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TP Combs, GR C Baker, AH Berg, M Ludgate, PE Scherer; ACRP30 Elevation in Sera of Transgenic Mice Results in Orbital Fat Proliferation and is Elevated in Patient's Sera with Graves' Disease and Ophthalmopathy: Further Insight Into Orbital Adipogenesis . Invest. Ophthalmol. Vis. Sci. 2002;43(13):2454.
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Purpose: ACRP30 is a recently discovered plasma protein produced exclusively in adipose tissue whose circulating levels are inversely related to energy stores in adult humans and mice. We generated transgenic mice (tgACRP30) to study the effects of elevated ACRP30. Surprisingly, female tgACRP30 develop severe exophthalmia by middle-age. Thus, we sought to investigate the relationship between elevated ACRP30 and Graves' disease. Methods: The ACRP30 transgene under the fat specific aP2 promoter was carried in the FVB strain. Murine sera were examined for thyroid binding inhibiting immunoglobulin (TBII), thyrotropin stimulating antibodies (TSAB) using cell bioassays and flow cytometry and thyroxine levels (RIA). Orbits and thyroids were examined with semi-thin histology. Levels of ACRP30 were measured in mice and patient sera by Western. Results: ACRP30 was elevated from tgACRP30 10 mg/ml to 40 µg/ml in males and from 25 µ g/ml to 100 µ g/ml in females (n=4; standard error < 20%). At 8 months female tgACRP30 globes and ocular muscles are normal though muscles are displaced by orbital fat proliferation arising from within the muscle cone. All female tgACRP30 developed severe proptosis at 12 months of age. By 18 months there is massive fat proliferation resulting in chronic exposure keratopathy. The corneas are scarred opaque, perforations are plugged with uveal tissue and ultimately globes undergo phthisical change. Neither tgACRP30 nor their littermate controls exhibit TBII or TSAB activity or alterations in levels of total thyroxine (2.4 + 0.6 mg/dl). ACRP30 was measured in TSAB and TBII positive patients with Graves' thyrotoxicosis and ophthalmopathy. ACRP30 levels in Graves' opthalmopathy patients were elevated (69 + 10 µ g/ml) when compared to euthyroid controls and euthyroid Hashimoto's thyroiditis patients (35 + 4 and 39 + 4 µ g/ml, respectively). Conclusion: This is the first example of a single genetic lesion that causes hyperproliferation of orbital fat and is not associated with thyroid autoimmunity. The elevation of ACRP30 in Graves' disease is likely to be from increased orbital adipogenesis, and whether there is an inflammatory component remains unclear. Measurement of ACRP30 may offer an index of disease activity that could guide us further in surgical vs immunosuppressive therapies and presents an unexplored mechanism to reduce the expansion of orbital fat volume.
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