Modulation of Glucagon-like Peptide-1 (GLP-1) Potency by Endocannabinoid-like Lipids Represents a Novel Mode of Regulating GLP-1 Receptor Signaling

Cheng, Yen Ju; Ho, Mei‐Shang; Huang, Weiting; Chou, Ying-Ting; King, Klim

doi:10.1074/jbc.m115.655662

Cited by 31 publications

(40 citation statements)

References 48 publications

(89 reference statements)

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“…These processes can be visualized (25), allowing for exclusion of false-positive hits. Because GLP-1R activation also leads to an increase in cAMP production (19), the RG-cAMP sensor (an Epac1 cAMP biosensor) (19) was used to monitor real time cAMP production in rat insulinoma RINm5F cells (19). This rapid real time cAMP response assay significantly reduced detection of nonspecific effects of the extract mixture and allowed us to detect receptorspecific responses.…”

Section: Resultsmentioning

confidence: 99%

“…RINm5F cells stably expressing the RG-cAMP protein were described previously (19). Stearoyl ethanolamide (SEA), 2-oleoylglycerol, and oleoyl ethanolamide (OEA) were purchased from Cayman Chemical Co. (Ann Arbor, MI).…”

Section: Methodsmentioning

confidence: 99%

“…cAMP Assay-Real time intracellular cAMP assay was performed as described previously (19). In brief, RINm5F cells stably expressing the RG-cAMP protein were seeded at 3 ϫ 10 4 cells/well in 96-well white plates in 0.15 ml of RPMI 1640 medium containing 400 g/ml G418.…”

Section: Methodsmentioning

confidence: 99%

“…Competition Binding Assay-Competition assays to evaluate the binding of signal non-enhancing SEA and N55 to Histagged GLP-1 were carried out as described previously (19 7 cell per 15 cm dish). The media were removed and washed twice with 30 ml of PBS, followed by adding 2.2 ml of ice-cold homogenization buffer (20 mM HEPES, 1 mM EDTA, 0.7% protease inhibitor mixture P8340 (Sigma) per dish.…”

Section: Methodsmentioning

confidence: 99%

“…One assay relates to GLP-1R internalization, a common step for activation of most of the G proteincoupled receptors (GPCRs) (17). Because activation of GLP-1R leads to an increase in intracellular cAMP production (18), the second assay employs a real time intracellular cAMP biosensor (RG-cAMP sensor) (19), capable of sensing intracellular cAMP production within minutes. These two assays were used in our initial screening of GLP-1 modulatory activity and for tracking and quantifying such activity during compound purification.…”

mentioning

confidence: 99%

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Isolation of Positive Modulator of Glucagon-like Peptide-1 Signaling from Trigonella foenum-graecum (Fenugreek) Seed

King

Lin

Cheng

et al. 2015

Journal of Biological Chemistry

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

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Isolation of Positive Modulator of Glucagon-like Peptide-1 Signaling from Trigonella foenum-graecum (Fenugreek) Seed

King

Lin

Cheng

et al. 2015

Journal of Biological Chemistry

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

et al. 2016

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The intestinal G protein-coupled receptor GPR119 is a novel metabolic target involving glucagon-like peptide-1 (GLP-1)-derived insulin-regulated glucose homeostasis. Endogenous and diet-derived lipids, including N-acylethanolamines and 2-monoacylglycerols (2-MAG) activate GPR119. The purpose of this work is to evaluate whether 2-oleoyl glycerol (2-OG) improves glucose tolerance through GPR119, using wild type (WT) and GPR 119 knock out (KO) mice. We here show that GPR119 is essential for 2-OG-mediated release of GLP-1 and CCK from GLUTag cells, since a GPR119 specific antagonist completely abolished the hormone release. Similarly, in isolated primary colonic crypt cultures from WT mice, GPR119 was required for 2-OG-stimulated GLP-1 release while there was no response in crypts from KO mice. In vivo, gavage with 2-oleyl glyceryl ether ((2-OG ether), a stable 2-OG analog with a potency of 5.3 µM for GPR119 with respect to cAMP formation as compared to 2.3 µM for 2-OG), significantly (P < 0.05) improved glucose clearance in WT littermates, but not in GPR119 KO mice. Finally, deletion of GPR119 in mice resulted in lower glucagon levels, whereas the levels of insulin and GIP were unchanged. In the present study we show that 2-OG stimulates GLP-1 secretion through GPR119 activation in vitro, and that fat-derived 2-MAGs are potent candidates for mediating fat-induced GLP-1 release through GPR119 in vivo. © 2016 BioFactors, 42(6):665-673, 2016.

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Endocannabinoids, endocannabinoid-like molecules and their precursors in human small intestinal lumen and plasma: does diet affect them?

et al. 2020

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Purpose To determine the small intestinal concentration of endocannabinoids (ECs), N-acylethanolamines (NAEs) and their precursors N-acylphosphatidylethanolamines (NAPEs) in humans. To identify relationships between those concentrations and habitual diet composition as well as individual inflammatory status. Methods An observational study was performed involving 35 participants with an ileostomy (18W/17M, aged 18–70 years, BMI 17–40 kg/m2). Overnight fasting samples of ileal fluid and plasma were collected and ECs, NAEs and NAPEs concentrations were determined by LC-HRMS. Dietary data were estimated from self-reported 4-day food diaries. Results Regarding ECs, N-arachidonoylethanolamide (AEA) was not detected in ileal fluids while 2-arachidonoylglycerol (2-AG) was identified in samples from two participants with a maximum concentration of 129.3 µg/mL. In contrast, mean plasma concentration of AEA was 2.1 ± 0.06 ng/mL and 2-AG was 4.9 ± 1.05 ng/mL. NAEs concentrations were in the range 0.72–17.6 µg/mL in ileal fluids and 0.014–0.039 µg/mL in plasma. NAPEs concentrations were in the range 0.3–71.5 µg/mL in ileal fluids and 0.19–1.24 µg/mL in plasma being more abundant in participants with obesity than normal weight and overweight. Significant correlations between the concentrations of AEA, OEA and LEA in biological fluids with habitual energy or fat intakes were identified. Plasma PEA positively correlated with serum C-reactive protein. Conclusion We quantified ECs, NAEs and NAPEs in the intestinal lumen. Fat and energy intake may influence plasma and intestinal concentrations of these compounds. The luminal concentrations reported would allow modulation of the homeostatic control of food intake via activation of GPR119 receptors located on the gastro-intestinal mucosa. Clinical trial registry number and website NCT04143139; www.clinicaltrials.gov.

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Modulation of Glucagon-like Peptide-1 (GLP-1) Potency by Endocannabinoid-like Lipids Represents a Novel Mode of Regulating GLP-1 Receptor Signaling

Cited by 31 publications

References 48 publications

Isolation of Positive Modulator of Glucagon-like Peptide-1 Signaling from Trigonella foenum-graecum (Fenugreek) Seed

Isolation of Positive Modulator of Glucagon-like Peptide-1 Signaling from Trigonella foenum-graecum (Fenugreek) Seed

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

Endocannabinoids, endocannabinoid-like molecules and their precursors in human small intestinal lumen and plasma: does diet affect them?

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