Role of FGF21 Action in Hypothalamic Neurons in Obesity-Associated Hypertension

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Project Summary / Abstract Hypertension affects one billion people and is a principal reversible risk factor for cardiovascular disease. Obesity which has become common in the US and throughout the world is a major cause of hypertension, but the mechanisms underlying the relationship between obesity and hypertension remain largely unknown. The goal of this proposal is to identify the neuronal and molecular processes that control blood pressure and how dysregulation in these processes contribute to obesity-associated cardiovascular risks. This proposal is based on the hypothesis that obesity-induced elevation in the hormone fibroblast growth factor 21 (FGF21) promotes hypertension by activating ventromedial hypothalamic neurons expressing steroidogenic factor 1 (SF1) to increase sympathetic nerve activity. We will use a multidisciplinary strategy combining cutting edge neuro- technologies to precisely and remotely modulate or monitor the activity of SF1 neurons in freely moving animals with unique genetically engineered mouse models that permit selective modulation of FGF21 signaling in SF1 neurons and sophisticated integrative physiology for sympathetic and cardiovascular phenotyping. We plan to test our central hypothesis by determining how chemogenetic- or optogenetic-mediated activation or inhibition of SF1 neuron activity affects sympathetic outflow and arterial pressure under normal conditions as well as in obesity. We will also explore the contribution of FGF21 signaling in ventromedial hypothalamus including SF1 neurons to sympathetic and arterial pressure control and obesity-associated hypertension and sympathetic nerve activation. This work should unravel novel mechanisms that underlie obesity-associated sympathetic activation and hypertension, making our work of high clinical relevance. Insights into the cellular and molecular processes that control the sympathetic tone that regulates cardiovascular function may make it possible to selectively interfere with the damage obesity inflicts on cardiovascular sympathetic functions.