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 .

The effects of a novel compound, BRL 26830A, on energy balance in normal and obese mice have been investigated. BRL 26830A reduced body weight or weight gain in genetically (ob/ob), goldthioglucose, and cafeteria diet obese mice and genetically obese (fa/fa) Zucker rats. Weight reduction was due to reduced body lipid content. BRL 26830A caused little or no reduction in food intake in these animals but it increased metabolic rate and in genetically obese mice this thermic effect was increased by repeat dosing. BRL 26830A did not reduce body weight gain in the lean counterparts of the genetically obese animals. Its thermic effect was smaller in the lean than the genetically obese mice and it caused an increase in food intake in the lean mice. The thermic effect of BRL 26830A was inhibited by dl- but not d-propranolol. BRL 26830A largely overcame the depression in metabolic rate caused by fasting.

No abstract

No abstract