(Pro)Renin Receptor in the Hypothalamic Tyrosine Hydroxylase‐Containing Neurons Contributes to High Fat Diet Induced Hyperglycemia

Abstract

Type 2 diabetes mellitus (T2D) is the major form of human diabetes, accounting for approximately 90–95% of diagnosed diabetes cases in the United States. The brain renin-angiotensin system (RAS), traditionally viewed as a cardiovascular regulatory system, has recently emerged as a critical part of metabolic and energy-expenditure signaling systems in the central nervous system (CNS). The (pro)renin receptor (PRR) is a key component of the brain RAS and plays a pivotal role in the development of hypertension. However, its importance in high fat diet (HFD)-induced metabolic physiology is not well understood. We recently showed that neuron-specific PRR deletion (PRRKO) improves fasting blood glucose and glucose tolerance in mice under 16 weeks of HFD. However, the specific neuronal cell types and synaptic mechanisms by which PRR acts is largely unknown. Tyrosine Hydroxylase (TH)-containing neurons are catecholaminergic neurons found in multiple regulatory nuclei throughout the brain. The TH neurons in the paraventricular nucleus (PVN, THPVN) have been previously implicated in metabolic and cardiovascular control via inhibition of brainstem regulatory nuclei. Accordingly, we hypothesize that PRR in THPVN neurons plays a critical role in the regulation of HFD-induced hyperglycemia. To test this hypothesis we injected male PRR-LoxP mice with adeno-associated virus serotype 2 (AAV2)-mediated Cre-recombinase driven by a rat TH promoter (AAV2-TH-Cre) to ablate PRR in the THPVN neurons (THPVN PRRKO) or AAV2-eGFP (Control) prior to 6 week HFD (60% calories from fat) treatment. Fasting blood glucose (FBG), glucose and insulin tolerance tests were performed to assess glucose handling and development of hyperglycemia following HFD. PRR-LoxP mice had significantly higher FBG when compared with the THPVN PRRKO mice (139.3 ± 6.551 vs. 118.0 ±3.715 mg/dl, P= 0.0409) and trended towards improved glucose tolerance when compared with the control mice following the treatment period (Area under the curve-AUC: 12990 ± 1494 vs. 9035 ± 1354, P=0.0782), suggesting that THPVN PRRKO protects against hyperglycemia and may improve glucose tolerance after 6 weeks HFD treatment. No significant difference between the two groups was observed in the insulin tolerance test (AUC: 10833 ± 727.7 vs. 10135 ± 729.5, P=0.7142), suggesting a possible mechanism of THPVN PRR glycemia regulation independent of insulin resistance. These data indicate a critical role of THPVN PRR in the regulation of HFD-induced hyperglycemia and a potential pathway for understanding the mechanism behind the metabolic action of neuronal PRR.