____________________________________________ Yuriy Usachev ____________________________________________ Huxing Cui ii To the people who believed in me, even when I didn't. iii *oh, be joyful* iv ACKNOWLEDGEMENTS It is so important to me to thank the many individuals without whom this work would not have been possible. I've always believed that science is most successful as a collaborative endeaver, and that together we are greater than the sum of our individual contributions. I wouldn't be the

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... cientist or the person I am today without the support of people who cared about and believed in me. To my mentor, Kamal Rahmouni, for his guidance, patience, and understanding. To the entire Rahmouni lab, especially Don Morgan for his unparalleled technical expertise. To Deng Guo and Ken Muta for always looking out for me, and to Mohamed Rouabhi for letting me look out for you. To Dr. Allyn Mark, who will always be an inspiration and to my thesis committee for investing their time and talents in me. To the mice, for their valiant efforts in the name of science and in spite thereof. To my family, who taught me to be curious, to question dogma, to advocate for what's right, and to leave the world a better place that I found it. And to my James, who lifts me up in every way. I can never thank you enough. v ABSTRACT Secreted by adipose tissue, leptin acts as a signal of energy reserve status, and acts in the brain as a negative feedback mechanism to suppress food intake and increase energy expenditure, the net effect of which is maintenance of energy homeostasis. In addition to its role as a satiety factor, leptin has widespread autonomic effects, increasing sympathetic tone to a variety of tissues, including those involved in arterial pressure regulation. Thus, leptin has been implicated as a critical link between obesity and hypertension. However, the specific mechanisms whereby leptin elicits its diverse effects are not fully understood. This is further complicated by the many sites of leptin action within the brain, as well as its diverse intracellular effects. Here, we investigate the possibility that distinct aspects of leptin function are controlled by different neuronal populations and/or molecular signaling cascades. Specifically, we identify unique roles for leptin action on POMC and AgRP neurons in differentially mediating the regional sympathetic effects of leptin. Furthermore, we show that leptin action via mTORC1 is required for the cardiovascular sympathetic but not the metabolic effects. Together, these findings point to complex neuroanatomical and molecular differences in the mechanisms underlying leptin's effects on different physiological processes, with important implications for future research into obesity-associated hypertension. vi PUBLIC ABSTRACT Obesity is a global health crisis. As the second-leading cause of preventable death in the United States, obesity is a major public health concern primarily because it is a risk factor for numerous co-morbid conditions including cardiovascular disease. The mechanisms underlying the relationship between obesity and hypertension are not fully understood, but previous research has implicated inappropriate actions of the hormone leptin. Leptin circulates in proportion to fat mass and acts on the brain as a signal of energy reserve status, serving as a negative feedback mechanism to prevent excess weight gain by suppressing food intake and increasing energy expenditure, in part through activation of the sympathetic nervous system. Leptin also increases sympathetic nerve activity to a number of tissues involved in cardiovascular regulation. During obesity, patients become resistant to the beneficial metabolic actions of leptin while remaining sensitive to the cardiovascular effects, demonstrating that the mechanisms underlying these processes are somehow distinct. Using genetically modified mouse models to disrupt specific aspects of leptin action, we identified several processes that explain the ability of leptin to differentially control the functions of various tissues. Our findings provide unique insight into the relationship between obesity and hypertension and suggest that the molecular mechanisms linking these diseases could be targeted therapeutically.