Abstract
The prevalence of obesity among pregnant women is increasing. Evidence from human cohort studies and experimental animals suggests that offspring cardiovascular and metabolic function is compromised through early life exposure to maternal obesity. Previously, we reported that juvenile offspring of obese rats develop sympathetically mediated hypertension associated with neonatal hyperleptinemia. We have now addressed the hypothesis that neonatal exposure to raised leptin in the immediate postnatal period plays a causal role. Pups from lean Sprague-Dawley rats were treated either with leptin (3 mg/kg IP) or with saline twice daily from postnatal day 9 to 15 to mimic the exaggerated postnatal leptin surge observed in offspring of obese dams. Cardiovascular function was assessed by radiotelemetry at 30 days, and 2 and 12 months. In juvenile (30 days) leptin-treated rats, hearts were heavier and night-time (active period) systolic blood pressure was raised (mm Hg; mean ± SEM: male leptin-treated, 132 ± 1 versus saline-treated, 119 ± 1, n=6, P<0.05; female leptin-treated, 132 ± 2 versus saline-treated, 119 ± 1, n=6, P<0.01), and the pressor response to restraint stress and leptin challenge increased compared with saline-treated rats. Heart rate variability demonstrated an increased low:high frequency ratio in 30-day leptin-treated animals, indicative of heightened sympathetic efferent tone. Echocardiography showed altered left ventricular structure and systolic function in 30-day female leptin versus saline-treated rats. These disorders persisted to adulthood. In isolated hearts, contractile function was impaired at 5 months in male leptin-treated rats. Exogenously imposed hyperleptinemia in neonatal rats permanently influences blood pressure and cardiac structure and function.
Highlights
The prevalence of obesity among pregnant women is increasing
We observed that juvenile offspring of obese rats have aberrant autonomic control of blood pressure (BP) resulting in hypertension, which occurs before the development of increased adiposity and persists into adulthood,[7] and that these animals demonstrate hyperphagia and leptin resistance associated with a functional, structural, and cell-signaling deficit in leptin-sensitive processes in the arcuate nucleus and paraventricular nucleus of the hypothalamus.[9]
We reported that the offspring of obese dams (OffOb) exhibit an exaggerated and prolonged physiological postnatal serum leptin surge,[9] known to play a critical role in the development of the normal rodent hypothalamus.[13]
Summary
The prevalence of obesity among pregnant women is increasing. Evidence from human cohort studies and experimental animals suggests that offspring cardiovascular and metabolic function is compromised through early life exposure to maternal obesity. Studies of maternal calorie-rich diets and obesity in rodents, sheep, and nonhuman primates have provided unequivocal evidence for persistent and adverse influences on the offspring.[5] We and others have repeatedly observed cardiovascular dysfunction secondary to maternal obesity in animal models.[6,7,8] Previously, we observed that juvenile offspring of obese rats have aberrant autonomic control of blood pressure (BP) resulting in hypertension, which occurs before the development of increased adiposity and persists into adulthood,[7] and that these animals demonstrate hyperphagia and leptin resistance associated with a functional, structural, and cell-signaling deficit in leptin-sensitive processes in the arcuate nucleus and paraventricular nucleus of the hypothalamus.[9] The cardiovascular response to exogenous leptin, which is mediated through hypothalamic sympathetic efferent activity,[10,11] was, enhanced.[7] This differential response to leptin, sometimes termed selective leptin resistance, had been observed in rodents, but previously only in association with chronic obesity.[12] We reported that the offspring of obese dams (OffOb) exhibit an exaggerated and prolonged physiological postnatal serum leptin surge,[9] known to play a critical role in the development of the normal rodent hypothalamus.[13] We hypothesized that neonatal exposure to supranormal leptin concentrations during this important window of hypothalamic plasticity may play a causal role in offspring cardiovascular. Because the heart weight is increased in offspring of obese rats[9,14] and mice[15] and because leptin has been implicated in neonatal rodent cardiomyocyte proliferation and remodeling,[16,17] we studied the morphology of the heart, and cardiac function as assessed in vivo and ex vivo
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