Obesity precipitates a variety of associated disease including Type 2 Diabetes, the Metabolic Syndrome, Cardiovascular Disease, Liver Disease, and many others. These conditions have greater occurrence in the Veteran population than in the total population, and thus, research into prevention and treatment of these conditions remains a high priority of VA research. The previous funding period of this award enabled us to make the novel discovery that fatty acids (which are elevated in plasma in obese individuals) increase the expression of sphingosine kinase 1 in cultured skeletal muscle cells. This event elevated muscle content of sphingosine-1-phosphate, a lipid mediator implicated in inflammation, migration, chemotaxis, and other key cell processes. We hypothesized that SK1 may mediate the pathophysiolgical consequences of obesity. To test this in vivo, we implemented a diet-induced obesity model in wild type and SK1-/- animals. We found that many pathological consequences of obesity were attenuated by ablation of SK1. Specifically, we observed decreased levels of obesity-indcued proinflammatory cytokines including IL-6 and MCP-1, which may link obesity to its downstream pathology. Moreover, we found that ablation of SK1 attenuated high-fat diet-induced immune cell infiltrate in adipose tissue. We thus hypothesize that SK1 mediates a significant portion of the inflammation in obesity that is thought to mediate systemic insulin resistance, and, thus, targeting SK1 may protect from insulin resistance. Thus, we propose 1-To determine the role of SK1 and S1P in obesity-induced inflammation and subsequent insulin resistance in vivo by measuring plasma cytokines associated with obesity in wild type or SK1-/- mice, and determining whether SK1-/- mice are protected from obesity-dependent insulin resistance. We will test the contribution of adipocyte vs. immune cell SK1 by generating adipocyte-specific and immune cell-specific SK1-/- mice and implementing the high fat diet in these animals and their controls and evaluate inflammation and insulin resistance. We will also 2-determine the downstream signaling of S1P in adipose by determining the S1P receptors and their signaling effectors that mediate these pro-inflammatory events. We then propose 3-to determine the mechanism by which HFF induces SK1. Our data indicate that high fat feeding may generate specific phosphatidylcholine (PC) species that have been implicated as novel endogenous ligands for PPAR?. Accomplishing these aims will reveal the role of SK1 in obesity induced inflammation and IR, providing a significant advance in our understanding of the roles of bioactive lipids in the pathophysiology of obesity, and potentially identifying novel therapeutic targets for disease treatment.
Obesity and associated health problems continue to plague the United States and other western countries. Veterans are more likely to suffer from obesity and overweight than the general population, and Veterans who utilize VA medical centers for health care suffer from obesity at even higher rates. Obesity causes inflammation that plays roles in insulin resistance, atherosclerosis, and cancers that occur at higher rates in obese patients. In the previous funding period, we discovered that plasma fatty acids, which are elevated in obesity, regulate production of a lipid metabolite that may promote inflammation. Our preliminary data here implicate this metabolite in insulin resistance, the first step along the way to type 2 diabetes. I this application we propose to target this pathway of lipid metabolism using various drugs;we will then evaluate whether they may ameliorate obesity-associated inflammation and/or insulin resistance. This will benefit Veterans by potentially leading to new therapeutic strategies for treating obesity-related diseases.