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Proc Natl Acad Sci U S A. 2014 Oct 7;111(40):14571-6. doi: 10.1073/pnas.1324130111. Epub 2014 Sep 22.

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

Author information

1
Shanghai Key Laboratory of Signaling and Disease Research, Laboratory of Receptor-Based Bio-Medicine, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China; Chinese Academy of Sciences Key Laboratory of Receptor Research, National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; and.
2
State Key Laboratory of Bio-Organic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China.
3
Chinese Academy of Sciences Key Laboratory of Receptor Research, National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; and.
4
State Key Laboratory of Bio-Organic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China xxie@simm.ac.cn byu@mail.sioc.ac.cn.
5
Shanghai Key Laboratory of Signaling and Disease Research, Laboratory of Receptor-Based Bio-Medicine, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China; Chinese Academy of Sciences Key Laboratory of Receptor Research, National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; and xxie@simm.ac.cn byu@mail.sioc.ac.cn.

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.

PMID:
25246581
PMCID:
PMC4210048
DOI:
10.1073/pnas.1324130111
[Indexed for MEDLINE]
Free PMC Article

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