The mitochondrial uncoupling protein (UCP) in the mitochondrial inner membrane of mammalian brown adipose tissue generates heat by uncoupling oxidative phosphorylation(1). This process protects against cold(2) and regulates energy balance(3). Manipulation of thermogenesis could be an effective strategy against obesity(4-9). Here we determine the role of UCP in the regulation of body mass by targeted inactivation of the gene encoding it. We find that UCP-deficient mice consume less oxygen after treatment with. a beta 3-adrenergic-receptor agonist and that they are sensitive to cold, indicating that their thermo-regulation is defective. However this deficiency caused neither hyperphagia nos obesity in mice fed on either a standard or a high-ibt diet, We propose that the loss of UCP may be compensated by UCP2, a newly discovered homologue of UCP; this gene is ubiquitously expressed and is induced in the brown fat of UCP-deficient mice.