Nuclear receptors and their coactivators have been shown to function as key regulators of adipose tissue biology. Here we show that a ligand-dependent transcriptional repressor for nuclear receptors plays a crucial role in regulating the balance between energy storage and energy expenditure. Mice devoid of the corepressor protein RIP140 are lean, show resistance to high-fat diet-induced obesity and hepatic steatosis, and have increased oxygen consumption. Although the process of adipogenesis is unaffected, expression of certain lipogenic enzymes is reduced. In contrast, genes involved in energy dissipation and mitochondrial uncoupling, including uncoupling protein 1, are markedly increased. Therefore, the maintenance of energy homeostasis requires the action of a transcriptional repressor in white adipose tissue, and ligand-dependent recruitment of RIP140 to nuclear receptors may provide a therapeutic target in the treatment of obesity and related disorders.