Isolation of Positive Modulator of Glucagon-like Peptide-1 Signaling from Trigonella foenum-graecum (Fenugreek) Seed.
The glucagon-like peptide-1 receptor (GLP-1R) is expressed in many tissues and has been implicated in diverse physiological functions, such as energy homeostasis and cognition. GLP-1 analogs are approved for treatment of type 2 diabetes and are undergoing clinical trials for other disorders, including neurodegenerative diseases. GLP-1 analog therapies maintain chronically high plasma levels of the analog and can lead to loss of spatiotemporal control of GLP-1R activation. To avoid adverse effects associated with current therapies, we characterized positive modulators of GLP-1R signaling. We screened extracts from edible plants using an intracellular cAMP biosensor and GLP-1R endocytosis assays. Ethanol extracts from fenugreek seeds enhanced GLP-1 signaling. These seeds have previously been found to reduce glucose and glycated hemoglobin levels in humans. An active compound (N55) with a new N-linoleoyl-2-amino-γ-butyrolactone structure was purified from fenugreek seeds. N55 promoted GLP-1-dependent cAMP production and GLP-1R endocytosis in a dose-dependent and saturable manner. N55 specifically enhanced GLP-1 potency more than 40-fold, but not that of exendin 4, to stimulate cAMP production. In contrast to the current allosteric modulators that bind to GLP-1R, N55 binds to GLP-1 peptide and facilitates trypsin-mediated GLP-1 inactivation. These findings identify a new class of modulators of GLP-1R signaling and suggest that GLP-1 might be a viable target for drug discovery. Our results also highlight a feasible approach for screening bioactive activity of plant extracts.
From the Genomics Research Center, bmkxk@ibms.sinica.edu.tw bmkxk@yahoo.com.
Klim
K
King
Institutes of Chemistry and.
Nai-Pin
NP
Lin
From the Genomics Research Center.
Yu-Hong
YH
Cheng
Molecular Biology, Academia Sinica, Taipei 11529, Taiwan.
Gao-Hui
GH
Chen
Institutes of Chemistry and rjchein@chem.sinica.edu.tw.
Rong-Jie
RJ
Chein
D002460:Cell Line; D004763:Glucagon-Like Peptides / Q000378:metabolism*; D006801:Humans; D010936:Plant Extracts / Q000494:pharmacology; D012639:Seeds / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D029910:Trigonella / Q000737:chemistry / Q000196:embryology*
D010936:Plant Extracts; D004763:Glucagon-Like Peptides
4-hydroxyisoleucine; G protein-coupled receptor (GPCR); bioluminescence resonance energy transfer (BRET); cyclic AMP (cAMP); diabetes; endocytosis; fenugreek; glucagon-like peptide-1; natural product