Mitochondrial uncoupling proteins: from mitochondria to the regulation of energy balance

The coupling of oxygen consumption to ADP phosphorylation is incomplete, as is particularly evident in brown adipocyte mitochondria which use a regula ted uncoupling mechanism to dissipate heat produced by substrate oxidation. In brown adipose tissue, uncoupling is effected by a specific protein in t he inner mitochondrial membrane referred to as uncoupling protein-1 (UCP1). UCP1 gene disruption in mice has confirmed UCP1's role in cold-induced the rmogenesis. Genetic analysis of human cohorts has suggested that UCP1 plays a minor role in the control of fat content and body weight. The recent clo ning of UCP2 and UCP3, two homologues of UCP1, has boosted research on the importance of respiration control in metabolic processes, metabolic disease s and energy balance. UCP2 is widely expressed in different organs whereas UCP3 is mainly present in skeletal muscle. The chromosomal localization of UCP2 as well as UCP2 mRNA induction by a lipid-rich diet in obesity-resista nt mice suggested that UCP2 is involved in diet-induced thermogenesis. A st rong linkage between markers in the vicinity of human UCP2 and UCP3 (which are adjacent genes) and resting metabolic rate was calculated. UCPs are kno wn or supposed to participate in basal and regulatory thermogenesis, but th eir exact biochemical and physiological functions have yet to be elucidated . UCPs may constitute novel targets in the development of drugs designed to modulate substrate oxidation. However, very recent data suggest an importa nt role for the UCPs in the control of production of free radicals by mitoc hondria, and in response to oxidants.