Transgenerational Inheritance of Obesity and Hypertension: Hypothalamic Regulation in Leptin mediated Sympathoexcitation
Authors: Lim Kyungjoon (Joon) , Burke Sandra L , Jackson Kristy L , Sata Yusuke , Head Geoffrey A 
Published: November 2023

BackgroundMaternal obesity is associated with a greater risk of developing hypertension in the offspring. Circulating leptin is closely linked to the control of sympathetic nerve activity (SNA) and blood pressure (BP) in the central nerve system (CNS). The ventromedial hypothalamus (VMH) is a key center of energy homeostasis, hemodynamic and sympathetic tone to renal vasculature. Exposure to overnutrition during early development changes the activity of the neurons and the receptors in the CNS, amplifying sympathetic output which leads to hypertension. Importantly, obesity can alter the neurons in adulthood as well. Hence, we assessed the effects of maternal high fat diet (HFD) feeding during pregnancy or in adult offspring on cardiovascular variables and sympathetic nerve activity (SNA) with changes in leptin and insulin signaling pathways.MethodsBreeder rabbits were fed a HFD (13%; HFD) or a control diet (4%; CD) during pregnancy and lactation. Offspring received CD after weaning. Offspring from control breeders (mCD) were subdivided and fed with HFD for 10days (mCD10d) at 15 weeks of age. All rabbits had a VMH cannula and a renal nerve recording electrode. Mean arterial pressure (MAP), heart rate (HR) and renal sympathetic nerve activity (RSNA) were measured at baseline and after receiving increasing doses of αMSH (α‐Melanocortin stimulating hormone, 0.3, 1nmol), SHU9119 (melanocortin receptor antagonist, 0.02, 0.04nmol), leptin receptor antagonist (5, 10μg) or insulin receptor antagonist (0.01, 0.05U). Hypothalamic expression of leptin receptor (LepR), brain derived neurotrophic factor (BDNF) and Phosphoinositide 3‐kinase(PI3K) was examined using real‐time PCR.ResultsOffspring from HFD fed rabbits (mHFD) showed higher MAP (+11%) and RSNA (+42%) than controls in adulthood (P<0.05). mCD10d rabbits showed increased MAP, HR and RSNA compared to mCD rabbits and showed highest MAP and HR in all groups (+11% and +14% than mHFD rabbits). αMSH into the VMH increased MAP, HR and RSNA (+6.6±1mmHg, +23.4±3.45 b/min and +3.66±0.7nu) and SHU9119 reduced MAP and RSNA (−5.6±0.8mmHg, −1.3±0.13 nu) in mHFD rabbits. Leptin receptor antagonist normalized hypertension (−5.8±0.8mmHg) in mHFD rabbits (P<0.05). There were trends of reduced MAP (P=0.056) and HR (P=0.06) by leptin receptor antagonist into the VMH of mCD10d rabbits. SHU9119 lead to reduction in MAP and HR (P<0.01) in mCD10d rabbits. Insulin receptor antagonist administration into the VMH showed dose dependent reduction in MAP (P<0.01) of mCD10d rabbits only. Offspring from maternal HFD rabbits exhibited an increase in LepR, PI3K and BDNF expression in the hypothalamus compared to the control group (+47%, +26% and +74%). mCD10d rabbits had higher expression of MC3R (54%) than mCD rabbits.ConclusionExposure to over‐nutrition during early development or in adulthood leads to altered leptin and MC signaling pathways, possibly due to programming of the key receptors and/or by neuronal plasticity, leading to sympathoexcitation and hypertension.