IGF-I treatment reduces hyperphagia, obesity, and hypertension in metabolic disorders induced by fetal programming

The discovery of a link between in utero experience and later metabolic and cardiovascular disease is one of the most important advances in epidemiolo gy research of recent years. There is increasing evidence that alterations in the fetal environment may have long-term consequences on cardiovascular, metabolic, and endocrine pathophysiology in adult life. This process has b een termed programming, and we have shown that undernutrition of the mother during gestation leads to programming of hyperphagia, obesity, hypertensio n, hyperinsulinemia, and hyperleptinemia in the offspring. Using this model of maternal undernutrition throughout pregnancy combined with postnatal hy percaloric nutrition of the offspring, we examined the effects of IGF-I the rapy. Virgin Wistar rats (age 75 +/- 5 d, n = 20 per group) were time mated and randomly assigned to receive food either ad libitum or 30% of ad libit um intake (UN) throughout pregnancy. At weaning, female offspring were assi gned to one of two diets (control or hypercaloric [30% fat]). Systolic bloo d pressure was measured at day 175 and following infusion with 3 mug/g per day recombinant human IGF-1 (rh-IGF-I) by minipump for 14 d. Before treatme nt, UN offspring were hyperinsulinemic, hyperleptinemic, hyperphagic, obese , and hypertensive on both diets, compared with ad libitum offspring and th is was exacerbated by hypercaloric nutrition. IGF-I treatment increased bod y weight in all treated animals. However, systolic blood pressure, food int ake, retroperitoneal and gonadal fat pad weights, and plasma leptin and ins ulin 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 bin ding proteins, although in UN animals, there was an impaired and differenti al up-regulation of these insulinlike growth factor binding proteins follow ing IGF-I treatment. The 24-kDa IGF binding protein representing lGF bindin g protein-4 was down-regulated in all IGF-I-treated animals, but the decrea se was more marked in UN animals. Our data suggest that IGF-I treatment all eviates hyperphagia, obesity, hyperinsulinemia, hyperleptinemia, and hypert ension in rats programmed to develop the metabolic syndrome X.