title: Experimental hyperleptinemia in neonatal rats leads to selective leptin responsiveness, hypertension, and altered myocardial function.
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.
authors.affiliation: Division of Women's Health, Women's Health Academic Centre, London SE1 7EH, United Kingdom. Anne-Maj.Samuelsson@kcl.ac.uk
authors.forename: Anne-Maj
authors.initials: AM
authors.lastname: Samuelsson
authors.forename: James
authors.initials: J
authors.lastname: Clark
authors.forename: Olena
authors.initials: O
authors.lastname: Rudyk
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Shattock
authors.forename: Sung Eun
authors.initials: SE
authors.lastname: Bae
authors.forename: Timothy
authors.initials: T
authors.lastname: South
authors.forename: Joaquim
authors.initials: J
authors.lastname: Pombo
authors.forename: Kathrine
authors.initials: K
authors.lastname: Redington
authors.forename: Esna
authors.initials: E
authors.lastname: Uppal
authors.forename: Clive W
authors.initials: CW
authors.lastname: Coen
authors.forename: Lucilla
authors.initials: L
authors.lastname: Poston
authors.forename: Paul D
authors.initials: PD
authors.lastname: Taylor
mesh_terms: D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D000818:Animals; D000831:Animals, Newborn; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D001835:Body Weight / Q000187:drug effects / Q000502:physiology; D002319:Cardiovascular System / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D005260:Female; D006321:Heart / Q000187:drug effects / Q000503:physiopathology*; D006339:Heart Rate / Q000187:drug effects / Q000502:physiology; D006973:Hypertension / Q000378:metabolism* / Q000503:physiopathology; D020738:Leptin / Q000097:blood* / Q000494:pharmacology; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects / Q000502:physiology; D009206:Myocardium / Q000378:metabolism*; D009765:Obesity / Q000378:metabolism / Q000503:physiopathology; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000378:metabolism* / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D020738:Leptin
keywords: developmental programming; hypertension; leptin; obesity; rats; sympathetic nervous system; ventricular dysfunction