Maternal food restriction during pregnancy results in intrauterine growth-restricted (IUGR) newborns with significantly decreased plasma
leptin levels. When nursed by ad libitum-fed controls, IUGR offspring exhibit
hyperphagia with adult
obesity, marked by increased percentage body fat and plasma
leptin, suggesting altered anorexigenic pathways. The authors examined
leptin signaling pathways and food intake responses to 2 putative anorexic effectors (
leptin and
sibutramine, a
serotonin reuptake inhibitor) in IUGR offspring. From 10 days to term gestation and through lactation, control pregnant rats received ad libitum food, whereas study rats were 50% food restricted. Following birth, litter size was standardized, and all offspring were nursed by control dams. At 3 weeks of age, offspring were weaned to ad libitum laboratory chow. At ages 1 day and 3 weeks, hypothalamic
leptin receptor (Ob-Rb)
mRNA and total
STAT3 protein expression were determined. In addition, phosphorylated STAT3 was measured in 1-day-old offspring administered peripheral
leptin. In prepubescent and adult offspring, anorexic effects of
leptin and
sibutramine were determined. At 1 day of age, IUGR pups showed increased hypothalamic Ob-Rb
mRNA and total
STAT3 protein expression though reduced
leptin activated phosphorylated STAT3. At 3 weeks of age, IUGR offspring had decreased hypothalamic Ob-Rb
mRNA expression, although with continued elevated
STAT3 protein levels. The IUGR offspring demonstrated resistance to anorexigenic agents,
leptin (6 weeks and 6 months), and
sibutramine (8 months), as evidenced by less reduction in food intake and less
body weight loss than controls. The IUGR offspring demonstrate suppressed
leptin-induced STAT3 phosphorylation and impaired anorexigenic response to 2 factors in the central satiety pathway. This reduced anorexigenic function, together with normal or perhaps enhanced orexigenic function, contributes to the development of programmed
obesity in IUGR rat offspring.