Abstract 059: (Pro)renin Receptor Ablation In Tyrosine Hydroxylase Neurons In The Paraventricular Nucleus Of The Hypothalamus Improves Insulin Sensitivity In Mice Fed A High-fat Diet

Abstract

We recently reported that neuron-specific (pro)renin receptor (PRR) deletion reduces blood pressure (BP), fasting blood glucose (BG) and improves glucose tolerance in high-fat diet (HFD)-treated mice. To investigate underlying mechanisms, we focused on tyrosine hydroxylase (TH) neurons in the hypothalamic paraventricular nucleus (TH PVN neurons), a largely GABAergic population that expresses PRR and projects to autonomic centers important for BP and BG regulation. The PRR was ablated specifically in the TH-positive neurons in the PVN using Cre-LoxP approach. Radio telemetric BP recording, fasting blood glucose (FBG) and frequently sampled intravenous glucose tolerance test (FSIVGTT) were performed following 6-week HFD (60% calories from fat). HFD induced elevation of BP within the first week ( p < 0.05) and maintained elevated during 6-week protocol; however, there was no difference in BP between TH PVN PRRKO and WT control mice in both sexes following HFD. In male mice, the controls had higher FBG when compared with the TH PVN PRRKO mice (144.1 ± 5.74 vs. 121.9 ± 4.34 mg/dl, p < 0.05) at the end of the 6-week HFD treatment. Interestingly, PRR ablation in the TH PVN neurons did not reduce FBG in female mice. The TH PVN PRRKO mice showed improved glucose handling during FSIVGTT (AUC: 3481 ± 247.5 vs. 4263 ± 153.9, p < 0.05), while there was no difference in insulin secretion (AUC: 1782 ± 339.2 vs. 2324 ± 495.6, p > 0.05) between the two groups suggesting that TH PVN PRR ablation attenuates HFD-induced glucose intolerance through either an increase in insulin sensitivity or an insulin-independent pathway. Detected by western blot, the glucose transporter 4, an insulin-dependent glucose transporter, was higher on the plasma membrane of skeletal muscle in the TH PVN PRRKO mice (1.9 ± 0.2 vs. 1.0 ± 0.1, p < 0.05) compared with the controls. The hepatic mRNA expression of glucose-6-phosphatase, a gluconeogenic gene transcriptional negative-regulated by insulin, was lower in the TH PVN PRRKO (0.60 ± 0.07 vs. 0.95 ± 0.10, p < 0.05) compared with the control mice, suggesting improvement of insulin sensitivity in the TH PVN PRRKO mice. In conclusion, PRR ablation in TH PVN neurons attenuates FBG and glucose tolerance through improvement of insulin sensitivity without impacting BP.