Uncoupling protein-3 (UCP-3) is a recently identified member of the mitochondrial transporter superfamily that is expressed predominantly in skeletal muscle. However, its close relative UCP-1 is expressed exclusively in brown adipose tissue, a tissue whose main function is fat combustion and thermogenesis. Studies on the expression of UCP-3 in animals and humans in different physiological situations support a role for UCP-3 in energy balance and lipid metabolism. However, direct evidence for these roles is lacking. Here we describe the creation of transgenic mice that overexpress human UCP-3 in skeletal muscle. These mice are hyperphagic but weigh less than their wild-type littermates. Magnetic resonance imaging shows a striking reduction in adipose tissue mass. The mice also exhibit lower fasting plasma glucose and insulin levels and an increased glucose clearance rate. This provides evidence that skeletal muscle UCP-3 has the potential to influence metabolic rate and glucose homeostasis in the whole animal.

Recent studies suggest that thermogenesis in brown adipose tissue has an important role in the regulation of energy balance. Thermogenesis is effected by noradrenaline released from sympathetic nerve endings; the noradrenaline stimulates beta-adrenoceptors, causing lipolysis, and the released fatty acids then promote the uncoupling of oxidative phosphorylation from electron transport. It has been widely accepted that mammalian beta-adrenoceptors exist as two subtypes, beta 1 and beta 2, and rat brown adipocyte beta-adrenoceptors have been classed as beta 1 or as a mixed beta 1/beta 2 population. The beta 1 subtype predominates in atria, whereas the beta 2 subtype predominates in trachea. However, we have now found a novel group of beta-adrenoceptor agonists that selectively stimulate lipolysis in brown adipocytes. In contrast, isoprenaline, fenoterol and salbutamol are less potent as stimulants of lipolysis than as stimulants of atrial rate or tracheal relaxation. Therefore, beta-adrenoceptors in rat brown adipocytes are of neither the beta 1 nor beta 2 subtypes. Compounds that selectively stimulate brown adipocyte beta-adrenoceptors should have potential as thermogenic anti-obesity agents and this has been demonstrated with BRL 26830A , BRL 33725A and BRL 35135A .

1 Urotensin-II (U-II) and its G-protein-coupled receptor, GPR14, are expressed within mammalian cardiac and peripheral vascular tissue and, as such, may regulate mammalian cardiovascular function. The present study details the vasoconstrictor pro®le of this cyclic undecapeptide in di erent vascular tissues isolated from a diverse range of mammalian species (rats, mice, dogs, pigs, marmosets and cynomolgus monkeys). 2 The vasoconstrictor activity of human U-II was dependent upon the anatomical origin of the vessel studied and the species from which it was isolated. In the rat, constrictor responses were most pronounced in thoracic aortae and carotid arteries: 7log[EC 50 ]s 9.09+0.19 and 8.84+0.21, R max s 143+21 and 67+26% 60 mM KCl, respectively (compared, for example, to 7log[EC 50 ] 7.90+0.11 and R max 142+12% 60 mM KCl for endothelin-1 [ET-1] in thoracic aortae). Responses were, however, absent in mice aortae (7log [EC 50 ] 56.50). These ®ndings were further contrasted by the observation that U-II was a`coronary-selective' spasmogen in the dog (7log [EC 50 ] 9.46+0.11, R max 109+23% 60 mM KCl in LCX coronary artery), yet exhibited a broad spectrum of vasoconstrictor activity in arterial tissue from Old World monkeys (7log [EC 50 ]s range from 8.96+0.15 to 9.92+0.13, R max s from 43+16 to 527+135% 60 mM KCl). Interestingly, signi®cant di erences in reproducibility and vasoconstrictor e cacy were seen in tissue from pigs and New World primates (vessels which responded to noradrenaline, phenylephrine, KCl or ET-1 consistently). 3 Thus, human U-II is a potent, e cacious vasoconstrictor of a variety of mammalian vascular tissues. Although signi®cant species/anatomical variations exist, the data support the hypothesis that U-II in¯uences the physiological regulation of mammalian cardiovascular function. British Journal of Pharmacology (2000) 131, 1262 ± 1274 Keywords: Urotensin-II; GPR14; SENR; endothelin-1; somatostatin; vascular reactivity; spasmogen; coronary artery; endothelium; vasoconstriction Abbreviations: FLIPR,¯uorescent imaging plate reader; GPCR, guanosine triphosphate-binding protein [G-protein]-coupled receptor; LAD coronary artery, left anterior descending coronary artery; LCX, left circum¯ex coronary artery; SENR, sensory epithelial neuropeptide-like receptor; U-II, Urotensin-II IntroductionThe integrated control of cardiovascular homeostasis is achieved through a combination of direct neuronal control and systemic activation of the neurohumoral axis. The principal mammalian vasoactive factors of this axis (angiotensin-II, endothelin [ET]-1, noradrenaline) exert their haemodynamic e ects exclusively via interactions with speci®c seven transmembrane heterotrimeric G-protein-coupled receptors (GPCRs). Drugs which antagonize such interactions constitute one of the most successful classes of therapeutic agents identi®ed to date (Stadel et al., 1997; Wilson et al., 1998). Nowhere is this more evident than within the vasculature where numerous agents have been developed successfully for the clinical ...

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