Molecular matchmaking between the popular weight-loss herb Hoodia gordonii and GPR119, a potential drug target for metabolic disorder

Abstract

African cactiform Hoodia gordonii (Asclepiadaceae) has been used for thousands of years by Xhomani Bushmen as an anorexant during hunting trips and has been proposed as a new agent for the management of body weight. However, its in vivo targets and molecular mechanisms remain elusive. GPR119, a G protein-coupled receptor highly expressed in pancreatic β cells and intestinal L cells, has been demonstrated to facilitate glucose-stimulated insulin secretion (GSIS) and represents a novel and attractive target for the therapy of metabolic disorders. Here, we disclose that Gordonoside F (a steroid glycoside isolated from H. gordonii), but not the widely known P57, activates specifically GPR119. Successful synthesis of Gordonoside F facilitates further characterization of this compound. Gordonoside F promotes GSIS both in vitro and in vivo and reduces food intake in mice. These effects are mediated by GPR119 because GPR119 knockout prevents the therapeutic effects of Gordonoside F. Interestingly, the appetite-suppressing effect of Hoodia extract was also partially blocked by GPR119 knockout. Our results demonstrate for the first time, to our knowledge, that GPR119 is a direct target and one of the major mechanisms underlying the therapeutic effect of the popular "weight loss" herb H. gordonii. Given the long history of safe application of this herb in weight control, it is foreseeable that the novel scaffold of Gordonoside F provides a promising opportunity to develop new drugs in treating metabolic diseases.

Oral 2‐oleyl glyceryl ether improves glucose tolerance in mice through the GPR119 receptor

“…Furthermore, the importance of dietary fat as a trigger of GLP‐1 release through GPR119 was recently demonstrated by the use of wt and GPR119‐KO mice . GPR119‐KO mice appear to have normal islet morphology, body weight and fed/fasted glucose levels . However, our GPR119‐KO mice had improved glucose tolerance (lower AUC) as also found by Scott et al , but not by others .…”

“…Several agonists made it to phase 2 clinical trials , but the results have not yet been convincing so far. A glucohomeostatic effect of GPR119 activation has been reported several times based on studies in GPR119‐KO mice, including studies with administration of AR231453 in wt and GPR119‐KO mice demonstrating the importance of GPR119 for plasma levels of glucose, GLP‐1, and GIP, as well as for gastric emptying and food intake . Similar findings were made in studies involving oleoyldopamide in wt and GPR119‐KO mice .…”

“…We found that it stimulated a GPR119-mediated increase in the concentration of cAMP in transiently transfected COS-7 cells with a potency in the same range as 2-OG, i.e. EC 50 Time course of effect of AR234153 plus glucose on plasma levels of glucose, GIP, and insulin. Overnight-fasted WT male mice, 16 weeks old, were dosed by oral gavage with the GPR119 agonist AR234153 (20 mg kg 21 ) dissolved in vehicle (25% 0.9% NaCl, 25% DMSO, 25% ethanol, 25% glycerol), 60 min before oral glucose (2 g kg 21 ).…”

New paradigms in GPCR drug discovery

“…The incidental thrombin inhibitory activity at PAR1 was then optimized leading to this approved antithrombotic agent (Table 2). Recently, Gordonoside F 25 , a pregnane steroidal glycoside from an African cactus that was used as an herbal medicine for weight loss, was found to activate G protein-coupled receptor 119 (GPR119) to improve glucose tolerance [44]. Although not a likely source for drug discovery, it is noteworthy that the gut microbiome produces a range of phytochemical metabolites, some of which interact with GPCRs [45].…”

“…There are still ~120 orphan GPCRs for which the endogenous ligand is unknown, but even for hundreds of nonorphan GPCRs there is still untapped potential. Formerly orphan GPCRs that are deorphanized, such as GPR40, GPR119 and GPR120, are proving useful in drug discovery [44,46,51]. Molecular modeling predictions have contributed to the deorphanizing of GPCRs [152].…”