Augmenting energy expenditure by mitochondrial uncoupling: a role of AMP-activated protein kinase

Abstract

Strategies to prevent and treat obesity aim to decrease energy intake and/or increase energy expenditure. Regarding the increase of energy expenditure, two key intracellular targets may be considered (1) mitochondrial oxidative phosphorylation, the major site of ATP production, and (2) AMP-activated protein kinase (AMPK), the master regulator of cellular energy homeostasis. Experiments performed mainly in transgenic mice revealed a possibility to ameliorate obesity and associated disorders by mitochondrial uncoupling in metabolically relevant tissues, especially in white adipose tissue (WAT), skeletal muscle (SM), and liver. Thus, ectopic expression of brown fat-specific mitochondrial uncoupling protein 1 (UCP1) elicited major metabolic effects both at the cellular/tissue level and at the whole-body level. In addition to expected increases in energy expenditure, surprisingly complex phenotypic effects were detected. The consequences of mitochondrial uncoupling in WAT and SM are not identical, showing robust and stable obesity resistance accompanied by improvement of lipid metabolism in the case of ectopic UCP1 in WAT, while preservation of insulin sensitivity in the context of high-fat feeding represents the major outcome of muscle UCP1 expression. These complex responses could be largely explained by tissue-specific activation of AMPK, triggered by a depression of cellular energy charge. Experimental data support the idea that (1) while being always activated in response to mitochondrial uncoupling and compromised intracellular energy status in general, AMPK could augment energy expenditure and mediate local as well as whole-body effects; and (2) activation of AMPK alone does not lead to induction of energy expenditure and weight reduction.

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