Fetal Programming Of Endocrine Function In Iugr Offspring Depends On The Cause Of Low Birth Weight: Evidence From Animal Models And The Human Fips-Study

Low birth weight and intrauterine growth restriction (IUGR) can be caused by a number of different conditions, which are not accounted for in many experimental settings. Therefore, the objective of our present studies is to analyze the impact of different causes of low birth weight on fetal programming of endocrine function using the example of two key candidate molecules: IGF-1 and leptin.Methodologically, we have established two different models of intrauterine growth restriction in the rat - the model of bilateral uterine artery ligation (UAL) and the model of low protein nutrition (LPN). In humans, we have established a prospective multicenter study ("FIPS") studying placental tissue and umbilical cord blood from growth-restricted neonates with anomalous placental Doppler velocimetry (IUGR), small for gestational age neonates with normal placental Doppler (small for gestational age [SGA]) and healthy controls (appropriate for gestational age [AGA]).Our results indicate that fetal programming of leptin and IGF-1 depends on the cause of low birth weight rather than birth weight itself. UAL and LPN both induce IUGR but have opposing impacts on placental as well as fetal hepatic leptin and IGF-1 gene expressions at birth. In addition to differing windows of exposure, we speculate that availability of nutrients and occurrence of hypoxia, respectively, might be the pivotal differences leading to distinct programming. In humans, the underlying cause for fetal programming of metabolic disease via reduced neonatal free leptin might be prenatal unfavorable placental environment (IUGR, as evidenced by reduced placental perfusion), not low birth weight (SGA). In conclusion, morbidity after low birth weight should be analyzed referring to the underlying pathophysiological cause rather than referring to low birth weight itself.