Upregulation of uncoupling protein 2 mRNA in genetic obesity: lack of an essential role for leptin, hyperphagia, increased tissue lipid content, and TNF-alpha

Uncoupling protein 2 (UCP2) has been proposed to play a prominent role in t he regulation of energy balance. UCP2 mRNA expression is upregulated in whi te adipose tissue (WAT) and liver, but is not altered in skeletal muscle in genetically obese ob/ob mice. The mechanisms involved in the upregulation of UCP2 in obesity have not been investigated. We have now examined the pot ential role of leptin, hyperphagia, increased tissue lipid content, and ove rexpression of tumor necrosis factor (TNF)-alpha in the upregulation of UCP 2 mRNA expression in the liver and WAT in ob/ob mice. Treatment of ob/ob mi ce with leptin for 3 days significantly reduced their food intake but had n o effect on the upregulation of UCP2 mRNA levels in the liver or WAT. To in vestigate the effect of feeding and higher tissue lipid content on the upre gulation of UCP2 in liver and WAT, we compared UCP2 mRNA levels in ad-libit um fed and 72-h fasted control and ob/ob mice. In controls, fasting had no effect on UCP2 mRNA levels in liver, but increased UCP2 mRNA in WAT suggest ing that the effects of fasting on UCP2 mRNA levels are tissue-specific. In ob/ob mice, fasting did not lower UCP2 mRNA levels in liver or WAT suggest ing that the upregulation of UCP2 in ob/ob mice is not merely a direct cons equence of increased food intake. 72-h fasting lowered hepatic total lipid content by 34% and 36% in control and ob/ob mice, respectively, without any corresponding decrease in hepatic UCP2 mRNA levels, suggesting that the en hanced UCP2 expression in the liver of ob/ob mice is not secondary to lipid accumulation in their livers. Although TNF-alpha has been shown to acutely increase UCP2 mRNA levels in liver and WAT, and is overexpressed in adipos e tissue in obesity, deletion of the genes for both TNF receptors in ob/ob mice produces a further increase in UCP2 mRNA expression in liver and adipo se tissue indicating a paradoxical inhibitory role. Taken together, these r esults suggest that the upregulation of UCP2 mRNA levels in the liver and W AT of ob/ob mice is not due to the lack of leptin, hyperphagia, increased t issue lipid content, or over-expression of TNF-alpha. (C) 2000 Elsevier Sci ence B.V. All rights reserved.