Discovery of TUG-770: A Highly Potent Free Fatty Acid Receptor 1 (FFA1/GPR40) Agonist for Treatment of Type 2 Diabetes

Christiansen, Elisabeth; Hansen, Steffen V. F.; Urban, Christian; Hudson, Brian D.; Wargent, Edward T.; Grundmann, Manuel; Jenkins, Laura; Zaïbi, Mohamed S.; Stocker, Claire J.; Ullrich, Susanne; Kostenis, Evi; Kassack, Matthias U.; Milligan, Graeme; Cawthorne, Michael A.; Ulven, Trond

doi:10.1021/ml4000673

Cited by 59 publications

(68 citation statements)

References 19 publications

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“…The ability of TUG469 and indomethacin to affect interaction between the mouse GPR40 and ␤-arrestin-2 constructs was assessed using a bioluminescence resonance energy transfer-based method (16). The resulting concentration-response data were fit to 3-parameter sigmoid curves using GraphPad Prism version 5.0 (GraphPad Software, Inc., San Diego, CA).…”

Section: Methodsmentioning

confidence: 99%

Indomethacin Treatment Prevents High Fat Diet-induced Obesity and Insulin Resistance but Not Glucose Intolerance in C57BL/6J Mice

Fjære

Aune

Røen

et al. 2014

Journal of Biological Chemistry

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Background: Obesity-associated insulin resistance is linked to inflammation. Results: Indomethacin, an anti-inflammatory cyclooxygenase inhibitor, prevented diet-induced obesity, but mice became glucose-intolerant with sustained hepatic glucose output and impaired glucose-stimulated insulin secretion. Conclusion: Inhibition of cyclooxygenase activity alters the metabolic consequences of an obesogenic high fat diet. Significance: Intake of anti-inflammatory cyclooxygenase inhibitors may impair glucose tolerance.

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Section: Methodsmentioning

confidence: 99%

Indomethacin Treatment Prevents High Fat Diet-induced Obesity and Insulin Resistance but Not Glucose Intolerance in C57BL/6J Mice

Fjære

Aune

Røen

et al. 2014

Journal of Biological Chemistry

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“…E max is expressed as % of 3. n = 3. d Previously published. [16][17][18][19] e Partial competition that fitted to an allosteric ternary complex model gave pK B = 4.46 and logα = -0.29 (see Figure S2). …”

Section: Characterization Of 4 As An Ffa1 Tracermentioning

confidence: 99%

Development and Characterization of a Potent Free Fatty Acid Receptor 1 (FFA1) Fluorescent Tracer

et al. 2016

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The free fatty acid receptor 1 (FFA1/GPR40) is a potential target for treatment of type 2 diabetes. Although several potent agonists have been described, there remains a strong need for suitable tracers to interrogate ligand binding to this receptor. We address this by exploring fluorophore-tethering to known potent FFA1 agonists. This led to the development of 4, a high affinity FFA1 tracer with favorable and polarity-dependent fluorescent properties. A close to ideal overlap between the emission spectrum of the NanoLuciferase receptor tag and the excitation spectrum of 4 enabled the establishment of a homogenous BRET-based binding assay suitable for both detailed kinetic studies and high throughput competition binding studies. Using 4 as a tracer demonstrated that the compound acts fully competitively with selected synthetic agonists but not with lauric acid and allowed for the characterization of binding affinities of a diverse selection of known FFA1 agonists, indicating that 4 will be a valuable tool for future studies at FFA1.3

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“…Activation of FFAR1 decreased blood glucose, reduced plasma insulin and improved glucose intolerance and insulin resistance in high fat diet (HFD)-induced diabetic mice . Assessment of the efficacy and safety of FFAR1 agonists has also been validated in patients with type 2 diabetes (Christiansen et al 2013, Kaku et al 2013. Although the therapeutic effects of FFAR1 on insulin resistance and diabetes are documented, the role of FFAR1 in hepatic steatosis is still unknown.…”

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Activation of free fatty acid receptor 1 improves hepatic steatosis through a p38-dependent pathway

Ou¹,

Lu³

et al. 2014

Journal of Molecular Endocrinology

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Hepatic steatosis is highly correlated with insulin resistance and diabetes. Although, it has been demonstrated that activation of free fatty acid receptor 1 (FFAR1) by agonists showed benefits for the improvement of diabetes, the effects of FFAR1 agonists on hepatic steatosis were unknown. In this study, a high fat diet (HFD)-induced hepatic steatosis animal model was utilized to evaluate the effects of an FFAR1 agonist, GW9508, on hepatic lipid accumulation, and HepG2 hepatoma cells were also used to clarify the possible mechanisms. Administration of GW9508 significantly decreased the hepatic lipid accumulation with decreased expressions of lipogenesis-related proteins in HFD mice. Knockdown of hepatic Ffar1 by lentiviral vectors containing short hairpin RNA targeted to Ffar1 diminished the effect of GW9508 in HFD mice. In addition, GW9508 decreased oleic acid-induced lipid accumulation in HepG2 cells by decreases in the expression of lipogenesis-related proteins. Moreover, GW9508 downregulated the expression of sterol regulatory element-binding protein 1 (SREBP1) through a p38-dependent pathway, whereas knockdown of Ffar1 in HepG2 cells diminished the effect of GW9508 on the decrease in SREBP1. Considering all these results together, GW9508 exerts a therapeutic effect to improve hepatic steatosis through a p38-dependent pathway. Thus, investigation of chemicals that act on FFAR1 might be a new strategy for the treatment of hepatic steatosis. Key Words" free fatty acid receptor 1 " hepatic steatosis " insulin resistance " p38-MAPK " sterol regulatory element-binding protein

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Discovery of TUG-770: A Highly Potent Free Fatty Acid Receptor 1 (FFA1/GPR40) Agonist for Treatment of Type 2 Diabetes

Cited by 59 publications

References 19 publications

Indomethacin Treatment Prevents High Fat Diet-induced Obesity and Insulin Resistance but Not Glucose Intolerance in C57BL/6J Mice

Indomethacin Treatment Prevents High Fat Diet-induced Obesity and Insulin Resistance but Not Glucose Intolerance in C57BL/6J Mice

Development and Characterization of a Potent Free Fatty Acid Receptor 1 (FFA1) Fluorescent Tracer

Activation of free fatty acid receptor 1 improves hepatic steatosis through a p38-dependent pathway

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