Obesity is a rapidly escalating epidemic that accounts for more health care expenditures in the US than any other medical condition, amounting to over $100 billion per year. One severe cardiovascular consequence is hypertension, due in part to increased sympathetic nerve activity (SNA) to muscle and the kidneys. However, the mechanisms have not been identified. In parallel to previous studies with leptin, our recent data indicate that obesity markedly amplifies the sympathoexcitatory effects of brain insulin, suggesting that insulin may play a greater role than previously appreciated. Our major goal is to identify the cellular-molecular mechanisms of this sensitization, which are currently unknown. We propose that obesity sensitizes insulin's site of action in the control of SNA, the hypothalamic arcuate nucleus (ArcN). Several lines of indirect evidence suggest that this sensitization is mediated by increased ArcN angiotensin II (AngII) AT1R activation. First, plasma AngII levels are increased in obese humans and rats with diet-induced obesity (DIO). Second, systemic AngII blockade prevents the acute increases in SNA and the chronic hypertensive actions of insulin. Third, hypertension in DIO rats is reversed by systemic blockade of the renin-angiotensin system (RAS), and treatment of obese humans with blockers of the RAS decreases SNA. Finally, the ArcN expresses AT1aR, and microinjection of AngII into the ArcN increases MAP and SNA. Therefore, we hypothesize that obesity-induced increases in AngII amplify the actions of ArcN insulin to increase SNA. We have chosen rodent models of DIO to test this hypothesis, because of broad similarities to the human condition. We will use complementary approaches, including brain nanoinjection of selective inhibitors and the measurement of the changes in activity of multiple sympathetic nerves, Western/qPCR analysis of microdissected hypothalamic tissue, and electrophysiologic recordings and immunocytochemistry of identified ArcN neurons to systematically dissect the interdependency of InsR and AT1R in Neuropeptide Y and pro-opiomelanocortin neurons in the ArcN to elevate basal SNA. This core information coupled with DREADDs technology and the use of viral vectors to chronically knockdown InsR or AT1R in the ArcN of obese and lean rats will allow us to establish the role of these neuromodulators as contributors to sympathoexcitation and ultimately to hypertension development and end organ damage in obese subjects.

Public Health Relevance

Obesity is a rapidly escalating epidemic that accounts for more health care expenditures in the US than any other medical condition. One serious consequence is hypertension, due in part to increased sympathetic nerve activity to muscle and the kidneys. However, the mechanisms are unclear. This proposal will establish in rats and mice that interactions of angiotensin and insulin in the brain form the basis for this sympathoexcitation. As a result, this work may reveal new therapeutic avenues of treatment for the tonic excitation of the sympathetic nervous system in obesity.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL128181-04
Application #
9609478
Study Section
Hypertension and Microcirculation Study Section (HM)
Program Officer
Charette, Marc F
Project Start
2016-01-15
Project End
2020-12-31
Budget Start
2019-01-01
Budget End
2020-12-31
Support Year
4
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Oregon Health and Science University
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
096997515
City
Portland
State
OR
Country
United States
Zip Code
97239
Komegae, Evilin Naname; Farmer, David George Stephen; Brooks, Virginia Leah et al. (2018) Vagal afferent activation suppresses systemic inflammation via the splanchnic anti-inflammatory pathway. Brain Behav Immun 73:441-449
Shi, Zhigang; Madden, Christopher J; Brooks, Virginia L (2017) Arcuate neuropeptide Y inhibits sympathetic nerve activity via multiple neuropathways. J Clin Invest 127:2868-2880
Cassaglia, Priscila A; Shi, Zhigang; Brooks, Virginia L (2016) Insulin increases sympathetic nerve activity in part by suppression of tonic inhibitory neuropeptide Y inputs into the paraventricular nucleus in female rats. Am J Physiol Regul Integr Comp Physiol 311:R97-R103