1812 Fig. 16 Examples of some 11β- HSD1 inhibitors. Witkamp formulation of its choline salt is under development by Essential Therapeutics (http://essentialistherapeutics.com/ pages/products.php). Angiogenesisis Inhibitors Adipose tissue is highly vascularized, and expansion requires the formation of new capillaries. Therefore, the use of selective inhibitors of angiogenisis has been proposed as a possible approach to reduce fat tissue (149,166,167). An interesting proof-of-concept study in mice was described by Rupnick et al. (166), who showed that systemic anti- angiogenic agents caused dose-dependent, reversible weight reduction and adipose tissue loss. However, an important challenge is to target adipose tissue resulting in “magic bullets” that “melt fat” (168). This principle was shown by Kolonin et al. (169) using a phage-display method in mice. Molecular targets could include one or several of the angiogenic factors secreted by adipocytes including leptin, angiopoietins, HGF, GM-CSF, VEGF, FGF-2, and TGF-β (170). One of the companies active in this area is Korean AngioLab (http://angiolab.co.kr/), who reports to develop a herbal preparation named ALS- L1023 for this purpose. TGR5 TGR5 is a G-protein coupled receptor that is activated by bile acids, including lithocholic acid and deoxycholic acid (171). TGR5 is widely expressed in the body, in particular in metabolic tissues such as liver, muscle, intestine, and brown adipose tissue. Interest in TGR5 as potential target for obesity and diabetes has been raised, since receptor activation was shown to be connected with an increase in energy expenditure, a reduction of diet-induced obesity and an increase of GLP-1 release in vitro (172,173). A number of companies have started to synthesize and test selective TGR5 agonists, with bile acid-derived or non-bile acid structures (171,174). One of these is the semi-synthetic TGR5 agonist INT-777, which was found to increase energy expenditure and reduce weight gain in mice on a high-fat diet (173). Furthermore, insulin sensitivity in obese mice was improved with INT-777. The development of TGR5 agonists is still in its infancy, and although results so far look promising, it is too early to draw conclusions on the potential of this target. There are no drug candidates yet that have reached the clinical phase. As TGR5 seems to be involved in a rather broad range of processes (171), more insight in potential off-target effects will also be needed.