Maternal Obesity Induced by Diet in Rats Permanently Influences Central Processes Regulating Food Intake in Offspring

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

Behavioural responses to leptin in juvenile and adult offspring of control and obese dams.

<p>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, <i>versus</i> offspring of control dams (n = 6).</p

Signalling responses to leptin in juvenile and adult offspring of control and obese dams.

<p>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 <i>versus</i> offspring of control dams (n = 4–8).</p

Constituents of milk from control and obese dams by analysis of pups' stomach contents.

<p>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 <i>versus</i> 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.</p

AgRP- and α-MSH-immunoreactivity in the PVH of offspring of control and obese dams.

<p>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 <i>versus</i> control. Scale bars = 200 µm.</p