Mice lacking mitochondrial uncoupling protein are cold-sensitive but not obese

Abstract

The mitochondrial uncoupling protein (UCP) in the mitochondrial inner membrane of mammalian brown adipose tissue generates heat by uncoupling oxidative phosphorylation. This process protects against cold and regulates energy balance. Manipulation of thermogenesis could be an effective strategy against obesity. 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 beta3-adrenergic-receptor agonist and that they are sensitive to cold, indicating that their thermoregulation is defective. However, this deficiency caused neither hyperphagia nor obesity in mice fed on either a standard or a high-fat 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.

Thermoneutrality, Mice, and Cancer: A Heated Opinion

“…Nevertheless, are these linkages being influenced by cold stress? A large body of literature links increased dietary fat intake with obesity and cancer progression [59], but it is becoming clear that factors affecting obesity are altered at ST. For example, a UCP-1 knockout mouse model showed deficits in coldinduced non-shivering thermogenesis as expected, but failed to develop the expected obesity phenotype [60,61]. Several groups have now shown that this unexpected lack of the predicted phenotype was because the mice were housed at ST, and when these mice are housed at TT (and are not burning energy through adaptive thermogenesis) they do become obese [61][62][63][64].…”

The uncoupling protein homologues: UCP1, UCP2, UCP3, StUCP and AtUCP

“…Other authors referred to this protein as thermogenin [2]. Finally, the demonstration of an important role for UCP1 in adaptive thermogenesis was provided by Enerba$ ck et al [48], who obtained null mutant mice unable to maintain their body temperature in a cold environment. UCP1 synthesis is strongly activated by noradrenaline, cAMP, thyroid hormones and retinoids (for reviews, see [2,8,9]).…”

“…The demonstration by Kozak and his collaborators that UCP1 −/− mice were sensitive to cold and unable to maintain their body temperature proved that the function of the UCP1 gene is to induce respiratory uncoupling and thermogenesis in order to maintain body temperature in a cold environment [48]. Interestingly, the authors noted an upregulation of UCP2 mRNA in the BAT of transgenic mice whose UCP1 gene was interrupted.…”

Genetics of human obesity: lessons from mouse models and candidate genes

“…UCP is primarily expressed in brown adipose tissue, where it is involved in the uncoupling of the mitochondrial membrane, leading to futile cycling and heat generation [99,100]. Although mice lacking UCP1 are not obese (possibly because of upregulation of other UCPs) [101], mice overexpressing UCP1 in adipose tissue are protected against obesity [102] and mice lacking brown adipose tissue, the main localization of UCP1, become obese [103]. We have analysed the coding region of the UCP1 gene for mutations in juvenile onset obesity, and have identified several gene variants.…”