A number of different disease states, including Graves' disease, are associated with hyperproliferation of the retro-orbital adipose tissue. While we have a good understanding of the underlying causes for Graves' disease, we fail to explain some of the pathophysiological changes observed during disease progression, such as the Graves'-associated exopthalmos due to hyperproliferation of the retro-orbital adipose tissue. Progress towards identifying a molecular mechanism for this adipose hyperplasia has been hampered in the past by the lack of an appropriate mouse model that adequately mimics this particular aspect of the disease. We have recently established a novel mouse model that for the first time displays changes in retro-orbital adipose tissue reminiscent of the pathophysiologic changes associated with Graves' disease in some patients. Exposure to chronically elevated serum levels of the adipocyte-specific secretory protein adiponectin through transgenic overexpression results in massive hyperplasia of the retro-orbital fat pad. In agreement with a possible role of adiponectin in the Graves' disease associated retro-orbital hyperplasia, serum adiponectin levels are elevated in a subset of Graves' patients. We propose to define the contribution of adiponectin to this hyperplasia. Our working hypothesis states that chronically elevated levels of adiponectin in association with other hormonal changes connected with Graves' disease leads to the selective hyperproliferation of this adipose tissue. We would like to: I) Further characterize this transgenic mouse line as a potential model system for Graves'-associated exophtalmos and explore possible hormonal manipulations that lead to premature or delayed onset of retro-orbital fat hyperplasia. II) Test pharmacological interventions through use of PPAR antagonists or agonists to establish a treatment modality. III) Establish a firmer correlation between increased serum adiponectin and retroorbital adipose hyperplasia in the subset of Graves patients in which adipose hyperplasia is particularly prominent. Combined, these experiments will establish whether the novel hormone adiponectin that has been shown to positively affect systemic insulin sensitivity, may at chronically high levels also be responsible for the hyperplasia of selective adipose pads in the course of Graves' disease. ? ?
