Sustained hyperleptinemia induced in normal rats causes the rapid disappearance of body fat. This is attributed to a marked increase in uncoupled fatty acid oxidation in the white adipocytes, which also occurs in hyperthyroidism. Because hyperleptinemic rats have normal plasma T3 or T4 levels, we tested the possibility of "localized hyperthyroidism" due to increased conversion of T4 to T3 in the adipose tissue. We therefore induced sustained hyperleptinemia in normal rats by intravenous injection of recombinant adenovirus containing the leptin cDNA (AdCMV-leptin) and measured the mRNA and the activity of enzymes involved in T4 metabolism in the disappearing fat. The epididymal fat pad remnants exhibited a decrease in mRNA of deiodinase 1 and a doubling of deiodinase 2 mRNA (p < 0.05), but their enzyme activities did not differ from normoleptinemic controls. To determine if thyroid hormone was required for the fat-wasting action of hyperleptinemia, we infused AdCMV-leptin into rats made athyroid by total thyroidectomy or by methimazole therapy. The fat loss in hyperleptinemic athyroid rats was as great as in euthyroid controls. We conclude that the fat-wasting effect of sustained hyperleptinemia does not involve "local hyperthyroidism" in white adipose tissue and does not require thyroid hormone. (C) 2004 Elsevier Inc. All rights reserved.