The Role of the Neuronal (Pro)Renin Receptor in the Regulation of Blood Glucose
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Authors
Worker, Caleb
Issue Date
2022
Type
Dissertation
Language
Keywords
Brain , Diabetes , Hypertension , Hypothalamus , PVN , Renin
Alternative Title
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 prorenin receptor (PRR) is a key component of the brain RAS and plays a pivotal role in the development of hypertension. The neuronal PRR is known to mediate formation of the majority of angiotensin (Ang) II—a key bioactive peptide of the RAS—in the central nervous system and to regulate blood pressure and cardiovascular function. However, its importance in high fat diet (HFD)-induced cardiometabolic physiology is not well understood. Here, we show that PRR deletion in neurons reduces blood pressure, neurogenic pressor activity and fasting blood glucose, and improves glucose tolerance without affecting food intake or body weight following a 16-week HFD. Mechanistically, we found that a HFD increases levels of the PRR ligand, (pro)renin, in the circulation and hypothalamus, and of Ang II in the hypothalamus, indicating activation of the brain RAS. Importantly, PRR deletion in neurons reduced astrogliosis and activation of the astrocytic NF-B p65 (RelA) in the arcuate nucleus and the ventromedial nucleus of the hypothalamus. Collectively, our findings indicate that the neuronal PRR plays essential roles in overnutrition-related metabolic pathophysiology. However, the specific neuronal cell types and synaptic mechanisms by which PRR acts in the regulation of blood glucose is largely unknown. Tyrosine Hydroxylase (TH)-containing neurons are catecholaminergic neurons found in multiple regulatory nuclei throughout the brain, and TH neurons (THPVN) in the paraventricular nucleus (PVN) have been previously implicated in metabolic and cardiovascular control via projections to brainstem regulatory nuclei. We demonstrate here that PRR in THPVN neurons plays a critical role in the regulation of HFD-induced hyperglycemia. We report here that THPVN PRR knockout ameliorates HFD-induced elevation in blood glucose and improves glucose handling in male mice following a 6-week diet without affecting body weight, food intake, or insulin tolerance. THPVN PRRKO also results in increased energy expenditure and metabolism at the end of the 6 week diet, as measured by indirect calorimetry using a metabolic cage. Mechanistically, we observed no significant effect of THPVN PRRKO on the expression of enzymes associated with production of glucose in the liver, but instead saw improvements in proteins associated with glucose uptake in skeletal muscle and thermogenic activity in brown adipose tissue using western blot. These data suggest that PRR knockout in THPVN neurons attenuates the development of glucose dysregulation and elevates energy expenditure in mice following HFD. We conclude that PRR THPVN neurons play a key regulatory role in glucose and metabolic regulation.