Roles of Sphingosine Kinase 1 in adipocyte thermogenesis

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Project Summary Obesity is a health crisis in America that affects both adults and children and leads to many adverse health outcomes. Therefore, novel approaches to treating obesity are of intense interest. Brown and beige adipose tissue has been the focus of many recent obesity-related studies. Brown and beige adipocytes have a high mitochondria content, and fatty acid oxidation is enhanced. Furthermore, because these tissues express Uncoupling Protein 1 (UCP1), a significant portion of energy from fatty acid metabolism is lost from heat. While the existence of brown adipose in humans is controversial, recent studies have focused on the process by which white adipocytes convert to beige, thermogenic adipocytes, because if this process could be deliberately regulated it would result in decreased adipose tissue and hence constitute a potential treatment for obesity. This proposal aims to shed light on a novel function of Sphingosine Kinase 1. β₃ adrenergic receptor stimulation promotes conversion of white adipocytes to beige (“beiging”). My preliminary data show that in vivo stimulation of β₃ adrenergic receptor with CL 316243 (CL) increases Ucp1 and SphK1 mRNA. Even further, these results were recapitulated in vitro where β₃ adrenergic receptor stimulation of white WT adipocytes showed increased SphK1 and Ucp1 mRNA expression, which was attenuated in SphK1-deficient white adipocytes. Additionally, SphK1 null adipocytes were unable to induce PGC1α and PGC1β, both of which are co-activators of transcription factors for UCP1, the driver for thermogenesis. Based on these preliminary data, I hypothesize that SphK1 mediates beiging of white adipocytes resulting in mitochondrial uncoupling, leading to adipose tissue thermogenesis. This project is divided into two aims to accomplish this goal. Aim 1 will investigate the role of SphK1 in adipocyte beiging in vivo and in vitro, and aim 2 will elucidate the mechanism(s) by which SphK1 regulates beiging in adipocytes. The experiments proposed here will establish the importance of SphK1 in the conversion of white adipocytes to beige and its role in thermogenesis in vivo. Additionally, this proposal will determine the pathway via which SphK1 signals to control adipocyte thermogenesis. Therefore, my study will reveal a new link between SphK1 signaling and adipocyte thermogenesis, which may then serve as a potential novel therapeutic target to reduce obesity.