The long-term goal of this research is to identify safe and effective dietary strategies to reduce the prevalence of obesity and associated diseases. One potential anti-obesity compound is conjugated linoleic acid (CLA), sold woridwide for weight loss. However, several adverse side effects have been reported in animals and humans such as hyperiipidemia, inflammation, and insulin resistance. Therefore, the safety of this supplement remains questionable. Furthermore, the specific cell type(s) in white adipose tissue (WAT) responsible for initiating an inflammatory response to CLA treatment, and the mechanism by which 10,12 CLA promotes delipidation, are unknown. Therefore, the specific aims of this proposal are to 1) determine which cell type in WAT (i.e., the preadipocyte or the adipocyte) that is the major mediator of 10,12 CLA- mediated inflammation, insulin resistance, and delipidation in primary cultures of newly differentiated human adipocytes, and 2) to identify the specific mechanism(s) involved. Based on my preliminary data, it is expected in Aim #1 that adipocytes are the major instigators of 10,12 CLA-induced inflammation, insulin resistance, and delipidation. It is anticipated in Aim #2 that 10,12 CLA mediates these effects through activating activator protein (AP)-1 via upstream activation of mitogen activated protein kinases (MAPKs). To complete the proposed studies in Aim #1, four different experimental models will be employed to determine whether the preadipocyte or the adipocyte is responsible for 10,12 CLA-mediated inflammation, insulin resistance, and delipidation.
In Aim #2, chemical inhibitors and siRNA will be used to determine the role of upstream MAPKs and AP-1 in mediating 10,12 CLA-induced inflammatory gene expression, insulin resistance, and delipidation. Inflammation will be examined by measuring inflammatory gene expression, protein activation, and secretion of adipocytokines and prostaglandins into the media. Insulin resistance will be determined by measuring insulin-stimulated glucose and fatty acid uptake. The rationale for the proposed research is that once we understand which cells in WAT trigger the inflammatory response by CLA and how this occurs, it's safe use as a dietary approach for weight control can be evaluated effectively. The proposed research is important to public health, because it will provide information needed to identify safe and effective dietary strategies to reduce body fat and improve overall health. The improvement of overall health is expected to reduce the amount of money spent on medications and health care needed for treating obesity and diabetes.
