Obesity induces expression of uncoupling protein-2 in hepatocytes and promotes liver ATP depletion

Uncoupling protein 2 (UCP2) uncouples respiration from oxidative phosphoryl ation and may contribute to obesity through effects on energy metabolism. B ecause basal metabolic rate is decreased in obesity, UCP2 expression is pre dicted to be reduced. Paradoxically, hepatic expression of UCP2 mRNA is inc reased in genetically obese (ob/ob) mice, In situ hybridization and immunoh istochemical analysis of ob/ob livers demonstrate that UCP2 mRNA and protei n expression are increased in hepatocytes, which do not express UCP2 in lea n mice. Mitochondria isolated from ob/ob livers exhibit an increased rate o f H+ leak which partially dissipates the mitochondrial membrane potential w hen the rate of electron transport is suppressed. In addition, hepatic ATP stores are reduced and these livers are more vulnerable to necrosis after t ransient hepatic ischemia. Hence, hepatocytes adapt to obesity by up-regula ting UCP2. However, because this decreases the efficiency of energy trappin g, the cells become vulnerable to ATP depletion when energy needs increase acutely.