Fetal origins of hyperphagia, obesity, and hypertension and postnatal amplification by hypercaloric nutrition

Environmental factors and diet are generally believed to be accelerators of obesity and hypertension, but they are not the underlying cause. Our anima l model of obesity and hypertension is based on the observation that impair ed fetal growth has long-term clinical consequences that are induced by fet al programming. Using fetal undernutrition throughout pregnancy, we investi gated whether the effects of fetal programming on adult obesity and hyperte nsion are mediated by changes in insulin and leptin action and whether incr eased appetite may be a behavioral trigger of adult disease. Virgin Wistar rats were time mated and randomly assigned to receive food either ad libitu m (AD group) or at 30% of ad libitum intake, or undernutrition (UN group). Offspring from UN mothers were significantly smaller at birth than AD offsp ring. At weaning, offspring were assigned to one of two diets [a control di et or a hypercaloric (30% fat) diet]. Food intake in offspring from UN moth ers was significantly elevated at an early postnatal age. It increased furt her with advancing age and was amplified by hypercaloric nutrition. UN offs pring also showed elevated systolic blood pressure and markedly increased f asting plasma insulin and leptin concentrations. This study is the first to demonstrate that profound adult hyperphagia is a consequence of fetal prog ramming and a key contributing factor in adult pathophysiology. We hypothes ize that hyperinsulinism and hyperleptinemia play a key role in the etiolog y of hyperphagia, obesity, and hypertension as a consequence of altered fet al development.