Targeting hypothalamic astrocytes in obesity-associated hypertension

About This Grant

PROJECT SUMMARY / ABSTRACT Obesity is a leading cause for primary hypertension, with >70% of the cases are estimated to be associated with elevated BMI. Chronic overnutrition alters brain circuits with the help of elevated adipose hormone leptin, causing increased sympathetic outflow and blood pressure (BP). Hypothalamic inflammation is a major hallmark of obese brain and abundantly contains features like reactive astrogliosis. Astrocytes are an integral part of leptin responsive circuits; they express leptin receptors and morphologically interact with melanocortin pathway neurons. Moreover, impairing leptin receptor signaling or inflammation selectively in astrocytes is sufficient to protect against hypertension, suggesting that obesity induced astrocytic adaptations play causal role in cardiovascular sequela. However, how overnutrition and subsequent inflammation change key astrocytic intracellular activity of Ca2+ and cAMP in vivo remains elusive. This is an important knowledge gap given the established functional roles played by these signaling molecules. Additionally, how astrocytic activity affects neighboring leptin responsive neurons in normal and obese states is unknown. Using in vivo fiber photometry imaging, we found that hypothalamic astrocytes display spontaneous Ca2+ waves. To understand its functional role, we used chemogenetics (hM3Dq) to increase Ca2+ and found that stimulating mediobasal hypothalamic astrocytes increased AgRP neuron activity and reduced renal sympathetic activity (rSNA). Importantly, leptin suppressed the baseline Ca2+ waves in astrocytes. Based on these findings, we hypothesized that tonic Ca2+ activity in astrocytes stimulates AgRP neurons to inhibit melanocortin pathway and acts as a brake on autonomic output. Suppression of this activity by elevated leptin, as seen in obesity, removes astrocytic brakes on sympathetic outflow and drives hypertension. Here we will test this hypothesis with the following complementary goals: aim 1 will use chemogenetics to modulate astrocytic Ca2+ and cAMP levels to uncover precise nature of interaction between astrocytic activity and rSNA, BP and heart rate (HR). Using in vivo fiber photometry, we will also monitor astrocytes’ impact on the activity of melanocortin pathway neurons (AgRP, POMC and MC4R), which mediates leptin induced hypertension. Aim 2 will determine how high fat diet induced obesity alters Ca2+ and cAMP dynamics in hypothalamic astrocytes in vivo and whether chemogenetically restoring this activity is sufficient to ameliorate hypertension. Collectively, these two aims will uniquely bring together expertise from two laboratories specialized on hypothalamic circuits of energy homeostasis and cardiovascular regulation. By employing a set of state-of-the-art approaches, successful completion of these aims will provide unprecedented insights into the mechanism(s) by which astrocytes contribute to obesity induced hypertension. Ultimately, these studies will likely provide novel therapeutic targets by unveiling the untapped potential of astrocytes for antihypertensive medicine.