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  • br Family A Receptors as Promiscuous Sensors for


    Family A Receptors as Promiscuous Sensors for Peptone and Free Fatty Acids (FFAs) In addition to the family C 7TM receptors, several family A 7TM receptors are promiscuous in their ligand preferences, and several respond to organic nutrients from food, notably protein degradation products and FFAs (Table 5.1).
    Therapeutic Perspectives It is tempting to speculate that the metabolic syndrome, diabetes and/or obesity could be treated by activating the organic nutrient sensors thereby “tricking” the body to believe it has eaten. As shown for at least some of the receptors reviewed here, this could initiate physiological effects such as release of incretins from the gut or Caspase-3/7 Inhibitor from pancreas and fatty tissue. Such a view might be oversimplified, but as shown in Fig. 5.2, many of the promiscuous receptors discussed in the review are expressed in relevant organs and 7TM receptor-mediated signaling appear to exist for the different types of nutrients (Table 5.1). Selective ligands and/or genetically modified mice are now becoming available for some of the receptors, which is making it possible to address their physiological roles as organic nutrient sensors and their potential as drug targets. These tools are most advanced for FFA1 and have shown very interesting results in terms of potential treatment of diabetes/obesity via release of GLP-1 and insulin (Christiansen et al., 2008, Stoddart et al., 2008b). However, the FFA1 receptor might also mediate the long-term toxicity of FFAs as shown in some but not all studies using FFA1 knockout mice (). More studies are thus needed to validate the FFA1 receptor as a drug target for long-term treatment of obesity/diabetes. A second case showing that the road to novel drugs might not be that straightforward is the T1R2/T1R3 receptor, activated by sugars and artificial sweeteners, which was recently found to mediate GLP-1 release from the gut (Jang et al., 2007, Kokrashvili et al., 2009) and insulin release from pancreas (). One would thus think that the artificial sweeteners could be used as drugs to treat type 2 diabetes via a dual GLP-1/insulin release. However, epidemiological studies have pointed to increased incidence of obesity and/or metabolic syndrome in diet soft-drink consumers (Dhingra et al., 2007, Lutsey et al., 2008). Additional studies are thus needed to sort out the therapeutic potential of the T1R2/T1R3 receptor.