The hypothalamus plays a central role in the integrated control of feeding and energy homeostasis. We have identified two novel neuropeptides, both derived from the same precursor by proteolytic processing, that bind and activate two closely related (previously) orphan G protein-coupled receptors. These peptides, termed orexin-A and -B, have no significant structural similarities to known families of regulatory peptides. prepro-orexin mRNA and immunoreactive orexin-A are localized in neurons within and around the lateral and posterior hypothalamus in the adult rat brain. When administered centrally to rats, these peptides stimulate food consumption. prepro-orexin mRNA level is up-regulated upon fasting, suggesting a physiological role for the peptides as mediators in the central feedback mechanism that regulates feeding behavior.

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 .

Cold acclimation has been shown to produce a substantial increase in the number of brown adipocytes in the parametrial fat pad of female BALB/c mice ‐ a site normally thought to consist of typical white adipocytes. The brown adipocytes have been identified not only on the basis of their morphology using light and electron microscopy, but also on the basis of the content of the mitochondrial ‘uncoupling protein’ (M r = 32 000) which is characteristic of the proton conductance pathway of brown adipose tissue.

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