The discovery of a link between in utero experience and later metabolic and cardiovascular disease is one of the most im- portant advances in epidemiology research of recent years. There is increasing evidence that alterations in the fetal en- vironment may have long-term consequences on cardiovas- cular, metabolic, and endocrine pathophysiology in adult life. This process has been termed programming, and we have shown that undernutrition of the mother during gestation leads to programming of hyperphagia, obesity, hypertension, hyperinsulinemia, and hyperleptinemia in the offspring. Us- ing this model of maternal undernutrition throughout preg- nancy combined with postnatal hypercaloric nutrition of the offspring, we examined the effects of IGF-I therapy. Virgin Wistar rats (age 75 5d , n 20 per group) were time mated and randomly assigned to receive food either ad libitum or 30% of ad libitum intake (UN) throughout pregnancy. At wean- ing, female offspring were assigned to one of two diets (control or hypercaloric (30% fat)). Systolic blood pressure was mea- sured at day 175 and following infusion with 3 g/g per day recombinant human IGF-1 (rh-IGF-I) by minipump for 14 d. Before treatment, UN offspring were hyperinsulinemic, hy- perleptinemic, hyperphagic, obese, and hypertensive on both diets, compared with ad libitum offspring and this was exacerbated by hypercaloric nutrition. IGF-I treatment in- creased body weight in all treated animals. However, systolic blood pressure, food intake, retroperitoneal and gonadal fat pad weights, and plasma leptin and insulin concentrations were markedly reduced with IGF-I treatment. IGF-I treat- ment resulted in a 3- to 5-fold increase in 38 - 44 kDa and 28 -30 kDa IGF binding proteins, although in UN animals, there was an impaired and differential up-regulation of these insulin- like growth factor binding proteins following IGF-I treatment. The 24-kDa IGF binding protein representing IGF binding protein-4 was down-regulated in all IGF-I-treated animals, but the decrease was more marked in UN animals. Our data suggest that IGF-I treatment alleviates hyperphagia, obesity, hyperinsulinemia, hyperleptinemia, and hypertension in rats programmed to develop the metabolic syndrome X. (Endocrinology 142: 3964 -3973, 2001)