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Thyroid hormone (3,3′,5-triiodo-L-thyronine) plays an important role in thermogenesis and maintenance of lipid homeostasis. The present article reviews the evidence that 3,3′,5-triiodo-L-thyronine regulates lipid metabolism via thyroid hormone receptors, focusing particularly on in-vivo findings using genetically engineered mice.That lipid metabolism is regulated via thyroid hormone receptor isoforms in a tissue-dependent manner was recently uncovered by using knockin mutant mice harboring an identical mutation in the Thra gene (Thra1PV mouse) or the Thrb gene (ThrbPV mouse). The mutation in the Thra gene dramatically decreases the mass of both white adipose tissue and liver. In contrast, the mutation in the Thrb gene markedly increases the mass of liver with an excess depot of lipids, but no significant abnormality is observed in white adipose tissue. Molecular studies show that the expression of lipogenic genes is decreased in white adipose tissue of Thra1PV mice, but not in ThrbPV mice. Markedly increased lipogenic enzyme expression, and decreased fatty acid beta-oxidation activity contribute to the adipogenic steatosis and lipid accumulation in the liver of ThrbPV mice. In contrast, reduced expression of genes critical for lipogenesis mediates decreased liver mass with lipid scarcity in Thra1PV mice.Studies using Thra1PV and ThrbPV mice indicate that apo-thyroid hormone receptor-beta and apo-thyroid hormone receptor-alpha-1 mediate distinct deleterious effects on lipid metabolism. Thus, both thyroid hormone receptor isoforms contribute to the pathogenesis of lipid abnormalities in hypothyroidism, but in a target tissue-dependent manner. These studies suggest that thyroid hormone receptor isoform-specific ligands could be designed as therapeutic targets for lipid abnormalities.