Fig. 1

Differential and common phenotypes induced by ectopic UCP1 in WAT (a) and SM (b) and possible involvement of AMPK. Mice with ectopic UCP1 expression in WAT are characterized by obesity resistance, which is apparent throughout the whole adult life, associated with minimal changes in lean body mass, while mice with ectopic UCP1 in SM are resistant to obesity only during the first 8 months of life. In both models, glucose homeostasis (evaluated as a tolerance to glucose load and/or as fasted glycemia) is permanently improved, suggesting better insulin sensitivity. However, a dissociation between the effects of ectopic UCP1 in SM on glucose homeostasis and obesity was observed. A relatively strong hypolipidemic effect of ectopic UCP1 in WAT, which is most pronounced under obesogenic conditions, is probably absent in mice expressing UCP1 in SM. Many of the observed phenotypes could be attributed to activation of AMPK induced by partial energy depletion caused by the uncoupling of respiratory chain. However, different mechanisms may be involved in the beneficial effects on glucose homeostasis exerted by mitochondrial uncoupling in WAT and SM, respectively. Thus, metabolic changes induced by ectopic UCP1 in adipocytes counteract release of fatty acids from WAT into circulation and prevent accumulation of ectopic lipids in liver as well as in SM, while preserving insulin sensitivity of these two organs, namely under obesogenic conditions. On the other hand, the beneficial effects of ectopic UCP1 in SM on muscle as well as whole-body insulin sensitivity, and on metabolic flexibility (i.e., a more rapid switch between glucose and fat oxidation under feeding and fasting conditions), are clearly unrelated to the prevention of lipotoxic accumulation of muscle lipids (Han et al. 2004) and must be mediated by another mechanism. A decreased mitochondrial ROS production in SM UCP1 expressing mice could possibly lead to decreased oxidative damage caused by detrimental diets and aging