Mitochondrial uncoupling protein as a target of pharmacotherapy for obesity

Abstract

Uncoupling protein (UCP) is a transporter family present in the mitochondrial inner membrane, and as its name suggests, it uncouples respiration from ATP synthesis by dissipating the transmembrane proton gradient as heat. UCP is now recognized as a key molecule in metabolic thermogenesis such as cold- and diet-induced heat production, which is a significant component of energy expenditure, and its dysfunction contributes to the development of obesity. Among the UCP family, UCP-1 is expressed exclusively in brown adipose tissue (BAT), while UCP-2 is present in many organs and UCP-3 is in skeletal muscle. BAT thermogenesis by UCP-1, which has been studied most extensively, is controlled directly by sympathetic nerves principally through the β-adrenergic action of norepinephrine. Since the β-adrenoceptor is present primarily in adipose tissues, its selective agonists stimulate BAT thermogenesis and also lipid mobilization in white adipose tissue without any noticeable effect on β1-and β2-adrenoceptos. Therefore, β3-adrenoceptor agonists would be promising for the pharmacotherapy of obesity. UCP gene expression is up regulated by ligands for nuclear receptors such as thyroid hormone receptor, peroxisome proliferator-activated receptors (PPAR) and retinoid-X receptor. Long chain fatty acids and some of their metabolites are known to activate PPAR and thereby lead to abundant expression of UCP, which may also contribute to increase in energy expenditure and prevention of obesity. The activity of UCP is suppressed by purine nucleotides but activated by fatty acids. Thus, fatty acids increase UCP-mediated thermogenesis by direct activation of UCP and also by increased gene expression, implying some specific fatty acids or their derivatives as an effective anti-obesity tool.