The adipocyte-expressed forkhead transcription factor Foxc2 regulates metabolism through altered mitochondrial function.

Objective: Previous findings demonstrate that enhanced expression of the forkhead transcription factor Foxc2 in adipose tissue leads to a lean and insulin-sensitive phenotype. These findings prompted us to further investigate the role of Foxc2 in the regulation of genes of fundamental importance for metabolism and mitochondrial function.

Research Design And Methods: The effects of Foxc2 on expression of genes involved in mitochondriogenesis and mitochondrial function were assessed by quantitative real-time PCR.

Mitochondrial uncoupling as a target in the treatment of obesity.

Purpose Of Review: Obesity is associated with many health problems and its prevalence is rapidly increasing worldwide. Very few pharmaceutical compounds are available for obesity treatment. Strategies for the development of compounds can be targeted to the outcomes of reduced dietary energy intake and/or increased energy expenditure/thermogenesis.

The energetic implications of uncoupling protein-3 in skeletal muscle.

Despite almost a decade of research since the identification of uncoupling protein-3 (UCP3), the molecular mechanisms and physiological functions of this mitochondrial anion carrier protein are not well understood. Because of its highly selective expression in skeletal muscle and the existence of mitochondrial proton leak in this tissue, early reports proposed that UCP3 caused a basal proton leak and increased thermogenesis. However, gene expression data and results from knockout and overexpression studies indicated that UCP3 does not cause basal proton leak or physiological thermogenesis.

Physiological increases in uncoupling protein 3 augment fatty acid oxidation and decrease reactive oxygen species production without uncoupling respiration in muscle cells.

Decreased uncoupling protein (UCP)3 is associated with insulin resistance in muscle of pre-diabetic and diabetic individuals, but the function of UCP3 remains unclear. Our goal was to elucidate mechanisms underlying the negative correlation between UCP3 and insulin resistance in muscle. We determined effects of physiologic UCP3 overexpression on glucose and fatty acid oxidation and on mitochondrial uncoupling and reactive oxygen species (ROS) production in L6 muscle cells.