Current and Future Drug Targets in Weight Management Fig. 13 Structure of trodusquie- mine, a natural PTP-1B inhibitor. 1809 disappointing (37). Nevertheless, targeting energy expendi- ture (cellular bioenergetics), in particular adaptive thermo- genesis, is regarded as a valuable option (137). Adaptive thermogenesis is generated by mitochondria of skeletal muscle and by brown adipose tissue (BAT) in response to external stimuli. Until five years ago, it was generally assumed that adult humans possess negligible amounts of BAT, which did not make this tissue an interesting option for pharma- cological intervention. However, recent findings have dem- onstrated that adults maintain active BAT (138–140). As a result, interest in BAT as a new target for human obesity has also returned (137,141,142). Examples of the rather heterogeneous group of com- pounds targeting local or total body fat are listed in Table IV. Beta-3 Receptor Agonists The β3-adrenergic receptor is expressed in adipocytes and some other tissues. The discovery, during the early 80s, of last century, of its role as a regulator of lipolysis and fatty acid oxidation in rodents pushed many pharmaceutical companies to start developing β3AR agonists for human weight management (141). However, clinical studies in humans did not meet the high expectations. For example, the selective human β3-agonist, L-796568 (Fig. 14) failed to reduce weight or 24-h energy expenditure Table IV Main Classes of Compounds Acting on Local or Total Body Fat Beta-3 adrenergic receptor agonists Selective thyroid hormone receptor subtype β-agonists Growth hormone analogues 11-β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) inhibitors Sirtuin 1 activators Diazoxide Inihibitors of angiogenisis TGR5 agonists over 28 days in overweight men (143). Similarly, no clear effects of the β3-agonist compound TAK-377 (Fig. 14) were found in a human trial (144). Recently, the development of a combination of the β3 agonist L-377604 plus subitramine was terminated. Compound KRP-204 (Fig. 14) appears to be still in development for obesity (and also for other indications), but its present status is unclear. Some other β3 agonists, for example SR58611A (Fig. 14) from Sanofi-Aventis, are now being investigated for use in anxiety and depression. The lack of efficacy of β3 agonists on human adipose tissue has been explained by the low numbers of β3-adrenoreceptors on human adipocytes as compared to mice or the weak effect of β3 activation on lipolysis in general. Furthermore, many compounds suf- fered from poor selectivity and unfavorable PK properties, such as a low oral bioavailability (141). However, the recent developments in the discovery of brown adipose tissue in humans expressing the β3AR have generated new optimism (137). There are indications that treatment with β3AR agonists may increase the amount and activity of this brown adipose tissue (141). Selective Thyroid Hormone Mimetics Thyroid hormone itself stimulates adaptive thermogenesis and lipolysis, but its use as anti-obesity compound is obsolete due to the many side effects, including tachycardia, muscle wasting and loss of bone mass. However, a number of selective thyroid hormone receptor (TR) subtype β- agonists have been developed that may have potential as anti-obesity and/or lipid-lowering agents. These include KB-141 (eprotirome, Fig. 15), GC-1 (sobetirome, Fig. 15), KB-2115 and MB07811. These molecules possess pharmacological profiles differ- ent from that of thyroid hormone (145–147). For example, KB-141 was shown to have anti-obesity, lipid-lowering and anti-diabetic effects in rodents, without causing tachycardia. This suggests that selective TRβ activation could provide a future strategy to attenuate features of the metabolic