Muons penetrate much further than X-rays, they do essentially zero damage, and they are provided for free by the cosmos.
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Edited by Robert J. Lefkowitz, Howard Hughes Medical Institute, Duke University Medical Center, Durham, NC, and approved August 19, 2014 (received for review December 29, 2013)
Significance
Obesity is one of the most common health concerns today. Herbal-based food supplements are widely used to treat obesity. Among them, the African cactiform Hoodia gordonii supplements are extremely popular. The development of Hoodia and P57, the purported active ingredient, has been problematic due to controversy about intellectual property rights and limited natural resources. To date, the true active components and molecular targets of Hoodia remain unclear. Here, we demonstrate that Gordonoside F, a compound from Hoodia, activates GPR119, a receptor critically involved in metabolic homeostasis, and leads to increased insulin secretion and reduced food intake. The successful synthesis of Gordonoside F described here will provide an opportunity for developing new drugs in treating metabolic diseases.
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.
Footnotes
↵1S.Z. and Y.M. contributed equally to this work.
- ↵2To whom correspondence may be addressed. Email: xxie{at}simm.ac.cn or byu{at}mail.sioc.ac.cn.
Author contributions: B.Y. and X.X. designed research; S.Z., Y.M., J.L., and J.M. performed research; S.Z., Y.M., J.L., J.M., B.Y., and X.X. analyzed data; and S.Z., Y.M., B.Y., and X.X. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1324130111/-/DCSupplemental.
Freely available online through the PNAS open access option.
Compound from Hoodia activates GPR119
Article Classifications
- Biological Sciences
- Pharmacology
- Physical Sciences
- Chemistry
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