Regulation of Lipolysis by Oxytocin

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ABSTRACT Adipose tissue lipolysis is a critical process that provides nutritional substrate to other organs during periods of fasting. Lipolysis also contributes to the metabolic pathology associated with obesity, as lipid species from adipose tissue promote hepatic glucose production and are also an important contributor to the excess fat seen in nonalcoholic fatty liver disease. Despite the importance of lipolysis in mammalian physiology and pathophysiology, there is still much to be learned about how it is regulated and what its consequences are. There have been reports over the years that the neuropeptide oxytocin (Oxt) is an inducer of lipolysis. Our preliminary data corroborates this, but goes much further in several important areas. First, we show that Oxt signaling is not only required for normal lipolysis in the setting of fasting and cold exposure, but is also needed for b-adrenergic agonists to exert their well-known pro-lipolytic effects. We also identify the relevant source of Oxt as a subpopulation of TH+ sympathetic neurons innervating white adipose depots. In this proposal we intend to fully characterize the intracellular signaling pathways by which Oxt promotes lipolysis. In addition, we will determine the local mechanism by which Oxt levels are controlled through degradation. Finally, we will follow up on preliminary data suggesting that maternal Oxt signaling in fat is required to ensure milk of proper nutritional content during lactation. Taken together, these studies will greatly advance our understanding of lipolysis. Furthermore, Oxt is being pursued as a pharmacological therapy for a variety of conditions, including anxiety and neurodegenerative disorders, and this work will provide important information about potential metabolic side effects.