Roles of Sphingolipids in the Pathophysiology of Obesity and Diabetes

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The rise in obesity has led to increased prevalence of metabolic disease including diabetes, fatty liver disease, cardiovascular disease, and others. Veterans suffer from these diseases at a disproportional rate relative to the general population. Additionally, obesity and diabetes are strongly linked with post-traumatic stress disorder, which, based on recent research is now actually considered predictive of diabetes. Scientists now posture that obesity per se is not deleterious to health, but it is the dysfunction of adipose tissue that leads to disease. Healthy adipose tissue stores and releases energy appropriately, and secretes endocrine factors that communicate with peripheral organs and tissues to regulate metabolism. However, unhealthy adipose tissue has limited capacity for lipid storage, and is often stretched to that limit, when it becomes inflamed, leading to disruption of many important processes. What determines whether adipose tissue is ‘healthy’ or ‘unhealthy’? It has become increasingly evident that increased adipocyte size is linked with diabetes. Adipocyte size is also inversely proportional to the hyperplastic potential of adipose tissue. That is, when new adipocytes can be made via cell hyperplasia, adipocyte size stays normal; when a limit to hyperplasia occurs, adipocyte size swells to handle the lipid load. Therefore, we might conclude that ability to proliferate adipocytes is key to metabolic health. Adipocytes arise from mesenchymal stem cells (MSCs), pluripotent cells that can also become muscle, bone cartilage, and other tissue types. How do these cells ‘decide’ which differentiation pathway to follow? While some pathways that regulate adipocyte differentiation (or adipogenesis) are known, the factors that regulate these pathways and thus determine cell fate are poorly understood. We have identified a potentially novel adipogenic signal, namely, sphingosine-1-phosphate (S1P). This molecule signals through g protein- coupled receptors to elicit a variety of cell outcomes. There are also receptor-independent functions for sphingosine-1-phosphate. Because our previous work led us to hypothesize that this molecule and therefore the enzyme that synthesizes it, Sphingosine Kinase 1 (SK1), may have a role in adipocytes, we made a mature adipocyte-specific SK1-deletion mouse. We found that these animals have a basal phenotype much like metabolic syndrome, but they are not obese. Specifically, they are insulin resistant, have high circulating levels of leptin and insulin, and show signs of non-alcoholic fatty liver disease. Further investigation revealed upregulation of osteo- and chondrogenic pathways and signaling in adipose tissue of these animals, which supports that they exhibit a defect in adipogenesis. We hypothesize that sphingosine-1-phosphate, intracellularly or in the extracellular milieu, participates in creating the adipose tissue microenvironment to promote adipogenesis in adipogenic precursors deriving from MSCs. In this proposal we present data supporting that SK1 and S1P downregulate anti-adipogenic signaling pathways, and that this is required for metabolic health. These studies will not only shed light on how to keep adipose tissue ‘healthy’ and therefore protect against metabolic disease, but the ‘flip side of the coin’ is that we will also discover new mechanisms regulating osteogenesis and chondrogenesis. Stimulating these pathways in adipose-derived stem cells is currently a major focus for regenerative medicine. We request funding for these studies from the VA, as both diabetes and tissue repair are of great concern for the veteran population and thus this work is highly relevant to veterans’ health.