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Leptin Receptors in Pro‐opiomelanocortin Neurons Involved in Blood Pressure and Glucose Homeostasis in Intrauterine Growth Restriction (IUGR) Mice

Intrauterine growth restriction (IUGR) or low birth weight has long been recognized as a risk factor for hypertension and metabolic diseases in later life. However, the underlying mechanisms remain unclear. The global prevalence of low birthweight ranges from 15–20% of all births, a percentage representing 20 million births each year. In the developed world, reduced uteroplacental perfusion, a common characteristic of preeclamptic pregnancies, is the main cause of low birth weight. We previously reported that mouse IUGR offspring exhibit high blood pressure and increased adiposity and serum leptin levels compared to control offspring. Leptin is a peptide hormone secreted mainly by adipocytes and act through the central nervous system to regulate appetite, energy expenditure and sympathetic nervous system. However, the effect of brain leptin receptors (LR), especially in pro‐opiomelanocortin (POMC) neurons, on blood pressure and metabolic status of IUGR offspring have never been investigated. The objective of this study was to test the hypothesis that conditional deletion of LR in POMC neurons of IUGR mice can protect against developmental programed hypertension and metabolic disorders. Pregnant wild type (WT) C57BL [crossed with WT) or LR Fox/fox [crossed with male LR Fox/fox POMC Cre ] mice either went through reduced uterine perfusion operation to induce IUGR in their litters or were sham operated and had their litters serve as controls. IUGR offspring had lower birth weights than controls (P<0.01) regardless of sex or strain. Offspring of WT and LR Fox/fox POMC Cre (LRP) were subjected to blood pressure measurements in their conscious state by carotid artery cannulation. Metabolic status including fasting blood glucose and intraperitoneal glucose tolerance test (IPGTT) (n=7–12) were also measured. Blood pressure was significantly decreased in male control LRP and IUGR LRP when compared to their same sex WT (P<0.05) counterparts. No statistical difference in MAP pressure was detected between IUGR and control female mice in both the genotypes. LR deletion decreased fasting blood glucose in male IUGR compared to male IUGR WT (67.7±2.5 vs. 85.8±3.4 mg/dL, P<0.01; IUGR LRP vs. IUGR WT, respectively). Both control LRP and IUGR LRP female had significantly decreased fasting blood glucose compared to the same sex WT strain (control WT 96.7±3.6, IUGR WT 105.8±2.9, control LPR 77.5±2.4, IUGR LPR 79.6±6.0 mg/dL). IPGTT showed both male and female IUGR WT have a significantly increased area under the curve (AUC) when compared to their WT control, and LPR restored the impaired IPGTT of IUGR in both sexes (P<0.05). Our findings suggest that the leptin POMC signaling pathway regulates glucose homeostasis in IUGR mouse offspring.