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. 2009 Jun 11;4(6):e5870.
doi: 10.1371/journal.pone.0005870.

Maternal obesity induced by diet in rats permanently influences central processes regulating food intake in offspring

Shona L Kirk  1 , Anne-Maj Samuelsson, Marco Argenton, Hannah Dhonye, Theodosis Kalamatianos, Lucilla Poston, Paul D Taylor, Clive W Coen
Affiliations

Maternal obesity induced by diet in rats permanently influences central processes regulating food intake in offspring

Shona L Kirk et al. PLoS One. .

Abstract

Hypothalamic systems which regulate appetite may be permanently modified during early development. We have previously reported hyperphagia and increased adiposity in the adult offspring of rodents fed an obesogenic diet prior to and throughout pregnancy and lactation. We now report that offspring of obese (OffOb) rats display an amplified and prolonged neonatal leptin surge, which is accompanied by elevated leptin mRNA expression in their abdominal white adipose tissue. At postnatal Day 30, before the onset of hyperphagia in these animals, serum leptin is normal, but leptin-induced appetite suppression and phosphorylation of STAT3 in the arcuate nucleus (ARC) are attenuated; the level of AgRP-immunoreactivity in the hypothalamic paraventricular nucleus (PVH), which derives from neurones in the ARC and is developmentally dependent on leptin, is also diminished. We hypothesise that prolonged release of abnormally high levels of leptin by neonatal OffOb rats leads to leptin resistance and permanently affects hypothalamic functions involving the ARC and PVH. Such effects may underlie the developmental programming of hyperphagia and obesity in these rats.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. Maternal body weight and food intake in rats fed control or obesogenic diet.
Body weight (A) was recorded for 6 weeks prior to pregnancy and throughout pregnancy and lactation for the animals on the control (open symbols) or obesogenic (closed symbols) diet; calorific intake was recorded throughout pregnancy and lactation (B). Average daily calorific intake from all sources during pregnancy (C) and average daily calorific intake from fat or simple sugars during pregnancy (D) or lactation (E) for the animals on the control (Con) or obesogenic (Ob) diet. Macronutrient content of ingested food (expressed as percentage by weight) for control (F) or obese (G) dams during lactation; “other” includes cellulose, ash, water etc. * p<0.05 and ** p<0.01 versus control dams (n = 11–12).
Figure 2
Figure 2. Post-weaning characteristics of offspring of control and obese dams.
Body weight for males (A) and females (B) and calorific intake for males (C) and females (D) were recorded post-weaning for offspring of control (open symbols) or obese (closed symbols) dams. Offspring body and tissue weights were recorded at postnatal Day 90 (E). OffCon = offspring of control dams; OffOb = offspring of obese dams; WAT = white adipose tissue; BAT = brown adipose tissue; s.c. = subcutaneous. * p<0.05 and ** p<0.01 versus offspring of control dams (n = 8–11).
Figure 3
Figure 3. Neonatal serum leptin concentrations and adipose leptin mRNA expression in offspring of control and obese dams.
Serum leptin was measured in offspring of control dams (open bars) and obese dams (closed bars) on postnatal days 2, 7, 8, 9, 11, 13, 14, 15 and 18 (A). Leptin mRNA expression in abdominal fat is presented for postnatal days 2–8, 9–11 and 13–18 (B). * p<0.05, ** p<0.01 and *** p<0.01 versus offspring of control dams for the same period (n = 3–6). For longitudinal comparisons, a significant difference (p<0.05) from the preceding period is indicated by # for offspring of control dams and by † for offspring of obese dams.
Figure 4
Figure 4. Constituents of milk from control and obese dams by analysis of pups' stomach contents.
The concentration of leptin (A), cholesterol (B), free fatty acids (FFA) (C), triglycerides (D) and glucose (E) was assayed in stomach contents (as a proxy measure of the dams' milk content) from offspring of control dams (open bars; n = 4–8) and obese dams (closed bars; n = 4–8) throughout suckling. * p<0.05 and ** p<0.01 versus offspring of control dams at the same period. For longitudinal comparisons, a significant difference (p<0.05) from the preceding period is indicated by # for offspring of control dams and by † for offspring of obese dams.
Figure 5
Figure 5. Behavioural responses to leptin in juvenile and adult offspring of control and obese dams.
Food intake for males (A) and females (B) and change in body weight for males (C) and females (D) recorded over 24 hours following administration of leptin (10 mg/kg, i.p.) in 30 day-old offspring of control or obese dams. Food intake for males (E) and females (F) and change in body weight for males (G) and females (H) in 90 day-old offspring of control or obese dams. OffCon = offspring of control dams; OffOb = offspring of obese dams; * p<0.05 and ** p<0.01 ***p<0.001, versus offspring of control dams (n = 6).
Figure 6
Figure 6. Signalling responses to leptin in juvenile and adult offspring of control and obese dams.
Representative images (A) and quantitative analysis (B and C) of leptin-induced pSTAT3-immunoreactive (ir) cells (per mm2) in the arcuate nucleus (ARC) and ventromedial hypothalamic nucleus (VMH). Leptin (10 mg/kg, i.p.) was administered 45 min prior to administration of anaesthetic and perfusion fixation of the brain. OffCon = offspring of control dams; OffOb = offspring of obese dams; dl = dorsolateral; vl = ventrolateral. * p<0.05 versus offspring of control dams (n = 4–8).
Figure 7
Figure 7. AgRP- and α-MSH-immunoreactivity in the PVH of offspring of control and obese dams.
Representative brightfield images (A) and quantitative comparisons (B,C) of AgRP-immunoreactivity in the paraventricular hypothalamic nucleus (PVH) and its subdivisions in male offspring of control and obese dams. Representative confocal images (D) and quantitative comparisons (D,E) of AgRP immunofluorescence in the PVH of female offspring of control and obese dams. Representative brightfield images (F) and quantitative comparisons (G,H) of α-MSH-immunoreactivity in the PVH and its subdivisions in male offspring of control and obese dams. OffCon = offspring of control dams (open bars); OffOb = offspring of obese dams (closed bars); mp = medial parvocellular; lm = lateral magnocellular; dp = dorsal parvocellular. * = p<0.05 and ** = p<0.01 versus control. Scale bars = 200 µm.
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