Uncoupling protein 2 (UCP2) uncouples respiration from oxidative phosphorylation and may contribute to obesity through effects on energy metabolism. Because basal metabolic rate is decreased in obesity, UCP2 expression is predicted to be reduced. Paradoxically, hepatic expression of UCP2 mRNA is increased in genetically obese (ob/ob) mice. In situ hybridization and immunohistochemical analysis of ob/ob livers demonstrate that UCP2 mRNA and protein expression are increased in hepatocytes, which do not express UCP2 in lean mice. Mitochondria isolated from ob/ob livers exhibit an increased rate of H ؉ leak which partially dissipates the mitochondrial membrane potential when the rate of electron transport is suppressed. In addition, hepatic ATP stores are reduced and these livers are more vulnerable to necrosis after transient hepatic ischemia. Hence, hepatocytes adapt to obesity by up-regulating UCP2. However, because this decreases the efficiency of energy trapping, the cells become vulnerable to ATP depletion when energy needs increase acutely.Obesity results from an imbalance between energy intake and energy expenditure (1). Uncoupling protein (UCP) 1 homologues uncouple mitochondrial respiration from oxidative phosphorylation, increasing thermogenesis while reducing the efficiency of ATP synthesis (2). While UCP1 is expressed exclusively in brown fat, UCP2 and UCP3 are also expressed in white fat and skeletal muscle (3). The tissue distribution of UCP2 and UCP3 has provoked speculation that these two proteins may be important regulators of energy homeostasis in adults (4), a possibility that is supported by evidence that the UCP2-UCP3 gene cluster maps to regions of human and murine chromosomes that have been linked to obesity (5).Because net energy expenditure is reduced in obese subjects, UCP2 and/or UCP3 expression or activity are predicted to be decreased. However, experimental evidence for this is relatively limited. A recent study of 6 lean and 6 obese, but otherwise healthy, men demonstrated a slight, but consistent, reduction in UCP2 mRNA levels in the abdominal muscle of the obese subjects (6). Polymorphisms of UCP2, but not UCP3, have been associated with decreased basal metabolic rate in young Pima Indian men, although UCP2 mRNA levels in skeletal muscle were not influenced (5). In mice, resistance to obesity induced by feeding high fat diets has been associated with an early, selective induction of UCP1 and UCP2 in brown and white fat, respectively, but not with changes in UCP3 expression (7).On the other hand, this evidence that decreased UCP2 may promote obesity is difficult to reconcile with observations that ob/ob and db/db obese mice have increased UCP2 mRNA levels in white adipose tissue (8), and that UCP2 mRNA levels in white fat are positively correlated with body mass index in humans (9). Also confusing are reports that caloric restriction, a situation that decreases resting energy expenditure, leads to increased UCP2-UCP3 mRNA expression in white fat and skeletal muscle in both obese and l...
