn and adult male offspring from control (■) and IUGR (□) groups. Data are normalized to β-actin and presented as fold difference. β-Actin was comparable between IUGR and control offspring at both ages. Number of animals studied per group per age was 4 males from 4 litters. *P < .001 versus control offspring.

Figure 4

mRNA levels of SREBP1c, lipoprotein lipase, fatty acid synthase, and hormone-sensitive lipase in newborn and adult male offspring from control (■) and IUGR (□) groups. Data are normalized to β-actin and presented as fold difference. β-Actin was comparable between IUGR and control offspring at both ages. Number of animals studied per group per age was 6 males from 6 litters. *P < .01 versus control offspring.

Figure 5

Protein levels of SREBP1, fatty acid synthase, and hormone-sensitive lipase in newborn and adult old male offspring from control (■) and IUGR (□) groups. Data are normalized to β-actin and presented as fold difference. β-Actin was comparable between IUGR and control offspring at both ages. Number of animals studied per group per age was 4 males from 4 litters. *P < .01 versus control offspring.

Figure 6

Adipocyte cell size in 3 week and 9 month male offspring from control (■) and IUGR (□) groups. Number of animals studied per group per age was 6 males from 6 litters. Each animal had 3 sections taken and each section had 4 images.*P < .05, **P < .01 versus control offspring.