From Brain to Pancreas: Beneficial Effects of the Neuronal (Pro)renin Receptor Deletion in High‐fat Diet Induced Type II Diabetes

Abstract

We recently reported that the (pro)renin receptor (PRR) is a key component of the brain renin‐angiotensin system, mediating the majority of Ang II formation, and plays a pivotal role in the development of hypertension. Its importance in obesity‐related metabolic syndrome is, however, unknown. We hypothesize that brain PRR plays a regulatory role in high‐fat diet (HFD) induced metabolic syndrome. To test our hypothesis, neuron‐specific PRR knockout (PRRKO) mice and wildtype (WT) littermates were fed with either HFD (60% calories from fat) or normal fat chow (NFD, 10% calories from fat) with matching calories for 16 weeks. Weekly body weight (BW) and monthly fasting blood glucose (FBG) measurements were recorded and end point glucose tolerance (GTT) and insulin sensitivity tests (IST) were performed. Liver samples were taken and paraffin‐embedded for histology. Plasma insulin and leptin were measured by ELISA using the UC Davis Mouse Metabolic Phenotyping Core service. Neuronal PRR deletion attenuated the elevation of FBG (127.12±10.46 vs. 167.77±16.57 mg/dl, p=0.039) induced by HFD. Glucose tolerance was significantly improved in PRRKO compared with WT following 16 weeks of HFD (AUC: 20557±894 vs. 29994±2976, p=0.006), while there was no significant difference in the IST between the groups. We evaluated the pancreatic islet number and size using H&E staining and found that pancreatic islet size was significantly increased following 6 weeks of HFD (33908±5890 mm, p=0.0005) compared with the NFD (11468±1246 mm) in the WT mice, and was reduced to normal size after 16 weeks of HFD (10991±1389 mm). The islet size was significantly smaller in PRRKO (17059±2968 mm, p=0.034) compared with WT mice following 6 weeks of HFD. More importantly, islets in PRRKO mice remained a similar size following 16 weeks of HFD when compared with WT mice in NFD, indicating that PRRKO may protect against islet hypertrophy in HFD. However, no change in islet number was observed among all groups. Sixteen weeks of HFD slightly increased the fasting plasma insulin level (740±100 pg/ml) compared with the NFD (437±59 pg/ml) in WT mice (p=0.05). Interestingly, the insulin level was significantly higher in the PRRKO (1292±234 pg/ml, p=0.05) compared to the WT mice following 16 weeks of HFD, suggesting a potential beneficial effect of neuronal PRRKO in promoting insulin secretion. Plasma leptin levels were significantly elevated in both WT (25983±3389 pg/ml) and PRRKO (32208±8516 pg/ml) mice following 16 weeks of HFD compared to NFD controls (5014±1022 pg/ml); however, there was no difference between these two groups. Our data indicates that PRR deletion in the neurons attenuates the development of HFD‐induced diabetes, protects against glucose intolerance, pancreatic islet hypertrophy and function during HFD possibly by promoting insulin secretion. We conclude that neuronal PRR plays a regulatory role in the development HFD‐induced type II diabetes.Support or Funding InformationNIH/NHLBI (R01HL122770) and Innovative Research Grant (17IRG33370128) to Y. FengThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.