Neuronal Mechanisms of Obesity-Induced Hypertension

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The high prevalence of obesity among the veterans is a major challenge for the VA healthcare system. This is because obesity is associated with increased sympathetic nerve traffic leading to hypertension, a major risk factor for end-organ damage, stroke, myocardial infarction and congestive heart failure. However, the cellular and molecular etiology of obesity-associated cardiovascular risks remain poorly understood. We and others have previously demonstrated the importance of the brain mechanisms in the pathophysiology of obesity- induced sympathetic activation and hypertension. Brain action of leptin and the melanocortinergic system have emerged as major drivers of the increase in sympathetic nerve traffic and blood pressure in obesity. Studies from our lab also revealed the importance of the mechanistic target of rapamycin complex 1 (mTORC1) in the control of sympathetic nerve activity and blood pressure. Moreover, we provide compelling preliminary data demonstrating that disruption of mTORC1 signaling in the leptin receptor (LepRb)-containing neurons interfere selectively with the ability of leptin to increase renal sympathetic activity and blood pressure. Notably, mTORC1 disruption in the LepRb neurons protect mice from the sympathetic overdrive and hypertension evoked by diet-induced obesity without affecting weigh gain and adiposity. Moreover, we identified serine peptidase inhibitor A3N (SerpinA3N) as a novel gene downstream to mTORC1 signaling. This led us to hypothesize that mTORC1 signaling and SerpinA3N in the LepRb neurons mediate obesity-induced sympathetic nerve activation and hypertension. We will test our hypothesis by examining the transcription mechanisms that regulate SerpinA3N gene. In addition, we will investigate the role of SerpinA3N in the control of sympathetic nerve traffic, arterial pressure and obesity-associated hypertension and sympathetic nerve activation. We will also dissect the neurocircuit underlying the protection conferred by disruption of mTORC1 signaling in LepRb neurons on obesity-induced hypertension and sympathetic nerve activation. This research will advance understanding of the mechanisms underlying the sympathetic overdrive and hypertension associated with obesity that has become common in the VA population.