Mitochondrial uncoupling proteins and obesity: Molecular and genetic aspects of UCP1

Genetic variation in brwon fat specific mitochondrial uncoupling protein-1 (UCP1) expression and brown adipocyte morphology, have provided models to t est the hypothesis that nonshivering thermogenesis is associated with the r egulation of body weight. Genetic manipulation using transgenic animals and gene targeting, has resulted in mice with an over-expression of UCP1. Thes e variant animals consistently show that over-expression of UCP1 reduced ad iposity. On the other hand, less agreement is found in models that reduce n onshivering thermogenesis. inactivation of the UCP1 gene, by gene targeting , does not increase adiposity when compared to control animals; however, a mouse expressing the UCP1-DTA transgene (UCPI-diphtheria toxin A chain), in which there is a modest reduction in the number of brown adipocytes, becom es obese. Other phenotypes of this mouse, the hyperphagia, extreme resistan ce to leptin administration, retinopathy and high residual content of brown adipocytes, suggest that the effects of the transgene may be more extensiv e than simply a 60% reduction in the number of brown adipocytes. Ectopic ex pression of UCP1-DTA in the brain could explain the phenotype of this mouse in a manner more consistent with the results of other models with altered UCP1 and brown adipocyte expression.